This study explores the efficacy of recombinant factor VIII (rFVIII) low-dose prophylaxis in Chinese pediatric patients with severe hemophilia A from the Retrospective Study in Chinese Pediatric Hemophilia A Patients With rFVIII Contained Regular Prophylaxis (ReCARE) population.
This is additional analysis of the multicenter, retrospective ReCARE study, in which the annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and safety of >12-week, low dose (10-30 IU/kg/wk) rFVIII prophylaxis divided into primary, secondary, and tertiary groups based on the joint status and joint bleeding history were analyzed.
A total of 57 patients (median age: 8.2 [0.4-17.3] years) from the ReCARE study receiving primary (n = 3), secondary (n = 21), and tertiary (n = 33) prophylaxes were included. Low-dose prophylaxis had significant bleeding reduction in all 3 groups compared to the baseline (S = 408.5, P < .001), with median ABR rates of –4.0 (–8.0 to –3.1), –4.0 (–24.0 to 8.0), and –13.9 (–110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively, with a significant difference between the secondary and tertiary groups (P = .008). Median AJBR reduction rates were –2.3 (–6.3 to 8.4) and –14.9 (–61.5 to 19.1) in the secondary and tertiary groups, respectively. But there was no significant difference in AJBRs between the secondary and tertiary groups (P = .061), which was related to damaged joint status. Hence, longer prophylaxis was associated with better prevention of joint bleeding (P = .024).
Despite significant ABR/AJBR reduction in all 3 groups, the efficacy of the primary prophylaxis was better than the secondary and tertiary prophylaxes.
von Willebrand disease (vWD) is the most common inherited disorder of hemostasis and comprises a spectrum of heterogeneous subtypes. Significant advances have been made in understanding von Willebrand factor (vWF) gene mutations, resultant physiologic deficits in the vWF peptide, and their correlation to clinical presentation. Diagnostic tests for this disorder are complex, and interpretation requires a thorough understanding of the underlying pathophysiology by the practicing physician. The objective of this review is to summarize our current understanding of pathophysiology, laboratory investigations, and evolving treatment paradigm of vWD with the availability of recombinant von Willebrand factor.
Thromboprophylaxis is not well defined after liver transplantation (LT). The aim of this study was to evaluate the incidence of splanchnic vein thrombosis (SVT) and nonsplanchnic vein thrombosis (NSVT) after LT. Liver transplantations performed between 2009 and 2013 in our institution were reviewed. Demographic, intraoperative, and postoperative data were recorded. Low-molecular-weight heparin was only administered postoperatively if intraoperative thrombectomy was performed or in patients preoperatively anticoagulated. Of a total of 328 patients, 72% were male with a median age of 56 years, score of model for end-stage liver disease 18 (11-23), and 88% had liver cirrhosis. The incidence of postoperative venous thrombotic events was 4.6%: 8 (2.4%) patients had SVT and 7 (2.1%) patients had NSVT. After logistic regression analysis, intraoperative thrombectomy and Child A classification emerged as risk factors for SVT (odds ratio [OR]: 77, 95% confidence interval [95% CI]: 14-421) and NSVT (OR: 20, 95% CI: 3-170), respectively. The incidence of SVT in patients who undergo intraoperative thrombectomy was 33%, whereas the incidence of NSVT in patients grouped as Child A was 7.5%. Our results suggest that thromboprophylaxis should be considered after LT in patients with cirrhosis grouped as Child A and in patients who undergo intraoperative thrombectomy.
Clinical and economic outcomes associated with venous thromboembolism (VTE) patient adherence to the American College of Chest Physicians (ACCP) anticoagulant (AC) treatment guidelines are incompletely understood. Patients with ≥1 inpatient or ≥2 separate outpatient claims for deep vein thrombosis and/or pulmonary embolism, based on International Classification of Diseases, Ninth Revision, Clinical Modification codes, were identified from the IMS PharMetrics Plus database. Patients had continuous insurance coverage for 12 months before (baseline) and after (follow-up) the index event (first VTE claim) but no baseline VTE claims. The ACCP recommends minimum AC treatment durations (3 or ≥6 months) dependent upon patient risk profiles. Patients were grouped into study cohorts based on their adherence status (adherent vs nonadherent) to the recommended minimum treatment durations. Patient baseline characteristics, health-care resource utilization, and associated costs were evaluated. The VTE recurrence and bleed-related hospitalization were measured during follow-up. Multivariate regression analysis was utilized to compare clinical and economic outcomes of cohorts. Of the 81 827 study patients, 74% (n = 60 550) were AC adherent. After controlling for key patient characteristics, risks for all-cause hospitalization (adjusted odds ratio [AOR]: 0.85, P < .0001), VTE recurrence (AOR = 0.92, P = .0014), and bleeding-related hospitalization (AOR = 0.74, P < .0001) were lower among adherent patients, as were all-cause health-care cost (–US$2121, P = .0003) and VTE-related (–US$2294, P < .0001) and bleed-related (–US$248, P < .0001) medical costs during the follow-up period. Approximately one-quarter of the study population was AC nonadherent; these nonadherent patients had more VTE recurrences, utilized more inpatient services, and had higher health-care costs.
Coronary artery disease (CAD), also known as atherosclerotic heart disease, is a leading cause of mortality and morbidity throughout the world. The role of insertion/deletion (I/D) polymorphisms of the angiotensin-converting enzyme (ACE) gene in the etiology of CAD remains to be more completely clarified. The aim of this study was to determine the role of the ACE I/D polymorphism in patients with CAD and to study the association together with traditional risk factors in assessing the risk of CAD.
Our study population included 145 Tunisian patients with symptomatic CAD and a control group of 300 people matched for age and sex. All participants in the study were genotyped for the ACE I/D polymorphisms obtained by polymerase chain reaction amplification on genomic DNA.
Our analysis showed that the ACE D allele frequency (P < 10–3; odds ratio [OR] = 5.2; 95% confidence interval [CI] = 3.6-7.6) and DD genotype (P < 10–3; OR = 6.8; 95% CI = 4.4-10) are significantly more prevalent among patients with CAD than in controls and may be predisposing to CAD. We further found that the risk of CAD is greatly potentiated by several concomitant risk factors (smoking, diabetes, hypertension, dyslipidemia, and a family history of CAD).
The ACE D allele may be predictive in individuals who may be at risk of developing CAD. Further investigations of these polymorphisms and their possible synergisms with traditional risk factors for CAD could help to ascertain better predictability for CAD susceptibility.
Factor XIII deficiency (FXIIID) is an extremely rare autosomal recessive disorder that has the highest incidence in Iran. The FXIIID is primarily due to mutations in the FXIII-A gene, most of which are unique. In the current study, we report all identified mutations among Iranian patients. Among 483 patients, 366 (75.8%) were molecularly analyzed; 11 different mutations were observed. Of 11, 8 (72.7%) are missense, whereas the remaining 3 (27.3%) are deletion/insertion. Among these patients, 347 (94.9%) had the unique mutation of c.562T>C and 5 (1.4%) had the c.233G>A mutation. c.1226G>A, c.2111G>A, and c.1142T>A are also common, whereas other mutations, including 3 missense and 3 deletion/insertion, were observed only in single patient. Although, in most cases, FXIII mutations are unique and restricted to a specific family, this differs in Iran where a considerable number of identified mutations, recurrently observed, appear to be due to the high rate of consanguinity.
Polymorphisms in vitamin K epoxide reductase complex subunit 1 (VKORC1) gene lead to interindividual variability in warfarin dose requirement. The characterization of genotype frequency distribution is required in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common VKORC1 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted and genotype analysis for VKORC1 1173C>T and VKORC1–1639G>A polymorphisms was done by polymerase chain reaction–restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of results. Data were analyzed using SPSS version 20. Genotype frequency distributions of VKORC1 1173C>T and VKORC1–1639G>A were found to be different from other populations. Both of these polymorphisms did not demonstrate significant effect on warfarin dose requirement. Although Cytochrome P450 2C9 (CYP2C9) and VKORC1 polymorphisms together attributed only 3.8% variability in warfarin dose but it was statistically significant (p value = .004). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome. At the same time, no effect on warfarin dose variation explained by VKORC1 polymorphisms and small variability explained by studied genotypes stresses the need for exploration of more genetic and nongenetic factors in Pakistani population.
We aimed to investigate whether soluble CD40 ligand (CD40L) levels are higher in patients with isolated coronary artery ectasia (CAE) compared to patients with angiographically normal coronary arteries and those with stable coronary artery disease (CAD).
In all, 55 patients with isolated CAE without stenosis, 55 with stable CAD, and 55 control participants with angiographically normal coronary arteries were included. The CAE severity was determined according to the Markis classification. Plasma levels of soluble CD40 ligand were measured by enzyme-linked immunosorbent assay.
The baseline characteristics of the 3 groups were similar. Plasma levels of soluble CD40 ligand were significantly higher in patients with CAE and CAD than in controls (2.6 ± 3.1 ng/mL and 2.0 ± 3.1 ng/mL vs 1.8 ± 2.1 ng/mL, P = .004). No difference was found between the CAE and CAD groups. Soluble CD40 ligand level was significantly higher in the type 1 Markis subgroup than that in the type 3 or type 4 subgroups (P = .01). A receiver operating characteristic curve analysis revealed that soluble CD40 ligand level >1.2 ng/mL identified patients with isolated CAE.
Significantly higher levels of soluble CD40 ligand were detected in patients with CAE than that in control participants with normal coronary arteries, suggesting that soluble CD40 ligand may be involved in the pathogenesis of CAE. The CD40–CD40 ligand system likely plays a role in the pathogenesis of CAE.
The stage 1 Norwood procedure and its variants represent the first step of palliation for hypoplastic left heart syndrome. Although appropriate postoperative thromboprophylaxis is integral, significant variance remains across institutional practices. The purpose of this systematic review is to estimate the incidence of thrombosis and thromboembolism following the Norwood or modified Blalock-Taussig shunt procedure and examine current thromboprophylaxis regimens.
Ovid MEDLINE and Embase were searched from January 2000 to June 2016 for primary studies explicitly reporting incidence of thrombosis, thromboembolism (strokes and pulmonary embolisms), or shunt occlusion in neonates, infants, and children undergoing the Norwood procedure or any variant. All-cause mortality was a secondary outcome of interest.
Of 887 identified articles, 15 cohort studies were deemed eligible, the majority including modified Blalock-Taussig shunt patients. Reported incidence of thrombosis ranged from 0% to 40%; thromboembolic events were rarely reported. Overall mortality ranged from 4.5% to 31.3% across studies. Although most studies involved the long-term acetylsalicylic acid use, thromboprophylaxis strategies varied across studies. Due to substantial variability in event rates, no correlation was identified with thrombotic complications.
Clinical practice guidelines recommend that patients receive intraoperative unfractionated heparin therapy and either aspirin or no antithrombotic therapy postoperatively. Our findings suggest a substantial risk of thrombosis and thromboembolism and demonstrate substantial variation in thromboprophylaxis practices.
Although postoperative thromboprophylaxis seems optimal, it remains controversial whether the long-term aspirin use is most effective. Our findings highlight the lack of a gold-standard thromboprophylaxis strategy and emphasize the need for more consistency.
Protocolled treatment with unfractionated heparin (UFH) is a subject of ongoing debate. Even though international guidelines prescribe calibration of the activated partial thromboplastin time (aPTT) to 0.3 to 0.7 U/mL anti-Xa activity to establish an UFH therapeutic range, evidence for this approach remains scarce. In this study, we evaluated different strategies to delineate the UFH therapeutic range and analyzed the effects on patient therapeutic classification.
In 109 patient samples, the aPTT was measured with 2 different reagents, both of which used mechanical clot detection. The UFH therapeutic range was determined using 3 previously described methods: calibration of the aPTT to 0.3 to 0.7 U/mL anti-Xa activity, application of 1.5 to 2.5 times the control aPTT, or using 0.3 to 0.7 U/mL anti-Xa activity directly. We also applied the UFH therapeutic range of a second hospital to our patient population.
Application of the guideline-prescribed anti-Xa calibration method would result in patients receiving increased UFH dosage in comparison to our previous UFH nomogram. Between-method and between-laboratory variations in aPTT and anti-Xa activity assays are a likely cause of these discrepancies. Additionally, we show that individual patient characteristics, such as weight and UFH treatment duration, likely contribute to the discordance between different strategies to establish an UFH therapeutic range.
No consensus is reached between different strategies to define the UFH therapeutic range, which could result in relevant differences in UFH doses applied in patients. Clinicians and laboratory specialists should critically evaluate UFH monitoring protocols and be aware of their shortcomings.
Although immobility is a common risk factor for venous thromboembolism (VTE) in medical inpatients, lack of a consistent definition of this term may limit accurate assessment of VTE risk for thromboprophylaxis.
To examine various definitions of immobility used in recent pharmacological thromboprophylaxis clinical trials.
PubMed and relevant references from articles/reviews from 2008 to 2016 were searched. Randomized controlled trials (RCTs) and other clinical studies involving adult hospitalized medical patients in acute care hospital settings that used the term immobility were selected. Two investigators independently abstracted data in duplicate, and accuracy was checked by a third investigator.
Twenty-one clinical studies were included. There was heterogeneity among individual VTE risk factors, with respect to the definition of immobility in medical inpatients in these trials. Thirteen studies utilized objective criteria to define "immobility" including duration (12 studies) and distance or time walked (6 studies). In contrast, 7 studies focused principally on subjective definitions (ie, describing the nature of immobility rather than specifying its quantitative measurement). Three RCTs vaguely defined the level of patient’s immobility after hospitalization.
Despite the well-known effectiveness of pharmacological thromboprophylaxis for the prevention of VTE in acutely ill medical patients, there is no current consensus on how to define immobility. The heterogeneous nature of definitions of immobility has led to uncertainty about the importance of immobility in VTE risk assessment models. Although clinical studies have incorporated varying definitions of immobility into their inclusion criteria, immobility as a specific VTE risk factor has not been clearly defined.
Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease (CVD). Although monocyte to high-density lipoprotein cholesterol ratio (MHR) is increasingly being implicated in cardiovascular morbidity and mortality, no study has attempted to determine the role of MHR in cardiovascular morbidity of patients with OSAS. We aimed to investigate the association between MHR and CVD in patients with OSAS and the relationship between severity of OSAS, polysomnographic parameters, and MHR.
In this cohort study, patients who had undergone a full-night polysomnography for the diagnosis of OSAS were recruited. Included patients were grouped according to the apnea–hypopnea index (AHI) as mild (5-15), moderate (15-30), and severe (>30) OSAS. Patients with AHI < 5 served as the control group. The presence of heart failure, coronary artery disease, or arrhythmia was defined as CVD.
A total of 1050 patients were included (131 controls, 222 mild, 228 moderate, and 469 severe OSAS). The severe group had higher MHR compared with the control and other OSAS groups (9.99, 12.11, 13.65, and 20.67 in control, mild, moderate, and severe OSAS groups, respectively, P < .001). The MHRs were significantly correlated with AHI, oxygen desaturation index, and minimum O2 saturation values (P < .001). Values of MHR were significantly higher in patients with CVD compared with those without (P < .001). Multiple regression analysis demonstrated that MHR is an independent predictor of CVD.
The MHR is strongly associated with CVD and the severity of OSAS and might be used as a biomarker to predict CVD in patients with OSAS.
Complications of deep vein thrombosis (DVT) are related to adequacy of initial anticoagulant therapy. In this study, we analyze consecutive patients with lower-limb proximal DVT and compare the characteristics, treatment, and clinical outcomes of patients receiving entirely ambulatory treatment versus those hospitalized for initial treatment.
This was a retrospective study of consecutive patients with a first proximal lower-limb DVT during a 2-year period. Patients were followed for 90 days. Major end points were all-cause mortality, bleeding requiring hospitalization, and recurrent venous thromboembolism (VTE). Events were determined for patients who were hospitalized versus those treated on an entirely ambulatory basis.
A total of 236 patients were included in the study. Of these, 147 patients were hospitalized and 89 patients received ambulatory treatment. There were 20 fatalities—18 in-hospital and 2 in-ambulatory patients (P = .008). By multivariable Cox regression analysis, the presence of active cancer (hazard ratio [HR] = 5.44; confidence interval [CI]: 2.16-13.7; P = .001), age (HR = 1.06; CI: 1.02-1.1; P = .001), and hospitalization (HR = 5.73; CI: 1.33-24.69; P = .019) were associated with death. Eight hospitalized and 2 ambulatory patients required readmission because of bleeding. Age was the only variable associated with bleeding (HR = 1.10; CI: 1.03-1.18; P = .004). There were no recurrent VTE events.
In this study of routine management of proximal DVT, we demonstrate that patients suitable for ambulatory care are adequately identified by physicians and may be treated with equal safety and efficacy to hospitalized patients.
Estimation of residual rivaroxaban plasma concentrations may be requested before invasive procedures and some patients at high thromboembolic risk will have a bridging therapy with heparins when rivaroxaban is interrupted.
The objective of this study was to assess the performance of the STA-Liquid Anti-Xa assay (STA LAX) and the low and normal procedures of the Biophen Direct Factor Xa Inhibitors (DiXaI) assay, in patients with and without bridging with low-molecular-weight heparins (LMWHs).
Seventy-nine blood samples were collected from 77 patients on rivaroxaban at CTROUGH or before an invasive procedure. Rivaroxaban plasma concentrations were estimated using Biophen DiXaI, Biophen DiXaI LOW, and STA LAX and compared to liquid chromatography coupled with mass spectrometry (LC-MS/MS) measurements. Stratifications were performed according to heparin bridging.
The Biophen DiXaI LOW and STA LAX showed better correlation with LC-MS/MS measurements than Biophen DiXaI in patients not bridged with LMWH (R: 0.97, 0.96, and 0.91, respectively). However, the performance of Biophen DiXaI LOW and STA LAX decreased when residual LMWH activity was present (R: 0.18 and 0.19 respectively) demonstrating that these tests are not specific to rivaroxaban.
In patients not bridged with LMWH, we suggest to use the Biophen DiXaI LOW and STA LAX for the estimation of rivaroxaban concentrations <50 ng/mL. These results should be confirmed on a larger cohort of patients. Patients bridged with LMWH have inaccurate estimates of low levels of rivaroxaban and the 3 assays studied should not be used to estimate if it is safe to perform a procedure.
To estimate the prevalence of thrombophilia in women with recurrent miscarriages and to assess the effect of antithrombotic therapy.
A retrospective cohort study between the years 2004 and 2010.
A hypercoagulation community clinic in northern Israel.
Four hundred ninety pregnant women referred for thrombophilia screening.
Screening results for thrombophilia and antithrombotic treatment with enoxaparin, aspirin, or both and pregnancy outcomes.
The most common thrombophilia in our study group was factor V Leiden mutation with a prevalence of 20.9% followed by protein S deficiency with a prevalence of 19%. Live birth rate was higher in the group of women who received enoxaparin regardless of whether a specific thrombophilia could be found. This finding was more pronounced in women who had ≥4 miscarriages.
The prevalence of thrombophilia was higher in our study group than in the general population. Furthermore, treatment with enoxaparin might improve the rate of live births in women with or without evidence of thrombophilia, especially in women with ≥4 miscarriages.
Bleeding is the most common complication of all anticoagulants. Any bleeding patient on an anticoagulant should be risk-stratified based on hemodynamic instability, source of bleeding, and degree of blood loss. Although minor bleed may be managed with discontinuation of anticoagulant, major bleed may require transfusion of blood products and use of specific antidote. The residual effects of each anticoagulant may be monitored with distinct coagulation assay. Intravenous or oral vitamin K can reverse the effect of warfarin within 24 to 48 hours and is indicated for any bleeding, international normalized ratio of >10 or 4.5 to 10 in patients with other risk factors for bleeding. Fresh frozen plasma or prothrombin complex concentrate (PCC) may be necessary in major bleeding related to warfarin. Protamine sulfate reverses the effect of unfractionated heparin completely and of low-molecular-weight heparin (LMWH) partially. Idarucizumab has recently been approved in United States for dabigatran reversal, whereas andexanet alfa is expected to get approved in the near future for reversal of oral factor Xa inhibitors. The PCC may reverse the effect of rivaroxaban to some extent, but no data are available regarding reversal of apixaban and edoxaban. Aripazine has shown promising results to reverse the effects of LMWH, fondaparinux, and direct oral anticoagulants but is still in the developmental phase.
Management of patients with acute pulmonary embolism has evolved from obligatory hospitalization to home treatment of carefully selected low-risk patients. The purpose of this investigation is to determine national trends in the prevalence of home treatment of pulmonary embolism.
The Nationwide Emergency Department Sample was used to determine the number of patients seen in emergency departments throughout the United States with a primary (first-listed) diagnosis of pulmonary embolism and the proportion hospitalized according to age, from 2007 to 2012. The National (Nationwide) Inpatient Sample was used to determine in-hospital all-cause mortality and length of stay of hospitalized patients. Patients were adults (≥18 years) of both genders and all races from all regions of the United States. Excluded patients were those in shock or on ventilator support. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify patients and comorbid conditions.
Home treatment was selected for 54 494 (6.0%) of 915 702 stable patients with acute pulmonary embolism. The proportion of patients treated at home was age-dependent, highest in those aged 30 years or younger, 12.1%, and lowest in those >80 years, 2.9%. Most patients treated at home, 66.8%, and had no comorbid conditions. In-hospital all-cause deaths were 2.6%. Deaths were ≤0.9% in those ≤40 years and 4.8% in those >80 years. Length of stay was 6 days or longer in 37.6% of patients.
In view of the lower death rate among younger patients, they might be a group in whom home treatment would be more advantageous than in elderly patients.
Parenteral vitamin K1 (phytonadione) is used for anticoagulant reversal, and a boxed warning exists with intravenous and intramuscular administration due to the possibility of severe reactions, including fatalities. These reactions resemble hypersensitivity or anaphylaxis, including anaphylactoid reaction, and have led to shock and cardiac and/or respiratory arrest. The objective of this review is to summarize the available literature detailing the anaphylactic/anaphylactoid reactions with parenteral vitamin K1 in order to better characterize the reaction and provide a more in-depth understanding of its importance. A comprehensive literature search of MEDLINE (1946 to June 2016) and EMBASE (1947 to June 2016) was conducted using the terms vitamin K1, phytonadione, phytomenadione, vitamin K group, anaphylaxis, polyoxyethylated castor oil, and cremophor. A total of 2 retrospective surveillance studies, 2 retrospective cohort studies, and 17 case reports were identified for inclusion and assessment. Based on a review of the literature, use of parenteral vitamin K1 may result in severe hypotension, bradycardia or tachycardia, dyspnea, bronchospasm, cardiac arrest, and death. These reactions are most consistent with a nonimmune-mediated anaphylactoid mechanism. It appears that intravenous administration is more frequently associated with these reactions and occurs at an incidence of 3 per 10 000 doses of intravenous vitamin K1. The solubilizer may also increase the risk of adverse reactions, which occurred in patients with and without previous exposure to vitamin K1. Although there are known factors that increase the risk of an adverse drug event occurring, reactions have been reported despite all precautions being properly followed.
The cutoff values of fibrin-related markers (FRMs) diagnosing or predicting the occurrence of a venous thromboembolism (VTE) were evaluated.
Fibrin-related markers such as fibrin monomer complex (FMC), D-dimer, and fibrinogen and fibrin degradation products (FDPs) before surgery were measured in 326 patients undergoing orthopedic surgery to diagnose subclinical VTE or predict postoperative VTE.
Although the FMC, D-dimer, and FDP levels were all useful for the diagnosis of acute VTE, the FDP level was not useful for diagnosing subclinical VTE or predicting postoperative VTE. The results of several D-dimer assays closely correlated with other D-dimer assays. There were various cutoff ranges for diagnosing or predicting VTE. Some D-dimer assays were useful for diagnosing low levels of D-dimer and others were useful for diagnosing moderate to high D-dimer levels. Increased D-dimer levels were useful for diagnosing acute (cutoff values: 2.0-5.9 μg/mL) or about 10% of subclinical VTE (cutoff values: 3.4-5.3 μg/mL), for predicting about 10% of postoperative VTE (cutoff values: 3.4-5.3 μg/mL), and for excluding VTE.
Although increased D-dimer levels were useful for diagnosing subclinical VTE and predicting the risk of VTE, there were various cutoff values for the diagnosis or prediction of VTE.
Present review highlights some new aspects of the role of individual components of blood coagulation process and proposes a modified concept of hemocoagulation cascade. The role of FXII in the initiation of the so-called intrinsic coagulation system is currently questioned. Its role has been recently demonstrated mainly in the thrombus propagation and final stabilization together with factors XI and XIII. The edited concept underlines the common part of the tissue factor (TF) in the initiation of both the intrinsic and extrinsic pathways of the coagulation system and therefore may make it not improperly be called the TF coagulation pathway. The search for new antithrombotic agents shows that the level of the coagulation system blockade depends on which step in the coagulation cascade is targeted and results in different degrees of the antithrombotic efficiency and the risk of bleeding complications.
Despite the identification of a wide range of inherited and acquired risk factors for arterial ischemic stroke (AIS) in children, genetic risk factors are incompletely characterized and may vary among different populations. We investigated the role of individual and combined inherited prothrombotic and intermediate-risk factors in 73 children with perinatal (n = 35) and childhood AIS (n = 38) and 100 age- and sex-matched controls. Ten polymorphisms in 8 candidate genes encoding coagulation and fibrinolytic proteins (factor V [FV] Leiden, FV HR2, factor II [FII] G20210A, β-fibrinogen [β-FBG]-455G>A, factor XIII [FXIII]-A p.Val34Leu, plasminogen activator inhibitor 1 4G/5G), homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR] C677T, MTHFR A1298C), and intermediate-risk factors (angiotensin-converting enzyme I/D, apoE 2-4) were detected using a multilocus genotyping assay. Allele-specific polymerase chain reaction was used for the determination of human platelet alloantigens (HPA-1, HPA-2, HPA-3, and HPA-5). Factor V Leiden was associated with an increased risk of AIS (odds ratio [OR]: 4.72, 95% confidence interval [CI]: 1.22-18.27) and perinatal AIS (OR: 8.29, 95% CI: 1.95-35.24). Human platelet antigen-3b allele carriers had a 2-fold lower risk of AIS (OR: 0.51, 95% CI: 0.26-0.98) and perinatal AIS (OR: 0.40, 95% CI: 0.18-0.92). A 2.21-fold increased risk of childhood AIS (95% CI: 1.03-4.73) was identified in FXIII-A Leu34 allele carriers. Combined FV Leiden/FV HR2, FV Leiden/MTHFR A1298C, FV Leiden/MTHFR C677T/MTHFR A1298C, and FV Leiden/FV HR2/MTHFR A1298C heterozygosity was identified in children with AIS but not in controls, which revealed a statistically significant difference. This case–control study shows that besides already documented association between FV Leiden and AIS, other previously unreported polymorphisms (FXIII-A p.Val34Leu, HPA-3) and several genotype combinations that always include heterozygous FV Leiden can be related to AIS in Croatian population.
Careful monitoring of the hypercoagulable state is required during pregnancy. However, coagulation and fibrinolysis markers are not fully utilized because there are no reference values reflective of coagulation and fibrinolysis dynamics during pregnancy, which differ from the nonpregnant state.
Changes in antithrombin (AT), fibrinogen (Fbg), prothrombin fragment 1+2 (F1+2), thrombin–antithrombin complex (TAT), soluble fibrin (SF), D-dimer (DD), and protein S (PS) were investigated in healthy pregnant women, and reference ranges in the early, mid, late, and end stages of pregnancy were established.
The AT was essentially constant throughout pregnancy. The Fbg, F1+2, TAT, and DD increased significantly as pregnancy progressed. In contrast, SF did not show a significant increase throughout the entire pregnancy period. Total PS antigen and total PS activity showed a corresponding decrease from early gestation. When test data in 3 cases in which deep vein thrombosis or intrauterine fetal death occurred during pregnancy were compared to the established reference ranges, all of the cases had multiple markers with values that exceeded the reference ranges.
Establishing reference ranges for each week could potentially make it possible to evaluate abnormalities of the coagulation and fibrinolysis systems during pregnancy. Of note, SF might be a useful marker that reflects thrombus formation during pregnancy. Larger-scale studies will be required to establish reference ranges for every gestational week.
We evaluated the diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH), in 232 patients with suspected DIC without hematopoietic injury or infection. The diagnoses of the patients were as follows: DIC (n = 116), pre-DIC (n = 54), and non-DIC (n = 63). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver operating characteristic analysis. The area under the curve and odds ratio for the global coagulation test (GCT) scores in the diagnosis of "DIC" were high, whereas those for the diagnosis of "DIC and pre-DIC" were low, suggesting that the addition of a reduced platelet count (RPC), antithrombin (AT), and soluble fibrin (SF)/thrombin AT (TAT) complex was required to diagnose DIC and pre-DIC. When the GCT score with the RPC, AT, and TAT/SF values was used, the cutoff DIC score for the diagnosis of DIC or DIC and pre-DIC was 6 points. For predicting the outcome, a scoring system that used the GCT result was useful, but the addition of RPC, AT, or SF/TAT was not. The modified diagnostic criteria of JSTH, which included the GCT score and the RPC, AT, and TAT/SF values, were useful for diagnosing both DIC and pre-DIC.
Venous thromboembolism (VTE) is a common and potentially lethal disorder that manifests mainly as deep vein thrombosis (DVT) of the extremities or pulmonary embolism (PE) and occurs as a consequence of genetic and environmental risk factors. We aimed to assess the role of inherited thrombophilia as a causative or additive factor in the development of VTE.
The study included 310 patients (female: 154; mean age: 52.3 ± 16.9 years) with a first episode of VTE and 289 age- and sex-matched healthy controls. All participants underwent screening for thrombophilia-associated polymorphisms including factor V Leiden (FVL), prothrombin G20210A (PTG), factor V H1299 R (factor V HR2), factor XIII V34 L, β-fibrinogen-455 G>A, plasminogen activator inhibitor-1 4G/5G, human platelet antigen-1 a/b, methylene tetrahydrofolate reductase (MTHFR) C677 T, MTHFR A1298C, angiotensin-converting enzyme I/D, apolipoprotein B R3500Q, and apolipoprotein E (Apo E). In addition, serum homocysteine (Hcy) levels were measured.
In the patient group, 247 (80%) had isolated DVT, 43 (14%) had DVT plus PE, and 20 (6%) had isolated PE. The mean Hcy levels were similar in VTE subgroups and controls. Compared to controls, patients with isolated DVT, DVT plus PE, and isolated PE showed significantly higher frequencies for the following—heterozygous FVL mutation, isolated DVT (28.3%), DVT plus PE (44.2%), isolated PE (50%), controls (8.3%; P < .001); heterozygous PTG mutation, isolated DVT (11.3%), DVT plus PE (20.9%), isolated PE (25%), controls (5.9%; P < .01); Apo E 2/4, isolated DVT (9.7%), DVT plus PE (9.3%), isolated PE (5%), controls (1%; P < .01).The MTHFR A1298C mutation showed a significantly higher frequency in isolated patients with PE than in those with isolated DVT (P = .006) and in controls (P = .008). The frequencies of other genetic mutations or polymorphisms showed similar frequencies in all comparisons. In logistic regression analysis, heterozygous FVL mutation was the only independent predictor of VTE (odds ratio: 3.9, 95% confidence interval: 1.3-11.2; P = .012).
Except than FVL, PTG, and Apo E 2/4 mutations, many of aforementioned thrombophilic factors known to be associated with VTE did not demonstrate any relationship with VTE. Heterozygous mutation of FVL was an independent predictor for VTE.
Available options for the treatment of advanced heart failure have expanded to include the use of mechanical circulatory assist devices to improve quality of life in those both eligible and ineligible for heart transplant. Although there have been significant advancements in device technologies, anticoagulation protocols, and multidisciplinary team management, bleeding and thrombosis are the most common adverse effects. Management strategies for pump thrombosis and their outcomes vary considerably among mechanical circulatory support centers and include intensification of antithrombotic therapy (medical) and device exchange (surgical). We describe a successful case of medical therapy for pump thrombosis with bivalirudin monotherapy.
Factor VII (FVII) deficiency is a rare inheritable bleeding disorder affecting 1/500 000 individuals. Clinical manifestations are heterogeneous, from asymptomatic to severe and potentially fatal bleeding. These clinical manifestations do not correlate well with FVII plasma levels. For this reason, FVII-deficient patient management during surgery or for long-term prophylaxis remains challenging. Laboratory testing for FVII activity is, however, the first-line method for FVII deficiency diagnosis and is helpful for managing patients in combination with clinical history. Additional testing consists of FVII immunoassay and genetic testing. Genetic abnormalities on the FVII gene are heterogeneous and can translate into quantitative or qualitative defects. Some of the latter can react differently with different thromboplastins; this can be misleading for the laboratory as no consensus exists at present on an FVII deficiency diagnosis methodology. Indeed, no single test is able to predict accurately the bleeding risk. This review provides a broad picture of inherited and acquired FVII deficiency with a particular focus on laboratory diagnosis.
The computerized antithrombotic risk assessment tool (CARAT) is an online decision-support algorithm that facilitates a systematic review of a patient’s stroke risk, bleeding risk, and pertinent medication safety considerations, to generate an individualized treatment recommendation. The CARAT was prospectively applied across 2 hospitals in the greater Sydney area. Its impact on antithrombotics utilization for thromboprophylaxis in patients with nonvalvular atrial fibrillation was evaluated. Factors influencing prescribers’ treatment selection were identified. The CARAT recommended a change in baseline therapy for 51.8% of patients. Among anticoagulant-eligible patients (ie, where the risk of stroke outweighed the risk of bleeding) using "nil therapy" or antiplatelet therapy at baseline, the CARAT recommended an upgrade to warfarin in 60 (30.8%) patients. For those in whom the bleeding risk outweighed the stroke risk, the CARAT recommended a downgrade from warfarin to safer alternatives (eg, aspirin) in 37 (19%) patients. Among the "most eligible" (ie, high stroke risk, low bleeding risk, no contraindications; n = 75), the CARAT recommended warfarin for all cases. Discharge therapy observed a marginal increase in anticoagulation prescription in eligible patients (n = 116; 57.8% vs 64.7%, P = .35) compared to baseline. Predictors of warfarin use (vs antiplatelets) included congestive cardiac failure, diabetes mellitus, and polypharmacy. The CARAT was able to optimize the selection of therapy, increasing anticoagulant use among eligible patients. With the increasing complexity of decision-making, such tools may be useful adjuncts in therapy selection in atrial fibrillation. Future studies should explore the utility of such tools in selecting therapies from within an expanded treatment armamentarium comprising the non-vitamin K antagonist oral anticoagulants.
Although the role of inflammation in DVT has been investigated in different studies, there is no definite answer as to whether increased systemic inflammation is the cause or the consequence of DVT.
To follow inflammatory parameters in a cohort of patients with idiopathic DVT.
Out of 49 patients with an acute idiopathic DVT, which were investigated four months after an acute episode (DEVTA 1), 43 patients were included in the follow-up study investigating inflammatory markers and hemostatic markers of endothelial damage five years after an acute DVT (DEVTA 2). A control group consisted of 43 sex and age matched healthy subjects (CONTROLS).
The levels of inflammatory markers were significantly higher in DEVTA 2 in comparison to CONTROLS: tumor necrosis factor alpha 2.0 pg/mL (1.1-2.3) vs 1.3 pg/mL (0.8-1.9), p < .001, high sensitivity C-reactive protein 3.2 mg/L (1.5-5.2) vs 1.7 mg/L (0.9-3.0), p = .008, interleukin-6 (IL-6) 2.7 pg/mL (2.0-3.5) vs 2.1 pg/mL (1.5-2.6), p = .025, IL-8 5.0 pg/mL (3.6-7.3) vs 2.4 pg/mL (1.8-2.8), p < .001. IL-10 was significantly decreased (0.9 pg/mL (0.7-1.8) vs 1.8 (1.5-2.2), p < .001. Most of the proinflammatory markers remained elevated in the DEVTA 2 in comparison to DEVTA 1. Markers of endothelial damage were higher in DEVTA 2 in comparison to CONTROLS and higher than in DEVTA 1.
Patients with idiopathic DVT have long-term increased inflammatory markers and markers of endothelial damage. These findings favor the hypothesis that inflammation is a cause and not merely a consequence of acute DVT.
Bridge therapy is associated with an increased risk of major bleeding in patients with atrial fibrillation and venous thromboembolism (TE) without a corresponding reduction in TE. The benefits of bridge therapy in patients with mechanical heart valve (MHV) prostheses interrupting warfarin for invasive procedures are not well described.
A retrospective cohort study was conducted at an integrated health-care delivery system. Anticoagulated patients with MHV interrupting warfarin for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified. Patients were categorized according to exposure to bridge therapy during the periprocedural period and TE risk (low, medium, and high). Outcomes validated via manual chart review included clinically relevant bleeding, TE, and all-cause mortality in the 30 days following the procedure. There were 547 procedures in 355 patients meeting inclusion criteria. Mean cohort age was 65.2 years, and 38% were female. Bridge therapy was utilized in 466 (85.2%) procedures (95.2%, 77.3%, and 65.8% of high, medium, and low TE risk category procedures, respectively). The 30-day rate of clinically relevant bleeding was numerically higher in bridged (5.8%; 95% confidence interval [CI], 3.9%-8.3%) versus not bridged procedures (1.2%; 95% CI, <0.1%-6.7%; P = .102). No TEs or deaths were identified.
The use of bridge therapy is common among patients with MHV and may be associated with increased bleeding risk. Further research is needed to determine whether bridge therapy reduces TE in patients with MHV interrupting warfarin for invasive procedures.
von Willebrand factor (VWF) is a biomarker for endothelial damage. Increased VWF levels are observed in hypertension (HTN) and disorders of endothelial dysfunction, for example, atherosclerotic heart disease (ASHD) and diabetes. Whether low VWF protects against HTN is unknown.
To determine prevalence and risk factors for HTN in patients with von Willebrand disease (VWD), we conducted a cross-sectional analysis of discharge data from the National Inpatient Sample, 2009 to 2011. Group comparisons were performed by Rao-Scott 2 test. Odds of HTN and HTN outcomes in VWD were estimated by weighted multivariable logistic regression.
The prevalence of hypertension in patients with VWD (N = 7556), 37.35%, was significantly lower than that in non-VWD patients (N = 19 918 970), 49.40%, P < .0001. Hypertension risk factors (hyperlipidemia, diabetes, smoking, hepatitis C, and HIV) and HTN outcomes (ASHD, myocardial infarction [MI], ischemic stroke, and renal failure) were less common in patients with VWD than in non-VWD patients, all P ≤ .0001. Patients with VWD were younger, 49.67 versus 57.30 years, Caucasian, 82.23% versus 68.35%, and female, 75.44% versus 59.61%, P < .0001. Patients with HTN were older, 67.55 versus 47.29 years, male, 45.99% versus 34.90%, and had more HTN risk factors and HTN outcomes than those without HTN, all P < .0001, including male and female subgroups, each P < .0001. The unadjusted odds of HTN in patients with VWD (odds ratio [OR] = 0.611, P < .0001) and of HTN outcomes in patients with VWD (ASHD, OR = 0.509; MI, OR = 0.422; ischemic stroke, OR = 0.521; renal failure, OR = 0.420, all P < .0001) became insignificant after adjustment for HTN risk factors plus demographics (age/race/gender), OR = 1.035, P = .260.
The risk of HTN is reduced in patients with VWD, but not after adjustment for HTN risk factors plus demographics, as patients with VWD not having HTN are also typically young, Caucasian, and female.
Poloxamer-188 (MST-188) is effective in the repair/recovery of damaged cell membranes. MST-188 is a promising agent for protecting blood cell viability. The aim of the study is to test the hypothesis that MST-188 can extend the duration of platelet function.
Blood samples were collected from 20 healthy volunteers. MST-188 (10 or 2 mg/mL) containing platelet-rich plasma (PRP) was prepared with 2 procedures. First, PRP prepared from MST-188 added whole blood (WB); second, MST-188 was added to PRP. These were referred to MST-188-WB preparation (WBP) and MST-188-PRP preparation (PRPP), respectively. For control, saline was used in the same manner. Agonist-induced aggregation (AIA) studies were performed at 30, 180, and 300 minutes using Platelet Aggregation Profiler (PAP-8) aggregometer (Bio/Data Corporation, Horsham, Pennsylvania) and Adenosine diphosphate (ADP), arachidonic acid, collagen, and epinephrine as agonists at final concentration of 20 µM, 500 µg/mL, 0.19 mg/mL, and 100 µM, respectively.
There was a protective effect of MST-188 on ADP and collagen AIA. At 300 minutes, ADP AIA was found to be 50.2% higher than saline control in 2-mg WBP, 43% at 10-mg PRPP, and 10.4% at 2-mg PRPP. Protective effect of on collagen AIA was 65.9% in 2-mg WBP, 42.74% at 10-mg PRPP, and 11.42% at 2-mg PRPP. In comparison between 30 and 300 minutes, MST-188 showed significant protection in terms of ADP and collagen receptors and for both types of preparations (WBP and PRPP).
The protective effects of MST-188 on ADP- and collagen-induced platelet aggregation may contribute to the preservation of platelet functionality upon storage in blood banks.
Conflicting data exist as to whether proton-pump inhibitors (PPIs) diminish the efficacy of clopidogrel. The aim of this study was to investigate the association between cytochrome P450 (CYP) genetic variants and clinical adverse outcomes of concomitant use of PPIs and clopidogrel by patients.
We consecutively enrolled 523 patients with ischemic stroke receiving clopidogrel. Platelet aggregation was measured before and after 7 to 10 days of clopidogrel treatment. Single-nucleotide polymorphisms of CYP3A4, CYP3A5, CYP2C19*2, and CYP2C19*3 were examined using mass spectrometry. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI), and vascular death that occurred during the 1-year follow-up period. The safety outcome was hemorrhagic episodes that occurred during the 1-year follow-up period.
This study comprised a total of 523 patients with IS, 96.3% (155/161) patients treated with PPIs and 95.9% (347/362) in patients treated without PPIs completed 1-year follow-up. The primary outcome was observed in 69 (13.7%) patients (56 RIS, 7 MI, and 6 died). There was no significant difference in the frequencies of primary outcome and safety outcome between patients treated with or without PPIs. The frequency of primary outcome was significantly higher in patients carrying CYP2C19*2 AG/AA genotype receiving PPIs compared with the same genotype in those not receiving PPIs. The PPIs used in patients carrying CYP2C19*2 AG/AA was independently associated with the primary outcome after adjusting for other risk factors.
The concomitant use of PPIs and clopidogrel may be associated with an increased risk of RIS, MI, or vascular death in patients with IS carrying reduced-function CYP2C19*2.
The Khorana score is a predictive risk model for venous thromboembolism (VTE) in patients with cancer planning to receive chemotherapy. Urothelial carcinoma and variant histologies (UC/VH) were underrepresented in the model. We sought to evaluate whether the Khorana score predicts for VTE in a retrospective multinational data set of patients with metastatic UC/VH.
Patients diagnosed with metastatic UC/VH who received chemotherapy were eligible. Those with incomplete or miscoded data were excluded. Khorana scores were calculated based on the pretreatment data and categorized into high (≥3) or intermediate (1-2) VTE risk. Other patient-, tumor-, and therapy-related factors were also analyzed. The 2 and logistic regression analyses were used to assess differences in VTE rates based on the clinical characteristics. Subgroup analyses were performed to evaluate the Khorana score and associated variables for early (<3 months) and late (>3 months) VTE.
A total of 943 patients were eligible for analysis. The cumulative VTE rate was 9.9%. There was no statistical difference in overall VTE rate between Khorana high- and intermediate-risk groups (P = .16). In the multivariate analysis, nonurothelial histology (odds ratio [OR] = 2.56; P = .002) and the presence of cardiovascular disease (CVD) or CVD risk factors (OR = 2.14; P = .002) were associated with increased VTE risk. In the first 3 months from initiation of chemotherapy, Khorana high risk (OR = 2.08; P = .04) was associated with higher VTE rates. White blood cell (WBC) count (OR = 1.05; P = .04) was the only significant Khorana variable for early VTE.
The Khorana score stratifies early but not overall VTE risk in patients with metastatic UC/VH. The WBC count drives the increased early VTE risk seen with the Khorana score.
Availability of universal marker for the diagnosis of platelet apoptosis is an important but currently unresolved goal of platelet physiology investigations. Mitochondrial inner transmembrane potential (m) depolarization is frequently used as a marker of apoptosis in nucleated cells and anucleate platelets. Since m depolarization in platelets is also frequently associated with concurrent induction of other apoptotic responses, it may appear that m depolarization is a good universal marker of platelet apoptosis. However, data presented in the current study indicate that this is incorrect. We report here fundamental differences in the effects of potassium ionophore valinomycin and calcium ionophore A23187 on human platelet apoptosis. Although both A23187-triggered and valinomycin-triggered m depolarization are strongly induced, the former is dependent on the opening of mitochondrial permeability transition pore (MPTP) and the latter is MPTP-independent. Furthermore, effects of calcium and potassium ionophores on other apoptotic events are also basically different. A23187 induces caspase-3 activation, proapoptotic Bax and Bak protein expression, phosphatidylserine exposure, and microparticle formation, whereas valinomycin does not induce these apoptotic manifestations. Discovery of targeted m depolarization not associated with apoptosis in valinomycin-treated platelets indicates that this marker should not be used as a single universal marker of platelet apoptosis in unknown experimental and clinical settings as it may lead to a false-positive apoptosis diagnosis.
A 4-factor prothrombin complex concentrate (4F-PCC, Kcentra®) was recently approved in the United States for the reversal of vitamin K antagonist-associated major bleeding, but it is often used to reverse coagulopathy in patients with liver disease (LD). This single-center, retrospective study analyzed the efficacy and safety of 4F-PCC administered in patients with and without LD. Prothrombin time/International Normalized Ratio (PT/INR) reversal with 4F-PCC was attempted in 85 patients; LD was documented in 31 patients. Coagulopathy reversal and hemostasis with 4F-PCC were inferior in patients with LD compared to patients without LD. Coagulopathy reversal, defined as INR = 1.5 after 4F-PCC administration, was achieved in 6 (19.4%) LD patients, compared to 44 (81.5%) non-LD patients (p < 0.01). Hemostasis was achieved in 6 LD patients (19.4%) compared to 23 non-LD patients (42.6%) (p = 0.03). Thromboembolic events occurred in 1 LD patient (3.2%) and 8 non-LD patients (14.8%) (p = 0.15). Mortality was 51.6% in LD patients and 18.5% in non-LD patients (p < 0.01). These observations suggest that the efficacy of 4F-PCC is suboptimal to correct coagulopathy and hemostasis in patients with LD, who have high rates of in-hospital mortality due to sequelae of LD. The incidence of thromboembolic events appeared comparable, suggesting that 4F-PCC does not cause undue thromboembolism in LD patients. In conclusion, 4F-PCC appears to be safe in LD patients when administered judiciously; however, further studies are necessary to optimize its use and elucidate its hemostatic potential in this patient population.
Unfractionated heparin (UFH) is a frequently utilized indirect anticoagulant that induces therapeutic effect by enhancing antithrombin (AT)-mediated procoagulant enzyme inhibition. In suspected heparin resistance (HR) during cardiopulmonary bypass, AT activity may be decreased and AT supplementation helps restore UFH responsiveness. The benefit of AT supplementation in HR over longer durations of UFH therapy is unclear. The objective of this study was to describe and evaluate the use of AT III concentrate in the intensive care units (ICUs) at our institution for improving UFH therapy response over 72 hours. A total of 44 critically ill patients were included in the analysis—22 patients received at least 1 dose of AT and 22 patients received no AT. Thirty (68.2%) of the 44 patients were receiving mechanical circulatory support. Baseline characteristics were similar between groups. The average AT activity prior to AT supplementation was 57.9% in the treatment group, and the median cumulative dose of AT was 786.5 U (9.26 U/kg) per patient. There were no significant differences observed in proportion of time spent in therapeutic range (31.9% vs 35.2%, P = .65), time to therapeutic goal (16.5 vs 15.5 hours, P = .97), or patients who experienced a bleeding event (5 vs 5, P = .99) between groups. In conclusion, AT supplementation had minimal impact on anticoagulant response in this cohort of ICU patients with mild to moderate HR receiving a prolonged UFH infusion. Additional research is needed to define AT activity targets and to standardize AT supplementation practices in patients receiving prolonged heparin infusion.
Despite direct oral anticoagulants (DOACs) have overcome the most relevant limitations of vitamin K antagonists, many patients with atrial fibrillation are not receiving the appropriate anticoagulant therapy. In addition, when patients are anticoagulated with DOACs, some of them are not taking the dose recommended in the summary of product characteristics. This may be related, at least in part, to the concern about the applicability of findings from randomized clinical trials to real-life patients. In this context, performing studies in daily clinical practice to assess the efficacy and safety of DOACs in real-world setting is mandatory. The aim of this review is to update the current evidence regarding safety of rivaroxaban in clinical practice. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) showed that rivaroxaban was at least as effective as warfarin for preventing stroke or systemic embolism, with similar rates of major bleeding but with lesser risk of intracranial and fatal bleedings. Data from noninterventional studies and registries have confirmed the good results of ROCKET-AF. Even more, rates of bleeding may be inferior in real-life patients, since they have a lower risk profile than those included in ROCKET-AF.
There is evidence that diet and variation in lipid metabolism can influence blood coagulation, but little is known about the effect of Ramadan fasting on plasmatic coagulation pattern. We investigated the effect of Ramadan fasting on thrombin generation (TG) in patients with cardiovascular disease (CVD) risks, and we aimed to assess the effect of lipid profile on TG parameters. The study was conducted in 36 adults having at least 2 CVD risks and in 30 healthy controls. Coagulation pattern was assessed by both classical clotting times and TG test. A complete lipid profile was performed simultaneously. Patients were invited 2 times: 1 week before Ramadan and during the last week of the Ramadan. The TG parameters were not different in patients with CVD risks compared to healthy controls. Fasting had no effect on plasmatic coagulation parameters and on TG profile. Individual analysis of the mean rate index (MRI) of TG revealed 3 groups: group 1 with no modification of MRI, group 2 with a significant increase in MRI (81.64 nM/min vs 136.07 nM/min; P < .001), and group 3 with a significant decrease in MRI (125.27 nM/min vs 73.18 nM/min; P = .001). Only in group 2, a significant increase was observed in total cholesterol and low-density lipoprotein cholesterol. Changes in lipid profile during Ramadan fasting did not influence the global coagulation pattern in patients with CVD risks. Whereas, a significant increase in the propagation phase of TG was associated with a significant increase in cholesterol levels, which was not found with the other TG parameters.
A documented relationship between ovarian cancer and thrombosis does exist. Low-molecular-weight heparins (LMWHs) are cornerstone drugs in the primary prevention and treatment of venous thromboembolic events in patients with cancer. However, cancer cells may alter the efficiency of these antithrombotic agents.
We aimed to characterize the procoagulant phenotype of human epithelial ovarian adenocarcinoma cells, IGROV1, and to compare the capacity of tinzaparin and enoxaparin to inhibit thrombin generation triggered by these cells.
Thrombin generation induced by different concentrations of IGROV1 cells on platelet poor plasma (PPP) was assessed by the calibrated automated thrombogram assay. Tissue factor (TF) expression was studied using Western blot analysis. Then, the experimental model of thrombin generation was used to compare the inhibitory effect of clinically relevant concentrations of both tinzaparin and enoxaparin. The inhibitory concentration 50 (IC50) of the mean rate index and the endogenous thrombin potential and the 2-fold increase in lag time were analyzed on the basis of the anti-Xa and anti-IIa activities of the LMWHs.
IGROV1 cells suspended into PPP resulted in a significant increase in thrombin generation in the absence of any exogenous source of TF and phospholipids. Tissue factor was expressed by IGROV1 cells. Tinzaparin was a more potent inhibitor of thrombin generation than enoxaparin. The inhibition of thrombin generation induced by IGROV1 cancer cells depended mainly on the anti-Xa activity of the LMWHs.
This experimental study in ovarian cancer cells demonstrates that the antithrombotic activity of LMWHs is not completely predicted by the anti-Xa or anti-IIa activities measured in PPP.
Recent studies have demonstrated that surgical menopause results in a significantly increased risk of nonalcoholic fatty liver disease (NAFLD) in women with endometrial cancer. In addition, venous thromboembolism (VTE) is known to be one of the major prognostic factors for decreased survival in endometrial cancer. Given the fact that coagulation factors are produced in the liver, the correlation between NAFLD and VTE was examined in endometrial cancer.
A retrospective study was conducted to examine patients with endometrial cancer who underwent surgical staging including oophorectomy between 2000 and 2013 (n = 714). Cumulative risk of VTE was examined based on the NAFLD status. A Cox proportional hazard regression model was used to determine the independent risk predictors of VTE.
Venous thromboembolism and NAFLD were seen in 57 (8.0%) and 181 (25.4%) cases, respectively. Two-year cumulative risks of VTE and NAFLD were 7.9% and 19.3%, respectively. In univariate analysis, VTE was significantly associated with decreased disease-free survival (2-year rate, 43.6% vs 91.4%, P < .001) and overall survival (65.8% vs 96.8%, P < .001), whereas NAFLD was associated with decreased risk of VTE (1.7% vs 10.4%, P < .001). In multivariate analysis controlling for clinicopathological factors, NAFLD remained an independent predictor of decreased risk of VTE (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.07-0.79, P = .02). Thrombocytosis (HR: 2.30, 95% CI: 1.22-4.35, P = .01), cancer antigen 125 ≥ 35 (HR: 3.81, 95% CI: 1.78-8.17, P < .001), and recurrent disease (HR: 4.57, 95% CI: 1.97-10.6, P < .001) remained as independent predictors of increased risk of VTE.
Our results suggest that NAFLD may be associated with decreased VTE risk in women with endometrial cancer.
Patients with sickle cell disease (SCD) are at high risk of renal dysfunction and cardiovascular morbidity. The association between cystatin C and renal function is well known, however, cystatin C has recently emerged as a strong predictor of cardiovascular events and adverse outcomes in patients with and without kidney disease, mostly related to both inflammation and atherosclerosis.
To determine cystatin C levels in 53 children and adolescents with SCD compared to 40 age- and sex-matched healthy controls and assess its relation to markers of hemolysis, iron overload, sickle vasculopathy, and carotid intima–media thickness (CIMT).
Patients with SCD in steady state were studied, focusing on hydroxyurea therapy, hematological profile, serum ferritin, high-sensitivity C-reactive protein (hs-CRP), urinary albumin–creatinine ratio (UACR), and serum cystatin C. Echocardiography and CIMT were assessed using high-resolution ultrasound. Heart disease was defined by systolic left ventricle dysfunction (shortening fraction <30% or ejection fraction <55%).
Carotid IMT was significantly higher in patients with SCD compared to controls (P < .001). Patients with SCD having nephropathy, heart disease, or history of frequent sickling crisis (≥3 attacks/y) had significantly higher cystatin C levels than those without (P < .05). Patients with SCD treated with hydroxyurea had lower cystatin C levels than untreated patients (P = .039). High-sensitivity C-reactive protein, UACR, ejection fraction, and CIMT were independently related to cystatin C in multiple regression analysis. The cutoff values of cystatin C for detection of renal or cardiovascular complications were determined.
Cystatin C may be considered a biological marker for vascular dysfunction and subclinical atherosclerosis in SCD.
We compared thrombophilia and hypofibrinolysis in 6 men with Klinefelter syndrome (KS), without previously known familial thrombophilia, who had sustained deep venous thrombosis (DVT)–pulmonary emboli (PE) or mesenteric artery thrombosis on testosterone replacement therapy (TRT). After the diagnosis of KS, TRT had been started in the 6 men at ages 11, 12, 13, 13, 19, and 48 years. After starting TRT, DVT-PE or mesenteric artery thrombosis was developed in 6 months, 1, 11, 11, 12, and 49 years. Of the 6 men, 4 had high (>150%) factor VIII (177%, 192%, 263%, and 293%), 3 had high (>150%) factor XI (165%, 181%, and 193%), 1 was heterozygous for the factor V Leiden mutation, and 1 was heterozygous for the G20210A prothrombin gene mutation. None of the 6 men had a precipitating event before their DVT-PE. We speculate that the previously known increased rate of DVT-PE and other thrombi in KS reflects an interaction between prothrombotic, long-term TRT with previously undiagnosed familial thrombophilia. Thrombophilia screening in men with KS before starting TRT would identify a cohort at increased risk for subsequent DVT-PE, providing an optimally informed estimate of the risk/benefit ratio of TRT.
Data regarding cerebral venous thrombosis in North Africa are scarce. This study aims to identify the clinical features, risk factors, outcome, and prognosis of cerebral venous thrombosis in Tunisia.
Data of 160 patients with radiologically confirmed cerebral venous thrombosis, hospitalized in Mongi Ben Hmida National Institute of Neurology (Tunis, Tunisia), were retrospectively collected and analyzed.
The mean age was 37.3 years with a female predominance (83.1%). The mode of onset was subacute in most cases (56.2%). Headache was the most common symptom (71.3%), and focal neurologic symptoms were the main clinical presentation (41.8%). The most common sites of thrombosis were the superior sagittal sinus (65%) and the lateral sinus (60.6%). More than 1 sinus was involved in 114 (71.2%) patients. Parenchymal lesions observed in 85 (53.1%) patients did not correlate with cerebral venous thrombosis extent. Major risk factors were obstetric causes (pregnancy and puerperium) found in 46 (38.6% of women aged <50 years) patients, followed by anemia (28.1%) and congenital or acquired thrombophilia (16.2%). Mortality rate was of 6.6%. Good outcome at 6 months (modified Rankin Scale ≤2) was observed in 105 (87.5%)of 120 patients available for follow-up. Predictors of poor outcome were altered consciousness and elevated plasma C-reactive protein levels.
Clinical and radiologic presentation of cerebral venous thrombosis in Tunisia was quite similar to other parts of the world with, however, a particularly high frequency of obstetric causes. Plasma C-reactive protein level should be considered as a prognostic factor in CVT.
A rapid and accurate diagnosis of venous thromboembolism (VTE) in the elderly individuals represents a dilemma due to nonspecific clinical presentation, confusing laboratory results, and the hazards of radiological examination in this age-group.
The outcome of patients with upper extremity deep vein thrombosis (UEDVT) has not been consistently compared with that in patients with lower extremity deep vein thrombosis (LEDVT).
We used the Registro Informatizado de Enfermedad Trombo Embólica (RIETE) registry to compare the outcomes during the course of anticoagulant therapy in patients with UEDVT versus outcomes in patients with LEDVT.
As of August 2015, 37,366 patients with acute DVT had been enrolled in RIETE: 35094 (94%) had LEDVT, 1334 (3.6%) non-catheter related UEDVT (672 unprovoked and 662 provoked) and 938 (2.5%) had catheter-related UEDVT. During the course of anticoagulation, patients with unprovoked UEDVT had a higher rate of DVT recurrences (hazard ratio [HR]: 2.22; 95% CI: 1.37-3.43) and a similar rate of PE recurrences or major bleeding than those with unprovoked LEDVT. Patients with non-catheter-related provoked UEDVT had a similar outcome than those with provoked LEDVT. Among patients with UEDVT, those with non-catheter related unprovoked UEDVT had a lower rate of PE recurrences (HR: 0.06; 95% CI: 0-0.35) and major bleeding (HR: 0.20; 95% CI: 0.08-0.46) than those with catheter-related UEDVT or those with non-catheter related provoked UEDVT (HR: 0.10; 95% CI: 0.004-0.60; and 0.22; 95% CI: 0.08-0.52, respectively). On multivariable analysis, any difference had disappeared.
During the course of anticoagulation, patients with UEDVT had a similar outcome than those with LEDVT. Among UEDVT patients, there were some differences according to the presence of catheter or additional risk factors for DVT. These differences disappeared after adjusting for potentially confounding variables.
Eltrombopag is an oral thrombopoietin receptor agonist that stimulates the production of normally functioning platelets. The aim of this meta-analysis is to synthesize evidence about the safety and efficacy of eltrombopag for both adult and children with primary immune thrombocytopenia (ITP).
A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted. Records were screened for eligible studies, and data were extracted and synthesized using Review Manager for Windows. Subgroup analysis and sensitivity analysis were conducted to investigate whether treatment effect varies significantly between adults and children.
Six randomized controlled trials (N = 611 patients) were included in the final analysis. The overall effect estimates favored eltrombopag group in terms of overall platelet response (relative risk [RR]: 3.42; 95% confidence interval [CI]: 2.51-4.65; P < .0001), incidence of significant bleeding (RR: 0.56; 95% CI: 0.41-0.77; P = .0004), and number of cases needed to rescue treatment (RR: 0.45; 95% CI: 0.32-0.65; P < .0001). The efficacy of eltrombopag did not differ significantly between children and adults except for incidence of any bleeding (RR: 0.83 vs 0.51; P = .008).
Eltrombopag is a tolerable and effective drug for the management of chronic ITP in children and adults.
Recurrent miscarriage (RM) is one of the most common clinical problems in reproduction with no definite cause in about 50% of the cases. The study aims to evaluate the effect of low-molecular-weight heparin (LMWH) in the treatment of women with RM negatively tested for antiphospholipid antibodies (APAs).
An open-labeled registered randomized controlled study (NCT 01608347) included women who attended the outpatient clinic in Assiut Women Health Hospital and Nag-Hamady Central Hospital, Egypt, with 3 or more unexplained RM. Eligible participants were randomly assigned into 2 groups. The study group included 150 patients receiving LMWH (Tinzaparin sodium 4500 IU) subcutaneous daily injection with 500 µg folic acid once daily orally started once positive pregnancy test till the 20th week of gestation. The control group included 150 patients receiving the same dose of folic acid alone. The primary outcome of the study was the rate of continuation of a viable pregnancy after 20 weeks of gestation.
There was no significant difference between both groups as regards age, parity, or number of previous miscarriages. There was a significant increase in women who continued their pregnancy beyond 20 weeks in the study group compared to the control group (73.3% vs 48%, respectively; P = .002). The take-home baby rate was also significantly higher in the LMWH group compared to the control group (P = .001).
Early start of LMWH decreases the incidence of miscarriage in the first 20 weeks of pregnancy in women with unexplained RM negative for APAs.
Recombinant factor VIIa (rFVIIa) is used in the management of bleeding in patients with hemophilia. A generic biosimilar version of NovoSeven is also developed (AryoSeven). To compare the activation profile of NovoSeven and AryoSeven, 2 commercially available protein complex concentrates (PCCs) were used. Profilnine activated by RecombiPlasTin 2G resulted in conversions of prothrombin to prethrombin and thrombin at 5 to 30 minutes. However, addition of rFVIIa at final concentration range of 0.25 to 0.5 µg/mL to the same mixture resulted in total conversion of prothrombin to thrombin with a doublet at 36 kDa. Recombinant factor VIIa alone did not generate thrombin in native Beriplex, and the addition of rFVIIa to Beriplex failed to generate thrombin. Beriplex activated by RecombiPlasTin 2G resulted in complete conversion of prothrombin to thrombin. Both NovoSeven and AryoSeven exhibited similar activation profiles. These studies indicate that the activation of PCCs by both rFVIIa preparations results in comparable generation of thrombin.
Intracoronary thrombus burden is associated with some adverse events and poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). Identifying predictors of the intracoronary thrombus burden may contribute to the management of STEMI. In this study, we evaluated whether monocyte count to high-density lipoprotein cholesterol ratio (MHR) is a predictor of intracoronary thrombus burden in patients with STEMI. The study population consisted of 414 patients with STEMI who underwent primary percutaneous coronary intervention (PCI). Angiographic thrombus burden was classified based on thrombolysis in myocardial infarction (TIMI) thrombus grades. The patients were grouped into 2 categories of low thrombus burden and high thrombus burden. The MHR was significantly higher in the high thrombus burden group compared with the low thrombus group (16.0 [9.2-22.1] vs 25.4 [13.5-44.6]; P < .001). In multivariate logistic regression analysis, MHR was an independent predictor of high thrombus burden (odds ratio: 1.067, 95% CI: 1.031-1.105; P < .001). The area under the receiver–operating characteristic curve of the MHR was 0.688 (0.641-0.733; P < .001) to predict high thrombus burden. In conclusion, MHR was independent predictor of high thrombus burden in patients with STEMI who underwent primary PCI.
Anticoagulation using intravenous bolus administration of unfractionated heparin (UFH) aims to prevent thromboembolic complications in children undergoing cardiac catheterization (CC). Optimal UFH dosage is needed to reduce bleeding complications. We analyzed the effect of bolus UFH on activated clotting time (ACT) in children undergoing CC focusing on age-dependent, anesthesia-related, or disease-related influencing factors. This retrospective single-center study of 183 pediatric patients receiving UFH during CC analyzed ACT measured at the end of CC. After bolus administration of 100 IU UFH/kg body weight, ACT values between 105 and 488 seconds were reached. Seventy-two percent were within target level of 160 to 240 seconds. Age-dependent differences were not obtained (P = .407). The ACT values were lower due to hemodilution (total fluid and crystalloid administration during CC, both P < .001), with premedication of acetylsalicylic acid (P = .014) and low-molecular-weight heparin (P = .049). Arterial thrombosis (3.85%), venous thrombosis (0.55%), and bleeding (1.65%) following CC did not correlate with ACT values but occurred more frequently in children between 1 month and 1 year of age (91%). In conclusion, with a bolus of 100 IU UFH/kg, an ACT target level of 160 to 240 seconds can be achieved during CC in children in 72%, which is influenced by hemodilution and anticoagulant and antiplatelet premedication but not by age.
We summarize the evidence for the safety and efficacy of catheter-directed thrombolysis (CDT) with and without ultrasound-assisted therapy for treating submassive and massive pulmonary embolism (PE) in a systematic review. The primary efficacy outcome was mortality. Outcomes were pooled across studies with the random-effects model. Twenty-four studies enrolled 700 patients in total; 653 received mechanical thromboembolectomy treatments for PE (mortality rate, 9% [95% confidence interval (CI), 6%-13%], P = .12; rate of minor complications, 6% [95% CI, 2%-13%]). In the ultrasound-accelerated thrombolysis (USAT) studies, the mortality rate was 4% (95% CI, 1%-11%) and in the non-USAT studies, it was 9% (95% CI, 6%-13%). Secondary safety outcomes were all bleeding events, which occurred in 12% (95% CI, 7%-20%) of the USAT studies and in 10% (95% CI, 5%-20%) of the non-USAT studies. Current clinical evidence does not prove USAT is superior over CDT methods.
Genes related to endothelial function are responsible for the regulation of vascular functions.
The aim of this study is to investigate whether endothelial gene-associated polymorphism and their plasma levels can be used to predict the risk for venous thromboembolism (VTE).
We studied 133 patients with VTE and 164 healthy controls. Endothelin (EDN) G8002A, EDN T1370G, EDN 3A/4A, eNOSG894T, angiotensin-converting enzyme I/D, vascular endothelial growth factor C936T, and endothelial cell protein C receptor A6936G polymorphism was genotyped by restriction fragment length polymorphism. Plasma levels of endothelin 1 (EDN1), endothelial nitric oxide synthase, and angiotensin-converting enzyme were measured by enzyme-linked immunoassay kit.
The genotype and allele frequency between control and patients with VTE were significantly altered only for EDN T1370G polymorphism. The plasma EDN1 concentration was relatively higher in patients with VTE (P = .0017) compared to healthy controls and showed an association with the EDN1 gene polymorphism in male Indian population. Logistic regression model analysis for EDN T1370G indicated a significant association between EDN G allele and occurrence of VTE.
The EDN1 gene polymorphism may play a significant role in predicting individual’s susceptibility toward VTE and its clinical progression.
We sought to compare the length of stay (LOS) and total costs for patients with pulmonary embolism (PE) treated with either rivaroxaban or parenterally bridged warfarin.
This retrospective claims analysis was performed in the Premier Database from November 2012 to March 2015. Adult patients were included if they had a hospital encounter for PE (an International Classification of Diseases, Ninth Revision code = 415.1x) in the primary position, a claim for ≥1 diagnostic test for PE on day 0 to 2, and initiated rivaroxaban or parenteral anticoagulation/warfarin. Rivaroxaban users (allowing ≤2 days of prior parenteral therapy) were 1:1 propensity score matched to patients receiving parenterally bridged warfarin. Length of stay, total costs, and readmission for venous thromboembolism (VTE) or major bleeding during the same or subsequent 2 months following the index event were compared between cohorts. Analysis restricted to patients with low-risk PE was also performed.
Characteristics of the matched PE cohorts (n = 3466 per treatment) were well balanced. Rivaroxaban use was associated with a 1.36-day shorter LOS and $2304 reduction in total costs compared to parenterally bridged warfarin (P < .001 for both). Rates of readmission for VTE were similar between cohorts (1.7% vs 1.6%; P = .64). No difference was observed between treatments for readmission for major bleeding (0.2% vs 0.2%; P > .99). In analyses restricted to low-risk patients (n = 1551 per treatment), rivaroxaban was associated with a 1.01-day and a $1855 reduction in LOS and costs, respectively (P < .001 for both). Rates of readmission were again similar between treatments (P > .56 for all).
Rivaroxaban significantly reduced hospital LOS and costs compared to parenterally bridged warfarin, without increasing the risk of readmission.
Aortic valve stenosis (AVS) is the most common valve disease in adults. Severe forms are associated with acquired von Willebrand syndrome (aVWS) with loss of the largest von Willebrand factor (VWF) multimers. Diagnostic gold standard is the VWF multimer analysis. Valve replacement rapidly restores the VWF structure. Uncertainty exists if this effect is permanent and how functional VWF assays perform compared with multimer analysis. We studied 21 consecutive patients with severe AVS before and 6 to 18 months after valve surgery and compared them with 14 controls without valve disease referred for coronary angiography. The VWF multimers, VWF antigen (VWF:Ag), VWF collagen binding capacity (VWF:CB), VWF:CB/VWF:Ag ratio, in vitro bleeding time (PFA-100), factor VIII coagulation activity (FVIII:C), and VWF ristocetin cofactor activity (VWF:RCo) were determined. In all patients with AVS, the large VWF multimers were strongly reduced (56 ± 13% of normal plasma); all controls had normal multimers. The PFA-100 collagen/ADP closure times (coll/ADP CT) were prolonged in patients with AVS compared with the controls (175 ± 56 seconds vs 86 ± 14 seconds, P < .001). The VWF:CB/VWF:Ag ratio was pathological in 20 of the 21 patients but normal in controls. After surgery, the multimers normalized in all patients and coll/ADP CT shortened (pre 184 ± 65 seconds vs post 102 ± 22 seconds; P < .001). The VWF:CB/VWF:Ag ratio strongly improved (P < .001) and normalized in 14 of 17 patients. In conclusion, all consecutive patients with severe AVS had an aVWS. The combination of coll/ADP CT and VWF:CB/VWF:Ag ratio detected the aVWS in all patients. More than 6 months after valve replacement, the VWF multimers were still normalized in all patients indicating a permanent cure of the aVWS.
Ischemic stroke represents one of the leading causes of death and disability in both the United States and abroad, particularly for patients with prior ischemic stroke or transient ischemic attack (TIA). A quintessential aspect of secondary stroke prevention is the use of different pharmacological agents, mainly antiplatelets and anticoagulants. Antiplatelets and anticoagulants exhibit their effect by blocking the activation pathways of platelets and the coagulation cascade, respectively. Clinical trials have demonstrated the safety and efficacy of antiplatelets for noncardioembolic stroke prevention, while anticoagulants are more often used for cardioembolic stroke prevention. Commonly used antiplatelets include aspirin, clopidogrel, and aggrenox (aspirin plus extended-release dipyridamole). Furthermore, commonly used anticoagulants include warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban. Each of these drugs has a unique mechanism of action, and they share some common adverse events such as gastrointestinal bleeding and intracranial hemorrhage in more serious cases. Consequently, physicians should carefully assess the benefits and risks of using different antiplatelet or anticoagulant therapies when managing patients with previous ischemic stroke or TIA. This review discuses the published literature on major clinical trials assessing the efficacy of different antiplatelet and anticoagulant drugs under varying circumstances and the subsequent guidelines that have been developed by the American Heart Association/American Stroke Association. Additionally, the role of imaging in stroke prevention is discussed.
The European Clinical Laboratory and Molecular (ECLM) classification of von Willebrand disease (vWD) is based on the splitting approach which uses sensitive and specific von Willebrand factor (vWF) assays with regard to the updated molecular data on structure and function of vWF gene and protein defects. A complete set of FVIII:C and vWF ristocetine cofactor, collagen binding, and antigen, vWF multimeric analysis in low- and medium-resolution gels, and responses to desmopressin (DDAVP) of FVIII:C and vWF parameters are mandatory. The ECLM classification distinguishes recessive types 1 and 3 vWD from recessive vWD 2C due to mutations in the D1 and D2 domains and vWD 2N due to mutations in the D'-FVIII-binding domain of vWF. The ECLM classification differentiates between mild vWD type 1 with variable penetrance of bleedings from symptomatic dominant type 1 vWD secretion defect and/or clearance defect with normal vWF multimers versus vWD 1M and 2M with normal or smeary vWF multimers in low- and medium-resolution gels. High-quality multimeric analysis of vWF in medium-resolution gels based on a DDAVP challenge test clearly delineates and distinguishes each of the dominant type 2 vWDs 1/2E, 2M, 2B, 2A, and 2D caused by vWF gene mutations in the D3 multimerization domain, loss or gain-of-function mutations in the glycoprotein Ib receptor A1 domain, gene mutations in the A2 proteolytic domain, and the C-terminal dimerization domain, respectively.
Interleukins play a central role in the immune system and are involved in a variety of immunological, inflammatory, and infectious disease states including sepsis syndrome. Levels of interleukins may correlate with overall survival and may directly or indirectly affect some of the regulators of coagulation and fibrinolysis, thereby disrupting hemostasis and thrombosis. Our hypothesis is that in sepsis-associated coagulopathies (SACs), interleukins may be upregulated, leading to hemostatic imbalance by generating thrombogenic mediators. We profiled the levels of interleukins IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10 in addition to
In this prospective review of cancer screening in unselected patients with unprovoked venous thromboembolism (VTE) presenting to a large teaching hospital in the Republic of Ireland, we aimed to determine the effects of the implementation of the National Institute for Health and Care Excellence screening policy in a "real-world" population. Within our institution, 64 individuals presented with unprovoked VTE during the study period, of whom 47 underwent a screening computed tomography (CT) scan. Two cases of previously undiagnosed cancer were identified. However, in both cases, the clinical history provided by the affected individuals would have prompted a CT scan regardless of the recommendations of the screening policy. The screening CT scans identified 18 incidental lesions within the cohort, which required further diagnostic studies. None of the additional investigations completed to date have detected any lesion of clinical significance. These findings support the view that cancer screening with CT imaging in unselected individuals with unprovoked VTE is not justified or cost-effective.
The risk of symptomatic infarct swelling has been reported to be higher in patients treated with recombinant tissue plasminogen activator (rt-PA). The aim of this study was to evaluate the timing of symptomatic infarct swelling after rt-PA treatment.
We retrospectively analyzed 14 868 patients with acute ischemic stroke from a stroke registry databank. We recruited patients with massive middle cerebral artery (MCA) infarction and symptomatic infarct swelling and excluded those with parenchymal or symptomatic hemorrhage. Multiple linear regression and multivariate logistic regression analyses were used to estimate the impact of rt-PA on the timing of symptomatic infarct swelling.
A total of 23 patients with rt-PA treatment and 117 patients without rt-PA treatment were included. The rt-PA treatment group had a lower rate of coronary artery disease (8.7% vs 32.5%; P = .023), lower severity of baseline National Institutes of Health Stroke Scale score (19 vs 23; P = .014), shorter duration of infarct swelling (27.6 vs 45.4 hours; P < .001), and higher rate of hemicraniectomy surgery (65.2% vs 28.2%; P =.001) than those without rt-PA treatment. After adjusting for variables in multiple linear regression analysis, rt-PA treatment and an elevated C-reactive protein level were associated with early symptomatic infarct swelling (P = .014 and P = .041, respectively). The rt-PA treatment was an independent factor related to early symptomatic infarct swelling within 36 hours (P = .005; odds ratio [OR]: 5.3; confidence interval [CI]: 1.65-17.0) or 48 hours (P = .009; OR: 16.4; CI: 2.00-134).
Intravenous rt-PA treatment may hasten the onset of cerebral edema and subsequent cerebral herniation in large MCA territory infarction.
In a randomized trial (ie, Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer [CLOT]) that evaluated secondary prophylaxis of recurrent venous thromboembolism (VTE) in patients with cancer, dalteparin reduced the relative risk by 52% compared to oral vitamin K antagonists (VKAs; hazard ratio = 0.48, P = .002). A recent subgroup analysis in patients with moderate to severe renal impairment also revealed lower absolute VTE rates with dalteparin (3% vs 17%; P = .011). To measure the economic value of dalteparin in these populations, a pharmacoeconomic analysis was conducted from the Dutch health-care system perspective.
Resource utilization data contained within the CLOT trial database were extracted and converted into direct cost estimates. Univariate analysis was then conducted to compare the total cost of therapy between patients randomized to dalteparin or VKA therapy. Health state utilities were then measured in 24 members of the general public using the time trade-off technique.
When all of the cost components were combined for the entire population (n = 676), the dalteparin group had significantly higher overall costs than the VKA control group (dalteparin = 2375 vs VKA = 1724; P < .001). However, dalteparin was associated with a gain of 0.14 (95% confidence interval [CI]: 0.10-0.18) quality-adjusted life years (QALYs) over VKA. When the incremental cost was combined with the utility gain, dalteparin had a cost of 4,697 (95% CI: 3824-4951) per QALY gained.
Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.
This study presents sample size considerations derived from the Efficacy of Thromboprophylaxis as an Intervention during Gravidity (EThIGII) trial (ClinicalTrials.gov: NCT00400387) to address the question of low-molecular-weight heparin (LMWH) treatment in women with recurrent pregnancy loss (RPL) depending on the M2/ANXA5 haplotype. To evaluate the possible influence of such treatment on miscarriage rates of trial participants, a post hoc analysis of ANXA5 promoter genotypes in the light of M2/ANXA5 (RPRGL3) distribution was performed using logistic models. DNA for genotyping was available from 129 LMWH and 95 control patients, 44 (19.6%) of whom were M2/ANXA5 carriers. Miscarriages occurred in 1 (4.0%) of 25 M2/ANXA5 carriers from the LMWH group compared to 4 (21.1%) of 19 in the control group, resulting in an odds ratio (95% confidence interval) for miscarriage of 0.16 (0.016-1.5) for women treated with LMWH. In noncarriers, miscarriage rates were 6 (5.8%) of 104 versus 7 (9.2%) of 76 for the LMWH and the control groups, respectively, corresponding to an odds ratio for miscarriage of 0.60 (0.19-1.9). The apparent beneficial effects of miscarriage rate reduction in M2/ANXA5 carriers with RPL concur with biological considerations about improvement in reduced ANXA5 function through LMWH treatment in an adequate murine model. The data obtained were instrumental to design proper assessment of the existence and magnitude of this effect.
Adults with hemophilia A (HA), hemophilia B (HB), and von Willebrand disease (VWD) frequently require surgery and invasive procedures. However, there is variability in perioperative management guidelines. We describe our periprocedural outcomes in this setting. A retrospective chart review from January 2006 to December 2012 of patients with HA, HB, and VWD undergoing surgery or invasive procedures was conducted. Type of procedures, management including the use of continuous factor infusion, and administration of antifibrinolytics were reviewed. Adverse outcomes were defined as acute bleeding (<48 hours), delayed bleeding (≥48 hours), transfusion, inhibitor development, and thrombosis. We identified 59 patients with HA and HB. In all, 24 patients had severe hemophilia and 12 had mild/moderate hemophilia. Twelve patients had inhibitors. There were also 5 female carriers of HA and 6 patients with VWD. There were 34 major surgeries (26 orthopedic, 8 nonorthopedic) and 129 minor surgeries. Continuous infusion was used in 55.9% of major surgeries versus 8.5% of minor surgeries. Antifibrinolytics were administered in 14.7% of major surgeries versus 23.2% of minor surgeries. In all, 4 patients developed acute bleeding and 10 patients developed delayed bleeding. Delayed bleeding occurred in 28.6% of genitourinary procedures and in 16.1% of dental procedures. Five patients acquired an inhibitor and 2 had thrombosis. In conclusion, patients with HA, HB, or VWD had similar rates of adverse outcomes when undergoing minor surgeries or major surgeries. This finding underscores the importance of an interdisciplinary management and procedure-specific guidelines for patients with hemophilia and VWD prior to even minor invasive procedures.
The aim of this study is to examine the relationship between initial magnesium (Mg) levels, electrocardiographic no-reflow, and long-term mortality in patients who underwent primary percutaneous coronary intervention (pPCI) due to ST-segment elevation myocardial infarction (STEMI).
A total of 111 patients with pPCI participated in the study. Magnesium and high-sensitive C-reactive protein (hs-CRP) were measured. The sum of ST-segment elevation was measured immediately before and 60 minutes after the restoration of coronary flow. The difference between the 2 measurements was taken as the amount of ST-segment resolution and defined as sum of ST-segment resolution (STR). The STR <50% was determined as electrocardiographic sign of no-reflow phenomenon. After the patients were discharged, they were followed up for major adverse cardiac events for up to 51 months after discharge.
Forty patients in the no-reflow group and 71 patients in the normal-flow group were included in the study. Magnesium value ≤1.87 mg/dL initially measured had 77% sensitivity and 59% specificity in predicting no-reflow on receiver operating characteristic curve analysis. In multivariate analyses, Mg (odds ratio [OR]: 0.01, <95% confidence interval [CI]: 0.01-0.12; P = .004), hs-CRP (OR: 1.06, <95% CI: 1.00-1.14; P = .05), left anterior descending artery lesion (OR: 6.66, <95% CI: 1.45-3.05; P = .01), and reperfusion time (OR: 1.01, <95% CI: 1.00-1.01; P = .03) were still independent predictors of electrocardiographic no-reflow, and only Mg (OR: 0.08, <95% CI: 0.01-1.03; P = .05) was still an independent predictor of long-term mortality.
Serum Mg level is an independent predictor of electrocardiographic no-reflow and long-term mortality in patients with STEMI.
Improved life expectancy of persons with hemophilia (PWHs) has led to a greater interest in the role of age-related chronic diseases, such as hypertension, in this cohort. Several observational studies have reported an increased prevalence of hypertension in PWHs; however, this has not been assessed using a large, national database in the United States.
We hypothesized the prevalence of hypertension is increased in PWHs and compared the prevalence of hypertension and associated risk factors among patients with and without hemophilia.
A cross-sectional analysis was performed using discharge data among adult males from the National Inpatient Sample over the 3-year period, 2009 to 2011. Hypertension was compared across groups using Rao-Scott 2 test. Multivariable logistic regression was used to estimate the odds of hypertension in patients with hemophilia after adjustment for hypertension-associated risk factors.
The prevalence of hypertension in patients with hemophilia was less than the prevalence of hypertension in patients without hemophilia (39.5% vs 56.3%, P < .001). Hemophilia was associated with a decreased odds of hypertension after adjusting for associated risk factors (odds ratio: 0.87; 95% confidence interval: 0.81-0.94).
In contrast to the findings of several other recent studies, we report a decreased prevalence of hypertension in PWHs. The discrepancy among the reported prevalence of hypertension in our study and several others highlights the potential biases inherent to retrospective and cross-sectional studies and underscores the need for well-designed prospective studies to determine the true incidence of hypertension in PWHs, which may lie somewhere in between our findings and the findings of others.
Chronic rheumatic heart disease (RHD) patients who undergo valve replacement with mechanical valves require lifelong anticoagulation. Acenocoumarol, a vitamin K antagonist has a narrow therapeutic range and wide inter-individual variability. Our aim was to investigate the influence of polymorphisms of VKORC1 and CYP2C9 genes on the mean daily dose requirement of acenocoumarol.
205 chronic RHD patients, with mechanical heart valves and on acenocoumarol therapy, were recruited. Genotyping for VKORC1 (–1639G>A and 1173C>T) and CYP2C9 (*2 & *3 alleles) polymorphisms was done by PCR-RFLP. There was complete linkage disequilibrium between VKORC1 polymorphisms (r2 = 0.98, D' = 1.0, LOD = 74.02). VKORC1 genotype distribution for GG/CC, GA/CT, and AA/TT were 57.6%, 36.1%, and 6.3%, respectively. CYP2C9 genotype distribution for *1/*1, *1/*3, *1/*2, *2/*2, and *2/*3 were 78.5%, 14.1%, 6.3%, 0.5%, and 0.5%, respectively. Patients with a wild type of both VKORC1 (–1639GG and 1173CC) and CYP2C9 gene variants required higher acenocoumarol dose compared to those with mutant genotype (P = 0.023 and P = 0.008 respectively). On combined genotype analysis, patients having a combination of wild type of VKORC1 with wild type of CYP2C9 (44.4%) required higher daily dose compared to patients bearing heterozygous VKORC1 (–1639GA & 1173CT) with wild type of CYP2C9 (30.2%, P = 0.008).
Presence of a mutant allele of VKORC1 (–1639A & 1173T) and CYP2C9 genes increased the odds of requiring a lower mean dosage of acenocoumarol. Studying the combination of genotypes in RHD patients could predict acenocoumarol dose requirement more accurately.
Human monocytes are heterogeneous and play an important role in autoimmune diseases. However, the distribution and function of monocyte subsets remain unclear in primary immune thrombocytopenia (ITP). In this study, we determined the frequencies of monocyte subsets in 71 untreated patients with active ITP and 49 healthy controls by flow cytometry. Compared with controls, the frequency of nonclassical monocytes was significantly increased in patients with active ITP but decreased after complete remission. The intermediate subset was also increased in patients with active ITP and produced the highest levels of tumor necrosis factor α and interleukin 1β. Both the nonclassical and intermediate subsets were negatively correlated with the platelet counts. We further determined the correlation between monocyte subsets and the proliferation of platelet-autoreactive T cells. The purified monocyte subsets were cocultured with CD4+ T cells and autologous platelets. The nonclassical subset showed the highest capability of promoting platelet reactive T-cell proliferation and significantly promoted the secretion of interferon among the 3 subsets. In conclusion, the nonclassical and intermediate monocyte subsets are both expanded and play different roles in the pathogenesis of ITP.
Platelet adhesion is mediated by von Willebrand factor (vWF), and disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13 (ADAMTS13) is a protease that cleaves vWF. A change in the balance between vWF and ADAMTS13 in favor of thrombosis might occur shortly before ischemic cardiovascular (CV) events.
To determine whether vWF, ADAMTS13, and the ratio of vWF and ADAMTS13 change during the months preceding an acute CV event.
Prospective longitudinal observational study.
Outpatient.
A total of 595 participants with peripheral artery disease (PAD).
Blood samples were obtained every 2 months for up to 3 years and hemostatic factors examined at intervals preceding events.
Sixty-one participants (cases) experienced events and were matched to 122 PAD controls. During the 2-month interval prior to an event, cases (n = 48) had higher levels of the vWF and ADAMTS13 than controls (n = 95; P = .05), but significance was lost after adjusting for the baseline differences in myocardial infarction, unstable angina, and stroke. During the 10 months prior to an event, median values for vWF and the ratio of vWF and ADAMTS13 were higher in cases than in controls, but the differences were not statistically significant. However, in a subset of 20 patients with complete bimonthly data, there was a trend toward an increase in the ratio in the 10 months prior to a CV event (P = .04).
In patients with PAD experiencing an ischemic CV event, a significant increase in the ratio of vWF to ADAMTS13 prior to the event could not be confirmed, although there was a weak trend in this direction.
Polymorphisms in cytochrome P450 (CYP) 2C9 (CYP2C9) gene result in interindividual variability in warfarin dose requirement. There is a need for characterization of genotype frequency distribution in different populations for construction of customized dosing algorithms to enhance the efficacy and reduce the toxicity of warfarin therapy. This study was carried out in Pakistani population to evaluate the contribution of common CYP2C9 polymorphisms to warfarin therapy. A total of 550 stable patients taking warfarin were enrolled after medical history, physical examination, and laboratory investigations. Single blood sample was collected after informed consent. Genomic DNA was extracted, and genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was done by polymerase chain reaction-restriction fragment length polymorphism assay. A number of samples were also analyzed by direct DNA sequencing for validation of the results. Data were analyzed using SPSS version 20. Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 was found to be different from other populations. Of these 2 polymorphisms, CYP2C9*2 did not demonstrate significant effect on warfarin dose requirement, whereas CYP2C9*3 did show significant effect (P value = .012). It is concluded that there is a need to study genotype frequency distribution and their effect on warfarin dose variability among different populations due to diversity in outcome.
Increased coagulation activity has been established in paroxysmal atrial fibrillation (PAF), but data on the anticoagulant system are scarce.
To examine the protein C anticoagulant pathway in the early hours of the disease.
Fifty-one patients (26 men and 25 women; mean age 59.84 ± 1.60 years) and 52 controls (26 men and 26 women; mean age 59.50 ± 1.46 years) were selected for the study. Protein C antigen and its activity, total protein S, free protein S and its activity, soluble forms of endothelial protein C receptor (sEPCR), and thrombomodulin (sTM) were examined in the plasma.
The indicators were studied in patients between the 2nd and the 24th hour after the onset of arrhythmia. Levels of protein C were significantly elevated in patients compared to controls (111.40% ± 6.66% vs 94.83% ± 4.47%; P = .039). Protein C activity showed significant reduction in PAF (73.13% ± 5.80% vs 103.3% ± 3.80%; P < .001). Total protein S levels did not differ significantly (108.20% ± 4.07% vs 102.40% ± 3.65%; P = .30). Free protein S (76.81% ± 6.01% vs 122.10% ± 3.97%; P < .001) and its activity (71.39% ± 6.27% vs 119.50% ± 6.54%; P < .001) were reduced in patients. Higher levels of sEPCR (203.10 ± 10.33 vs 133.10 ± 7.37 ng/mL; P < .001) and sTM (6.50±0.40 vs 4.48±0.28 ng/mL; P < .001) were measured in PAF.
Protein C activity is reduced still in the first hours (until the 24th hour) of PAF clinical manifestation, determining reduced activity of the anticoagulant pathway as a whole. The established low levels of free protein S and its activity as well as low sEPCR and sTM levels are a possible explanation of the changes in protein C activity.
We evaluated the modified diagnostic criteria for disseminated intravascular coagulation (DIC), which was published by the Japanese Society of Thrombosis and Hemostasis (JSTH) in 108 patients with suspected infectious DIC.
The diagnoses of the patients were as follows: DIC (n = 63), pre-DIC (n = 22), and non-DIC (n = 45). The efficacy of the diagnostic criteria for DIC was evaluated using a receiver–operating characteristic analysis.
Although the area under the curve for global coagulation test (GCT) scores in the diagnosis of "DIC" was high that for the diagnosis of "DIC and pre-DIC" was low, suggesting that the addition of antithrombin (AT), soluble fibrin (SF)/thrombin–AT complex (TAT), and reduced platelet count (PLT) values was required to diagnose "DIC and pre-DIC." Using GCT score with the AT, SF/TAT, and reduced PLT values, the cutoff value of the DIC score for the diagnosis of "DIC and pre-DIC" was 5 points.
The modified JSTH’s diagnostic criteria for DIC, which used the GCT score and the reduced PLT, AT, and TAT/SF values, were useful for diagnosing "DIC and pre-DIC."
Vascular thrombosis, both arterial and venous, is a condition associated with significant morbidity and mortality. There are multiple risk factors for thrombosis, both congenital and acquired, and in the majority of cases, these risk factors are not modifiable. Over the past 2 decades, multiple drugs (both illegal and legal) have been associated with increased risk of thrombosis. However, due to limited scientific literature regarding the prothrombotic tendencies of these drugs, there is a concomitant limited understanding of the pathophysiology of drug-induced thrombosis. As drugs are one of the few modifiable risk factors for thrombosis, further study and dissemination of knowledge regarding drug-associated and drug-induced thrombosis are essential and have the potential to lead to decreased future incidence of thrombosis. The mechanisms at the basis of the thrombophilic activity of these drugs are variable and sometimes still ill recognized. Increased levels of clotting factors, reduction in coagulation natural inhibitors, decreased fibrinolysis, activated clotting factors, increased blood viscosity, endothelial damage, and increased platelet number and activation are the most frequent causes. Arterial steal or coronary arteries no flow has also been implicated. In some cases due to the intake of several drugs, more than one mechanism is present in a given patient. The purpose of the present review is to analyze all the drugs demonstrated to be potentially thrombotic. It is hoped that a prudent use or nonuse of these drugs might result in a reduction of thrombosis-associated diseases.
Antithrombin III (AT) is the most important endogenous anticoagulant, and genetic variability in SERPINC1, gene encoding AT, is low. Mutations leading to AT deficiency and increased thrombotic risk are well known; however, only 2 studies have reported mutations in regulatory region of SERPINC1 gene till date. Aim of the present study was to identify genetic variations in SERPINC1 5' untranslated region (UTR) in Indian patients with deep vein thrombosis (DVT) having AT deficiency. DNA sequencing was used to identify underlying genetic defects in SERPINC1 regulatory region. In silico tools TFBIND and PROMO were used to identify transcription factor binding sites in the promoter region. We have identified 2 novel polymorphisms, g.25G>A and g.–1A>T, and 2 known g.67G>A and rs3138521 5' UTR polymorphisms in SERPINC1 regulatory region in Indian patients with DVT for the first time. In present study, allele frequencies of rs3138521 (S: 0.37 and F: 0.63) were similar to that reported in Western population and were not associated with low plasma AT levels (P value .5). This is the first report of regulatory region polymorphisms in SERPINC1 gene in Indian population. Our results strongly suggest that similar studies should be included when ever no mutation is detected in protein-coding region of AT gene.
Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Factors such as the presence of transient risk factors for VTE, risk of bleeding, and location of deep vein thrombosis (DVT) determine the duration of anticoagulation. Extended anticoagulation is offered to patients with unprovoked pulmonary embolism (PE) or proximal DVT and a low risk of bleeding. Anticoagulation for 3 months is advised in patients with provoked DVT or PE, high risk of bleeding, and isolated distal or upper extremity DVT. In patients with unprovoked PE or proximal DVT and a low risk of bleeding, who want to stop anticoagulation after 3 months, further risk stratification is necessary. Clinical scoring system, and thrombophilia testing otherwise not routinely performed, may be considered to measure risk of annual recurrence in such cases. Short-term anticoagulation may be considered in subsegmental PE and superficial vein thrombosis, particularly if patients are at low risk of bleeding and have persistent risk factors for recurrent VTE. In cases of catheter-associated thrombosis, the catheter need not be removed routinely, and the patient may be anticoagulated for 3 months or longer if the catheter is maintained in patients with cancer. Extensive screening for occult cancer in cases of unprovoked VTE is not beneficial. New oral anticoagulants such as apixaban, rivaroxaban, or dabigatran may be preferred to vitamin K antagonists in patients without cancer or renal failure, more so after the development of reversal agents such as idarucizumab and andexanet alfa.
Cardiac surgery involving cardiopulmonary bypass (CPB) is often associated with important blood loss, allogeneic blood product usage, morbidity, and mortality. Coagulopathy during CPB is complex, and the current lack of uniformity for triggers and hemostatic agents has led to a wide variability in bleeding treatment. The aim of this review is to provide a simplified picture of the data available on patients’ coagulation status at the end of CPB in order to provide relevant information for the development of tailored transfusion algorithms. A nonsystematic literature review was carried out to identify changes in coagulation parameters during CPB. Both prothrombin time and activated partial thromboplastin time increased during CPB, by a median of 33.3% and 17.9%, respectively. However, there was marked variability across the published studies, indicating these tests may be unreliable for guiding hemostatic therapy. Some thrombin generation (TG) parameters were affected, as indicated by a median increase in TG lag time of 55.0%, a decrease in TG peak of 17.5%, and only a slight decrease in endogenous thrombin potential of 7%. The most affected parameters were fibrinogen levels and platelet count/function. Both plasma fibrinogen concentration and FIBTEM maximum clot firmness decreased during CPB (median change of 36.4% and 33.3%, respectively) as did platelet count (44.5%) and platelet component (34.2%). This review provides initial information regarding changes in coagulation parameters during CPB but highlights the variability in the reported results. Further studies are warranted to guide physicians on the parameters most appropriate to guide hemostatic therapy.
Sonoclot is used to measure kaolin-based activated clotting time (kACT) for heparin management. Apart from measuring kACT, the device assesses the patient’s coagulation status by glass bead–activated tests (gbACTs; measuring also clot rate [CR] and platelet function [PF]). Recently, a new version of the Sonoclot has been released, and the redesign may result in performance changes. The aim of this study was to evaluate and compare the performance of the new (S2) and the previous (S1) Sonoclot.
The S1 was used in the routine management of 30 patients undergoing elective cardiac surgery. Blood samples were taken at baseline (T1), after heparin administration (200 U/kg, 100 U/kg; T2 and T3), during cardiopulmonary bypass (T4), after protamine infusion (T5), and before intensive care unit transfer (T6). Kaolin-based activated clotting time and gbACTs were measured in duplicate by both the old and the new device and performance compared by Bland-Altman analysis and percentage error calculation.
A total of 300 kACT and 180 gbACTs were available. Bland-Altman analysis for kACT revealed that S2 consistently reported results in shorter time compared to S1 (overall = –14.7%). Comparing S2 and S1, the glass bead–activated tests showed mean percentage differences of –18.9% (gbACTs), +37.4% (CR), and –3.7% (PF).
Since clotting is faster in the new S2 compared to S1, shorter clotting times have to be considered in clinical practice. The use of S2 kACT in heparin management will result in higher heparin and protamine dosing unless heparin kACT target values are adjusted to correct for the differences in results between S1 and S2.
Clopidogrel is a clinically important oral antiplatelet agent for the treatment or prevention of cerebrovascular disease. However, different individuals have different sensitivities to clopidogrel. This study assessed variants of different genes for association with response to clopidogrel, clinical outcome, and side effects in patients with ischemic stroke (IS).
We consecutively enrolled 375 patients with IS after they received clopidogrel therapy, and venous blood samples were subjected to genotyping allelic variants of genes modulating clopidogrel absorption (ATP binding cassette subfamily B1, ABCB1), metabolic activation (cytochrome P450[CYP] 3A and CYP2C19), and biologic activity (platelet membrane receptor [P2Y12, P2Y1)], and glycoprotein IIIa [GPIIIa]) and statistically analyzing their interactions with clopidogrel sensitivity (CS) and adverse events, risk of IS recurrence, myocardial infarction, and death during 6 months of follow-up.
Adverse events occurred in 37 patients (31 had IS recurrence, 4 died, and 2 had myocardial infarction) during the first 6 months of follow-up. Single locus analysis showed that only the CYP2C19*2(rs4244285) variant was independently associated with CS and risk of adverse events after adjusting covariates. However, there was significant gene–gene interaction among CYP2C19*2(rs4244285), P2Y12(rs16863323), and GPIIIa (rs2317676) analyzed by generalized multifactor dimensionality reduction methods. The rate of adverse events among patients with the 3-loci interaction was 2.82 times the rate among those with no interaction (95% confidence interval: 2.04-8.63).
Sensitivity of patients with IS to clopidogrel and clopidogrel-induced adverse clinical events may be multifactorial but is not determined by single gene polymorphisms.
There are limited studies evaluating the ability of the Hestia criteria to accurately identify patients with acute pulmonary embolism (PE) at low risk of early mortality. We sought to externally validate the Hestia criteria for predicting in-hospital and 30-day post-PE mortality.
We retrospectively identified consecutive, adult, objectively confirmed PE patients presenting to the emergency department at our institution from November 21, 2010, to January 31, 2014. We ascertained the total number of Hestia criteria met for each patient, calculated the proportion of patients categorized as low risk (ie, no Hestia criteria met), and determined the accuracy of the Hestia criteria for predicting in-hospital and 30-day all-cause mortality. Mortality was determined through Social Security Death Index searches.
A total of 577 patients with PE were included, of which 19 (3.3%) and 35 (6.6%) died in hospital or within 30 days of presentation. Both in-hospital and 30-day case fatality rates rose as the number of Hestia criteria increased. One-hundred forty nine (25.8%) patients were classified as low risk for early mortality, and none of these patients died within 30 days (negative predictive values of 100%). The Hestia criteria had excellent sensitivity (100%, 95% confidence interval [CI] = 79.1%-100% and 100%, 95% CI = 87.7%-100%) for predicting in-hospital and 30-day mortality but low specificity (<27.5% for both). The c-statistics for in-hospital and 30-day mortality were 83.5%, 95% CI = 77.1%-89.9% and 78.5%, 95% CI = 71.9%-85.1%. The predictive accuracy of the Hestia criteria remained acceptable in patients >80 years of age, with active cancer or chronic cardiopulmonary disease.
The Hestia criteria have an acceptable predictive accuracy to identify patients with PE at low risk for in-hospital or 30-day mortality.
Monthly or seasonal changes in the incidence of venous thromboembolism (VTE) were previously reported; however, the mechanism of such variability is not completely understood.
In the present retrospective single-center analysis, consecutive patients with proximal deep vein thrombosis and/or pulmonary embolism (PE) diagnosed between January 2009 and December 2013 were evaluated.
The study population included 1496 patients, 48% men, mean age 63 ± 18 years. Most (82%) cases with VTE were provoked and 39% of patients had active cancer. Four months of peak incidence (3, 7, 10 and 11) were compared with 4 months of the lowest incidence (4, 5, 6, and 12), showing a significant difference in VTE numbers (597 vs 405 cases/year, P = 0.001). In all subgroup analyses, including gender, provoked or unprovoked event and presence or absence of cancer, significant differences between the months of peak and lowest incidence remained. Blood urea nitrogen (BUN)–creatinine ratio was significantly higher in all cases in the peak incidence group compared to the lowest incidence group (24 ± 1.5 vs 21 ± 1.6, P = 0.03). In patients with unprovoked VTE (n = 269), levels of BUN and hematocrit were significantly increased in the peak incidence group compared to lowest incidence group (19.5 ± 0.8 mg/dL vs 16 ± 1.1 mg/dL, P = 0.03; 39.2 ± 0.3% vs 37.4 ± 0.5%, P = 0.01, respectively).
The current study demonstrates that occurrence of VTE exhibits monthly variation also existing in patients with provoked events and even in those with cancer. Dehydration is suggested as a potential explanation to the month-related variation in incidence of VTE.
In patients presenting non-high clinical pretest probability (PTP), a negative
Heparin-induced thrombocytopenia (HIT) occurs in up to 5% of patients exposed to unfractionated heparin for 5 or more days. Direct thrombin inhibitors (DTIs) are currently the only Food and Drug Administration (FDA)-approved agents for the treatment of HIT. The purpose of this study is to determine whether fondaparinux is an appropriate first-line alternative anticoagulant in patients with suspected or confirmed HIT.
A retrospective study was conducted by identifying all patients who received a DTI or fondaparinux during a 5 year period, August 2009-August 2014. Patients were included if they had a HIT panel/serotonin-release assay analysis (regardless of the result) and were initiated on a DTI or fondaparinux for alternative anticoagulation. The primary outcome was new, recurrent, or progressive thromboembolic event. Secondary outcomes included bleeding events, platelet count recovery, and hospital stay.
A total of 1022 patients were evaluated, and 47 patients met the inclusion criteria. Twelve patients were HIT positive and 35 were HIT negative. Seven (14.9%) of the 47 patients experienced a new thrombosis, none of whom were on fondaparinux only (FONDA). There were 4 new minor bleeds, with 1 bleed as a result of being on fondaparinux. FONDA treatment resulted in a slightly shorter median duration of hospital stay compared to the DTI-only group and the DTI followed by fondaparinux group. There is a potential for cost savings with fondaparinux due to the ease of administration and availability to be given in the outpatient setting.
In this small retrospective review, fondaparinux appeared similarly efficacious and safe compared to DTIs for the treatment of suspected HIT.
The aim of this study was to examine the effect of the traditional oral anticoagulant, warfarin (W), and new anticoagulants, apixaban (A) and rivaroxaban (R), on the level of thrombotic biomarkers in patients with atrial fibrillation (AF). Circulating plasma levels of von Willebrand factor (vWF), prothrombin fragment 1.2 (F1.2), microparticle tissue factor (MP-TF), and plasminogen activator inhibitor (PAI-1) were analyzed as potential markers of clot formation in 30 patients with AF prior to ablation surgery. Patients with AF were divided into 2 groups based on their usage (n = 21) and nonusage (n = 9) of any oral anticoagulant. Furthermore, those on anticoagulants were divided based on their use of newer (R and A, 16) or traditional (W, 4) anticoagulants. A statistical increase (P < .05) in the levels of vWF, MP-TF, and PAI-1 were seen in anticoagulated patients with AF, whereas F1.2 and PAI-1 were increased in nonanticoagulated patients with AF compared to normal. There was no statistical difference (P > .05) in levels of any thrombotic biomarker between patients treated with the traditional anticoagulant, W, and those treated with new anticoagulants, R and A. Our data suggest that, despite the use of traditional or newer anticoagulants, prothrombotic biomarkers are still generated at increased levels in patients with AF. Further studies to confirm these findings are warranted.
CHA2DS2-VASc score includes similar risk factors for coronary artery disease. We hypothesized that admission CHA2DS2-VASc score might be predictive of adverse clinical outcomes for patients with ST-segment elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention. A total of 647 patients with STEMI enrolled in this study. The study population was divided into 2 groups according to their admission CHA2DS2-VASc score. The low group (n = 521) was defined as CHA2DS2-VASc score ≤2, and the high group (n = 126) was defined as CHA2DS2-VASc score >2. Patients in the high group had significantly higher incidence of in-hospital cardiovascular mortality (8.7% vs 1.9%; P < .001). Long-term mortality was significantly frequent in the high group (13.4% vs 3.6%, P < .001). Hypertension, admission CHA2DS2-VASc score, and Killip class >1 were independent predictors of long-term mortality. Admission CHA2DS2-VASc score >2 was identified as an effective cutoff point for long-term mortality (area under curve = 0.821; 95% confidence interval: 0.76-0.89; P < .001). CHA2DS2-VASc score is a simple, very useful, easily remembered bedside score for predicting in-hospital and long-term adverse clinical outcomes in STEMI.
Although recent studies have reported the efficacy of antithrombin (AT) supplementation for sepsis-associated disseminated intravascular coagulation (DIC), the factors that influence AT’s effect have not been sufficiently studied. The purpose of this survey was to identify factors that modulate the effects and the adverse effects of AT.
We performed a multi-institutional survey. The data from 159 patients with septic DIC with AT ≤70% and who had undergone AT supplementation were analyzed. The patients’ demographic characteristics, including the infection site, baseline sepsis-related organ failure assessment (SOFA) score, baseline DIC score, and baseline AT activity, were analyzed in relation to the 28-day mortality. Bleeding-related adverse events were also examined.
Overall, 116 patients survived and 43 did not (28-day mortality: 27.0%). A logistic regression analysis revealed that the baseline SOFA score (odds ratio [OR]: 0.816, P = .001), coadministration of recombinant thrombomodulin (rTM; OR: 3.989, P = .006), and respiratory tract infection (OR: 0.129, P = .000) were significantly associated with the survival. Survivors exhibited a higher peak AT activity than nonsurvivors (85.1% vs 65.0%, P = .027). Bleeding events were observed in 4.13% (major bleeding: 1.65%) of the patients, and the coadministration of rTM did not increase the risk of bleeding (with rTM: 4.11% vs without rTM: 4.17%). Heparin was concomitantly used in 22 (18.2%) cases, and its use nonsignificantly increased the bleeding risk (with heparins: 9.09% vs without heparins: 3.03%; P = .224).
The coadministration of rTM may improve survival without increasing the risk of bleeding in patients with sepsis-associated DIC treated with AT.
To test for the presence of inflammatory biomarkers in blood taken from varicose veins versus antecubital blood of the same patient and compare this to levels in healthy controls.
Using a multiplex biochip array method (Randox, United Kingdom), the interleukins (ILs) IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10; vascular endothelial growth factor; interferon , tumor necrosis factor α ; monocyte chemotactic protein 1 (MCP-1); and epidermal growth factor were measured in citrated plasma samples drawn from the arms and legs of 24 patients with varicose veins and 24 controls.
Expressed as median (interquartile range) in pg/mL, leg samples from patients with varicose veins had significantly higher levels of IL-8 and MCP-1 compared to their own arm samples (IL-8: local 2.3 [1.71-3.3] vs systemic 2.3 [1.62-2.98], P = .023; MCP-1: local 114.42 [84.29-139.05] vs systemic 103.56 [79.75-126.42], P < .0005). This was not observed in the control group. Leg samples from both patients with varicose vein and controls had higher levels of IL-6 compared to their own arm samples (patients: local 1.67 [0.82-4.48] vs systemic 1.24 [0.58-3.26], P = .002; controls: local 1.23 [0.83-1.7] vs systemic 1.03 [1.7-1.52], P = .005). No significant differences were detected with the other biomarkers.
Blood drawn from the site of varicose veins appears to have significantly increased concentrations of IL-6, IL-8, and MCP-1 when compared to the same patient’s arm blood. This supports the hypothesis that inflammation is activated from the tissues drained by the varicose veins.
Total joint arthroplasty (TJA) improves the quality of life for patients with end-stage osteoarthritis but is associated with an increased risk of venous thromboembolism (VTE), thus pharmacologic thromboprophylaxis is recommended for most patients. Patients with congenital bleeding disorders may develop severe arthropathies due to repeated hemarthroses and derive similar benefit from TJA as the general population. No guidelines for pharmacologic thromboprophylaxis in this population exist, however, as the risks and benefits are not well defined. We undertook the current study to assess the safety and efficacy of pharmacologic VTE prophylaxis in patients with congenital bleeding disorders undergoing TJA. We retrospectively reviewed the medical records of patients with bleeding disorders who underwent TJA at our academic institution between 1987 and 2012. We identified 28 patients who underwent 38 TJA procedures. Low-molecular-weight heparin (LMWH) was administered in 29 procedures (76%) and was discontinued early in 3 procedures (2 patients) due to nonjoint bleeding. No symptomatic VTE was identified, and no joint or deep wound infections were seen. Twenty-two patients accounting for 31 procedures were contacted to discuss their experience with TJA. All reported decreased pain, and 97% reported improved function after the surgery. Impressively, 97% stated that they would choose to have the surgery again. These results confirm the benefit of TJA in patients with congenital bleeding disorders and end-stage arthropathies and suggest that LMWH thromboprophylaxis is safe. No patient in our cohort developed symptomatic VTE, whether or not thromboprophylaxis was administered, thus necessity of thromboprophylaxis remains an unanswered question.
Heparin is a widely used clinical anticoagulant. It is also a linear glycosaminoglycan with an average mass between 10 and 20 kDa and is primarily made up of trisulfated disaccharides comprised of 1,4-linked iduronic acid and glucosamine residues containing some glucuronic acid residues. Heparin is biosynthesized in the Golgi of mast cells commonly found in the liver, intestines, and lungs. Pharmaceutical heparin currently used in the United States is primarily extracted from porcine intestines. Other sources of heparin including bovine intestine and bovine lung are being examined as potential substitutes for porcine intestinal heparin. These additional sources are intended to serve to diversify the heparin supply, making this lifesaving drug more secure. The current study examines bovine heparins prepared from both intestines and lung and compares these to porcine intestinal heparin. The structural properties of these heparins are examined using nuclear magnetic resonance, gel permeation chromatography, and disaccharide analysis of heparinase-catalyzed depolymerized heparin. The in vitro functional activities of these heparins have also been determined. The goal of this study is to establish the structural and functional similarities and potential differences between bovine and porcine heparins. Porcine and bovine heparins have structural and compositional similarities and differences.
Discordance between international guideline recommendations and anticoagulant prescribing patterns among patients with nonvalvular atrial fibrillation (NVAF) has been frequently reported. This study was designed to compare the anticoagulant utilization pattern to earlier data in the same population and identify predictors of anticoagulant prescribing among patients with NVAF. We reviewed patients with NVAF admitted to Tasmania’s 3 major hospitals between January 2011 and June 2012 and compared the anticoagulant utilization pattern to earlier data. Patients were excluded if they had only 1 episode of NVAF that reverted spontaneously or upon cardioversion. Multivariate logistic regression analysis was used to identify predictors of anticoagulant prescribing. Overall, 53.8% of patients received anticoagulant treatment compared to 40.4% 15 years ago. Among eligible patients at high-risk of stroke, 52.5% were receiving anticoagulant therapy (vs 42.1% 15 years ago). Approximately 10% of patients with a CHADS2 score ≥2 were not receiving any antithrombotic treatment, reduced from 18.2% in the earlier cohort, whereas anticoagulant use increased among those at low risk (score 0) to 48.5% from 14.2%. Younger age (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.97-1.0; P = .04); CHADS2 = 1, relative to 0 (OR 1.68, 95% CI 1.07-2.63; P = .02); CHF (OR 1.56, 95% CI 1.12-2.15; P = .008); and embolic disease history (OR 1.77, 95% CI 1.09-2.86; P = .02) were significant predictors of anticoagulant prescribing. While there has been improvement over the past 15 years, suboptimal use of anticoagulant therapy among high-risk patients with NVAF remains common. There is significant potential for improvement in the quality of stroke prophylaxis in patients with NVAF.
Antiphospholipid antibodies (APLAs) have been variably reported in 14% to 75% of patients with immune thrombocytopenia (ITP). There is lack of Indian data on incidence of APLA in ITP.
We studied the incidence of APLA in patients with pediatric and adult Indian ITP.
We prospectively studied 100 patients including acute (n = 37), persistent (n = 13), and chronic (n = 50) ITP. Male to female ratio was 1.22:1. Median age was 18 years (1.5-56). All patients underwent investigations for lupus anticoagulant (LA), anticardiolipin (aCL) immunoglobulin G (IgG) and IgM antibodies, and anti-β2 glycoprotein 1 (β2GP1) IgG and IgM antibodies. Patients with secondary ITP were excluded. Bleeding manifestations were recorded. Patients with acute and persistent ITP were assessed for steroid response. Response rates were compared between APLA-positive and APLA-negative patients.
Antiphospholipid antibodies were detected in ~12% of patients with ITP: 8.1% (3 of 37) in acute, 0% (0 of 13) in persistent, and 18% (9 of 50) in chronic ITP. Anti-β2GP1 antibodies were most frequent (9%). Only 2 patients each were positive for anti-aCL antibodies and LA. Although platelet counts were significantly higher in APLA-positive patients, there was no significant difference in bleeding between the APLA-positive versus APLA-negative patients with ITP. There was also no significant difference in steroid response between APLA-positive and APLA-negative patients with acute/persistent ITP. In the short follow-up (median 8 months), none of the APLA-positive patients developed thrombosis.
Incidence of APLA in Indian population was lower than reported in the West, which indicates that not all patients of ITP need to be subjected to these manifestations upfront at diagnosis.
Antiphospholipid antibodies (aPL Abs) represented an independent factor that was associated with the occurrence and/or progression of nephropathy in patients with antiphospholipid syndrome, but their role in diabetic nephropathy is not elucidated. Therefore, we evaluated the association of aPL Abs with the renal impairment parameters in patients with diabetic nephropathy.
Concentrations of analyzed antibodies were measured by enzyme-linked immunosorbent assay.
Cystatin C and anticardiolipin (aCL) antibodies of the immunoglobulin (Ig) G (r = .349, P = .004) and the IgM isotype (r = .316, P = .009) were in positive correlation. The IgG isotype of the aCL Abs was in positive correlation with creatinine (r = .252, P = .038), urea (r = .241, P = .048), and uric acid (r = .271, P = .025). The concentrations of the IgG isotype of the aCL Abs were significantly different between subgroups of patients with diabetic polyneuropathy and patients without this clinical finding (Mann-Whitney, P = .033).
This is the first report on positive correlation between aCL Abs and renal impairment parameters. Larger studies are necessary for elucidation whether this association is involved in further progression of the disease.
In randomized controlled trials, non-vitamin K antagonist oral anticoagulants (NOACs) demonstrated noninferiority to vitamin K antagonists (VKAs) in patients who spent limited time in therapeutic range (TTR). In real-life patients, TTR is known to vary significantly across countries and health-care settings.
We aim to evaluate the quality of VKA treatment in Swiss primary care (PC) by comparing patients’ median TTR to levels achieved in the phase III NOAC trials RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48. Patient characteristics affecting TTR control shall be estimated.
This is a retrospective longitudinal study in Swiss PC patients receiving VKA for ≥6 months. We identified patients from the PC research database FIRE (Family medicine International Classification of Primary Care Research using Electronic medical records) and calculated TTR according to Rosendaal formula. Comparative data from NOAC trials were retrieved from medical literature. Linear regression models were used to assess predictors of TTR.
Primary care encounters of 215 patients were analyzed. Like in the NOAC trials, median observation period was 2.2 years, but patients were older (67.9% vs 38% ≥75 years) and differed in terms of concomitant diseases and drugs. Median TTR was 75% (65% in the NOAC trials). Female sex was independently associated with a lower TTR and significantly modified by increasing age.
Practitioners should consider that patients in NOAC trials are only partly representative of PC patients, particularly in terms of TTR control. Only a minority of the observed patients would require a therapy switch to NOACs due to inadequate TTR. Further research is needed in order to identify specific features of care management that are associated with these outcomes.
Glomerular filtration rate (GFR) and blood urea nitrogen (BUN) are important prognostic indicators for cardiovascular disease. However, data on the relationship between renal dysfunction (RD) and prognosis in patients with acute pulmonary embolism (APE) are limited. The estimated-GFR (eGFR), based on the Modification of Diet in Renal Disease (MDRD) equation, has been suggested as a possible prognostic marker in patients with APE; however, at present, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is thought to be more accurate than the MDRD equation for the estimation of RD.
We investigated whether eGFRCKD-EPI or BUN could predict adverse outcomes (AOs) better than eGFRMDRD in normotensive patients with APE.
Ninety-nine normotensive patients with APE (aged 22-96, 56% male) were enrolled in the study retrospectively. Adverse outcomes were defined as the occurrence of any of the following: death, cardiopulmonary resuscitation, use of vasopressors, thrombolysis, or mechanical ventilation.
In univariate analyses, age, gender (male), heart rate (>110 bpm), serum creatinine, BUN, cardiac troponin (cTn) positivity, right ventricle–left ventricle ratio, eGFRMDRD, and eGFRCKD-EPI were found to be significantly different between those with and without AOs. Comparing area under the curves for AO, we found statistically significant differences between eGFRCKD-EPI and eGFRMDRD (P = .01) but not between BUN and eGFRCKD-EPI or BUN and eGFRMDRD. Furthermore, 30-day mortality was 36% versus 11% in cTn-positive patients with an eGFRCKD-EPI < and ≥ 60 mL/min, respectively.
There is a close relationship between RD and APE prognosis. We conclude eGFRCKD-EPI is a potential prognostic marker for risk stratification in normotensive patients with APE.
Appropriate timing of bivalirudin discontinuation as a bridge to warfarin is complicated, as bivalirudin may cause a falsely prolonged international normalized ratio (INR). The purpose was to evaluate patient and medication characteristics associated with differences in INR prolongation caused by bivalirudin. Adult patients receiving bivalirudin as a bridge to warfarin in 2014 were retrospectively evaluated. Patients were excluded if they had known thrombophilia or inappropriate INR monitoring after discontinuation of bivalirudin. Data recorded included indication for bivalirudin use, bivalirudin dosing, and coagulation assays. Univariate analysis was performed to determine variables associated with a larger change in INR when discontinuing bivalirudin. Variables with P < .3 were included in multivariate analysis. In total, 50 patient admissions were included in the analysis. Patients with ventricular assist devices represented the majority of the patient population (74%). The most common INR goals were 2.0 to 3.0 and 2.5 to 3.5. The mean initial weight-based bivalirudin rate was 0.076 mg/kg/h, and the mean increase in INR when starting bivalirudin was 0.6. The mean final weight-based bivalirudin rate was 0.13 mg/kg/h, and the mean change in INR after stopping bivalirudin was 0.8. On multivariate analysis, factors associated with a larger change in INR after stopping bivalirudin included higher serum creatinine (P = .033), greater change in INR after initiation of bivalirudin (P = .028), and higher final bivalirudin rate (P < .001). The change in INR when starting or stopping bivalirudin appears to be patient specific and dose related. A nomogram was developed to predict the ideal timing of bivalirudin discontinuation. Prospective evaluation of the nomogram is under way.
Oral anticoagulants are essential drugs for the prevention of thromboembolic events in patients with atrial fibrillation (AF). Anticoagulants are, however, commonly withheld due to a perceived risk of severe adverse events. The underutilization of anticoagulants in patients with AF has been demonstrated internationally, but to date, there are limited data available in the Australian context. The aim of this study was to determine the utilization patterns of anticoagulants (including novel oral anticoagulants) with respect to stroke and bleeding risk among patients with AF within the community.
We performed a nonexperimental, retrospective analysis designed to evaluate antithrombotic usage for AF in Australia. The utilization of antithrombotic therapy and the appropriateness of therapy were determined based on CHADS2, CHA2DS2-VASc and HAS-BLED risk stratification schemes. D risk stratification schemes. The presence of documented contraindications was used to determine the appropriateness of antithrombotic therapy.
Anticoagulants were overutilized in patients at low risk of stroke and underutilized in patients at higher risk of stroke. As the HAS-BLED score increased, the likelihood of patients receiving an anticoagulant decreased regardless of CHADS2 or CHA2DS2-VASc scores.
Atrial fibrillation (AF) is a significant risk factor for stroke and peripheral thromboembolic events (TEs). Preventing blood clots in the heart to reduce stroke and TE risk is a key goal of AF therapy. Traditional stroke risk assessment tools for patients with nonvalvular AF include the CHADS2 and CHA(2)DS(2)-VASc scores, while long-term outcome data with the newer direct oral anticoagulants (DOACs) are emerging. The goals of this review were to assess traditional therapies and existing treatment guidelines and to discuss key pharmacologic properties of the DOACS, noting how these may benefit at-risk patients with AF. This narrative review was developed on the basis of the authors’ clinical knowledge, extensive reading of the literature, and broad pharmacy experience in the management of patients with AF. Limitations of oral vitamin K antagonists (VKAs) include slow onset of action, the need for regular monitoring of their anticoagulation effect, significant food and drug interactions, and unpredictable dose–response properties. Key clinical trial data led to the approvals of apixaban, dabigatran etexilate, edoxaban, and rivaroxaban in the United States to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF. With predictable pharmacologic properties and limited drug and/or dietary interactions, the DOACs offer several benefits over traditional oral anticoagulation therapy with VKA. However, they have limitations, including the absence of immediate reversal agents and limited options for monitoring their anticoagulation effects in clinical practice. As experience with the use of DOACs grows, optimized treatment regimens and improved patient care are expected.
The prompt assessment and the reversal of direct oral anticoagulants (DOACs) are urgent matters in the emergency care setting. Thus, we planned to elucidate the adequate prothrombin time (PT) test for the evaluation of the anticoagulant effects of various DOACs.
The anticoagulant effects of rivaroxaban, apixaban, and edoxaban were measured with 3 PT tests (Triniclot PT Excel S, Neoplastin R, and Thromborel S). Human plasma was spiked with each DOAC at a range of 0 to 1000 ng/mL, and the PT was measured using each PT test. In another series, the reversal effect of either 4-factor prothrombin complex concentrate (PCC) or activated PCC (aPCC) was evaluated with each PT test.
All PT reagents correlated with the concentrations of each DOAC, however, the reactivity was considerably different between the DOACs and the PT tests. A prolonged PT with DOACs was reversed both by PCC and aPCC in a dose-dependent manner; however, Triniclot PT Excel S showed reprolongation of the PT with a higher dose of PCC.
The proper choice of PT test is necessary for the assessments of the anticoagulant activity of DOACs. It is also important to understand the different characteristics of each PT test for the assessment of the reversal effects of PCC.
To investigate whether LEP G2548A and LEPR Q223R polymorphisms influence serum lipid levels and whether the 2 polymorphisms affect the efficacy of simvastatin treatment in Chinese patients with primary hyperlipidemia.
We used an extreme sampling approach by selecting 212 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n = 106 in each group of good or bad response) from a total of 734 samples with primary hyperlipidemia. They were treated with simvastatin orally 20 mg/d. Fasting serum lipids were measured at baseline and after 4 and 8 weeks of treatment. Genotyping was carried out using polymerase chain reaction-restriction fragment length polymorphism.
More patients in the good response group (27%) had LEPR Q223R than in the bad response group (16%, P = .046). Secondary stratified analyses showed that patients carrying the RR genotype of the LEPR Q223R gene had significantly higher high-density lipoprotein cholesterol levels than those with the QR genotype at baseline (P = .034) among good responders. After 29 consecutive days of treatment with simvastatin, patients carrying the RR genotype had a significantly larger decrease in triglycerides (change: –0.74 ± 0.92, P = .036) and total cholesterol levels (change: –1.77 ± 0.68, P = .023) compared with those carrying QR genotype among bad responders. After Bonferroni correction, the results were not statistically significant.
LEPR Q223R polymorphism, but not LEP G2548A, could modulate the efficacy of simvastatin in Chinese patients with primary hyperlipidemia.
Orosomucoid is an acute-phase serum protein that is upregulated in urine samples of patients with diabetic nephropathy. We assessed serum and urinary orosomucoid levels in children and adolescents with type 1 diabetes and their relation to microvascular complications and carotid intima–media thickness (CIMT). Sixty patients with type 1 diabetes were divided into 2 groups according to the presence of microvascular complications and compared with 60 healthy controls. High-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c (HbA1c), urinary albumin–creatinine ratio (UACR), serum and urinary orosomucoid, and CIMT were assessed. Both serum and urinary orosomucoid levels were significantly increased in patients with and without microvascular complications compared with controls, and the highest levels were in patients with complications (P < .001). Serum and urinary orosomucoid were higher in patients with microalbuminuria than normoalbuminuric group (P < .001). The cutoff value of urinary orosomucoid at 2825 ng/mL could differentiate patients with and without microvascular complications. Serum and urinary orosomucoid were positively correlated. Multiple regression analysis showed that HbA1c, UACR, hs-CRP, and CIMT were independently related to orosomucoid. We suggest that orosomucoid is a significant independent factor for diabetic microvascular complications and can be considered as an early marker of renal injury. High orosomucoid levels in type 1 diabetes reflect endothelial dysfunction and subclinical atherosclerosis.
Increased
The aim of this study is to evaluate quality of life (QOL) in patients with rare bleeding disorders (RBDs). In this cross-sectional study, 52 consecutive children aged between 4 and 18 years old with RBDs registered at the Haemophila Center of Fars province in Southern Iran were investigated from January to April 2015. Quality of life was evaluated using Haemo-QOL questionnaire. Final score is defined between 0 and 100, and higher score of QOL shows worse condition. P value less than .05 was considered statistically significant. Mean age of the patients was 13.96 ± 4.50 and ranged from 4 to 18 years old including 28 males and 24 females. Family and friends were the 2 most impaired domains of Haemo-QOL in these patients. In univariate analysis, bleeding severity based on bleeding score, health status, and being bothered by the disease showed statistically significant correlations with QOL of the patients (P < .05). In multiple linear regression models, only degree of being bothered by the disease was determined as an independent influencing factor on QOL. Taking together, Haemo-QOL of children with RBDs was better than what was reported in patients with hemophilia in our region, but it was worse than that reported in patients with hemophilia in other developing and developed countries. Due to chronic feature of bleeding disorders, more attention to different aspects of the disease, especially in 2 dimensions of family and friends through considering educational and psychological program for the patients and their family, are recommended to improve QOL of the patients with RBDs.
Plasma levels of estimated whole blood viscosity (eWBV) have been increased by endothelial inflammation. Because there were no consistent data for assessing the eWBV levels for prediction of cardiovascular event (CVE) in patients with chronic kidney disease (CKD). We aimed to investigate the relationship between plasma eWBV levels and CVEs in patients with CKD.
We conducted a prospective, cross-sectional, long-term follow-up study, assessing the relationship between plasma eWBV levels and CVE (either fatal or nonfatal) in patients with newly diagnosed CKD. We also evaluated estimated glomerular filtration rate (eGFR), pentraxin 3 (PTX3), high-sensitivity C-reactive protein (hsCRP), and flow-mediated dilatation (FMD).
Study patients were divided into 2 groups: patients with CVE and patients without CVE. The eWBV levels were higher in patients with CVE. Additionally, PTX3 and hsCRP were higher, and FMD and eGFR were lower in patients with CVE compared to those without CVE. According to the Cox regression analysis, WBV, plasma asymmetric dimethylarginine levels, FMD, hsCRP, eGFR, systolic blood pressure, calcium, and history of diabetes were independent predictors of CVEs in patients with CKD. Kaplan Meier survival curves were generated to establish the impact of the WBV on the cumulative survival of the cohort. Patients with eWBV values higher than 5.2 centipoise (cP) had lower survival rates when compared to patients with eWBV values lower than 5.2 cP (log rank = 4.49 df = 1 P = .034).
In conclusion, plasma eWBV levels may increase the presence of lower eGFR and affect CVE in patients with CKD independent of classical and unconventional risk factors.
The close relationship between inflammation and thrombosis affects the progression and severity of inflammatory bowel disease (IBD). The prevalence of venous thromboembolism (VTE) varies between 1% and 7% among patients with IBD. The VTE risk in patients with IBD is at least 3 times higher than that in the normal general population. The absolute risk is very high during hospitalization, active disease, and surgery. The IBD-related VTE occurs at younger ages and recurs more frequently. The development of thrombosis in IBD is due to the interaction of many hereditary and acquired risk factors. Each patient diagnosed with IBD should be evaluated for a personal and family history of thrombosis and for prothrombotic drug use. Although procoagulant factors are increased during the natural course of inflammation, natural anticoagulants and fibrinolytic activity are decreased. Although IBD is accepted as a prothrombotic condition, there is no treatment that can remove this risk from daily practice. Patient training is required to control important factors, such as long-term immobilization and smoking. Oral contraceptives and hormone replacement therapy should be avoided. Inducing permanent disease remission must be the key approach for the prevention of thrombosis. Low-molecular-weight heparin (LMWH) is the basis of prophylactic treatment, which reduces the thrombosis risk by 50%. Prophylaxis with LMWH should be administered to all patients with IBD hospitalized due to disease attack or surgery. Long-term or even life-long anticoagulation therapy should be planned if there is insufficient disease control, recurrent VTE attacks, positive thrombophilia tests, or thrombosis in vital veins.
Intravenous fluids with synthetic colloids such as hydroxyethyl starch (HES) are known to interfere with plasma fibrinogen concentration measurements. The aim of this study was to evaluate the effects of an HES solution on fibrinogen measurements in a clinical setting.
The study was performed in patients who received at least 1 L of HES during intracranial tumor resection surgery. Blood samples were drawn before the start of surgery (baseline), after infusion of 1 L of HES, and at later time points. The fibrinogen concentration was measured using 3 different methods: (a) enzyme-linked immunosorbent assay (ELISA), (b) Clauss method with a photometric readout, and (c) Clauss method with an electromechanical readout. In addition, the fibrin-based clot quality was evaluated with the thromboelastometric FIBTEM test.
Forty patients were enrolled, and 25 patients were included in the analysis. The fibrinogen concentrations at baseline were 2.2, 2.3, and 2.6 g/L and after 1 L of HES 1.6, 1.7, and 1.9 g/L as measured by ELISA, the photometric test, and the electromechanical test, respectively. The electromechanical Clauss test measured significantly higher concentrations at these time points. The relative decrease, however, was comparable between methods (31%, 29%, and 25%, respectively) but significantly lower than the 44% relative decrease with FIBTEM maximum clot firmness.
Despite providing different fibrinogen concentration values at baseline, the relative decrease in fibrinogen concentration after HES infusion was comparable among the 3 tests. In contrast, fibrin-based clot quality was more affected than fibrinogen concentration tests by HES infusion.
Venous thromboembolism (VTE) in adolescents is a serious condition that requires prompt recognition and optimal management to prevent mortality and long-term morbidity. Adolescents account for a large proportion of cases of VTE in children. As teenagers transition from childhood to adulthood, they are at risk of developing medical conditions and exposure to risky habits that predispose them to VTE. This review focuses on the variety of risk factors and comorbidities seen in adolescent VTE and takes a quick look into risk-based preventive strategies for primary and secondary prevention.
The goal of this study was to determine the levels of factor VII (FVII), factor VIIa–antithrombin complexes (FVIIa-AT), total tissue factor (TF), and tissue factor-bearing microparticles (MPs-TF) in patients with acute ischemic stroke. Further, we sought evidence of an association between hemostatic markers, time of blood sampling, type of treatment, and patient outcomes.
Venous blood samples were collected from 33 patients on the first day and on the seventh day after stroke diagnosis. Age-matched controls were also included (n = 20). Plasma levels of FVII, FVIIa-AT, total TF, and MPs-TF were measured by enzyme-linked immunosorbent assay. We divided patients into 2 groups: thrombolysis group (n = 13) and nonthrombolysis group (n = 20). Furthermore, evaluation of the National Institutes of Health Stroke Scale and the Barthel Index was performed on the first day and the seventh day.
Patients with ischemic stroke showed significantly lower plasma FVII, FVIIa-AT, and total TF levels than controls (median, 112.25% vs 132.05%, P = .004; 107.97 pmol/L vs 154.94 pmol/L, P < .001; 81.74 pg/mL vs 105.71 pg/mL, P < .001, respectively). In contrast, levels of plasma MPs-TF were significantly higher in patients with stroke compared to healthy controls (1.60 pg/mL vs 0.74 pg/mL, P < .001). Additionally, the thrombolysis group had lower FVII levels on the seventh day compared to the first day (median, 109.80% vs 115.74%, P = .04).
Factor VII, FVIIa-AT, and total TF are decreased, while MPs-TF are elevated in patients with ischemic stroke. We observed a slight but significant effect of alteplase on FVII plasma levels.
Clopidogrel is an antiplatelet drug widely used in patients with acute coronary syndromes or stroke. Despite adequate antiplatelet therapy, some patients develop acute ischemic events. This is partly attributed to the fact that they have poor inhibition of platelet reactivity, despite treatment. This study aimed to assess the impact of clinical and demographic variables and of cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms on platelet response to clopidogrel evaluated using impedance aggregometry in an East European population.
The study included 189 clopidogrel-treated patients with acute coronary syndromes and noncardiogenic ischemic stroke. Platelet aggregation was evaluated by impedance aggregometry. CYP2C19 loss-of-function polymorphisms were detected using the polymerase chain reaction restriction fragment length polymorphism technique. Various clinical and demographic data were also recorded.
In our data set, 81% of the patients were responders and 19% nonresponders to clopidogrel therapy. The distribution of CYP2C19 polymorphisms was as follows: 61.1% of patients were CYP2C19 wild-type homozygotes, 27.7% of patients were CYP2C19*2 heterozygotes, 1.1% of patients were CYP2C19*3 heterozygotes, and 10% of patients were CYP2C19*2 homozygotes. The highest level of association with clopidogrel response status was found for CYP2C19 polymorphisms, concomitant aspirin treatment, leukocyte and platelet count, history of myocardial infarction, arterial hypertension, and ward where patients were admitted.
The prevalence of clopidogrel resistance in our East European population was in line with that reported for Western populations. Clopidogrel response was significantly influenced by the presence of CYP2C19 polymorphisms. Interestingly, the concomitant use of aspirin had a significant impact on platelet response to clopidogrel, indicating a synergic interaction between these drugs.
Relation of plasma fibrinogen levels with extent, severity, and complexity of coronary artery disease (CAD) in patients with stable angina pectoris (SAP) has not been adequately investigated. The aim of this study was to evaluate whether plasma fibrinogen level is associated with coronary complexity, severity, and extent assessed by SYNTAX (Synergy between percutaneous coronary intervention with TAXUS and Cardiac Surgery) score (SS).
We enrolled 134 consecutive patients with SAP who underwent coronary angiography. Baseline serum fibrinogen levels were measured, and SS was calculated from the study population. The patients were classified into 3 groups by tertiles of SS (SS, control group = 0; intermediate group < 22; and high group ≥ 22).
Plasma fibrinogen levels demonstrated a stepwise increase from control group to high SS group. There was a strong correlation between fibrinogen and the SS (r = .535, P < .001). Area under the receivers operating characteristic curve of fibrinogen was 0.72 (95% confidence interval [CI] 0.61-0.82; < .001) for predicting a high SS. Fibrinogen value higher than 411 mg/dL has a sensitivity of 75% and a specificity of 64% in prediction of high SS. In multivariate analyses, plasma fibrinogen was observed to be an independent predictor for high SS in patients with stable CAD (odds ratio [OR] 1.01; 95% CI, 1.01-1.02; P < .001).
Plasma fibrinogen is a readily measurable systemic inflammatory marker and is independently associated coronary severity and complexity in patients with CAD.
Apolipoprotein E (APOE) is a member of the apolipoprotein gene family. APOE is polymorphic with 3 main allelic types: 2, 3, and 4. Certain of these alleles have been associated with higher vascular risk. However, the association of APOE genotypes with retinal biomarkers and risk of retinal stroke is less clear. This study evaluated the role of APOE polymorphisms in retinal vein occlusion (RVO). In the present study, 2-point mutations coding amino acid residues 112 and 158 were amplified using the polymerase chain reaction (PCR) from DNA extracted from Tunisian participants. APOE genotypes were determined by multiplex PCR followed by molecular hybridization. Eighty-eight patients (26 women and 62 men) and 100 age- and gender-matched healthy participants were enrolled. The statistical study revealed a higher frequency of the 4 allele in patients as compared to controls (27.3% vs 9%) with a significant association of the 4 allele with the disease (P < 10–3, P a < 10–3, odds ratio [OR] = 3.8, 95% confidence interval [CI] = 2.1-6.8). The frequency of the 3 allele was significantly lower in the patients with RVO compared to the controls (60.2% vs 82.5%, respectively; P < 10–3, P a < 10–3, OR = 0.32, 95% CI = 0.19-0.53). The 3 allele seems to be protective against the disease. There was no association between the APO 2 allele and RVO. The association of APOE allele and genotype with RVO requires further investigation in different populations.
Distal deep venous thrombosis (DVT) accounts for approximately half of all the cases of lower limb thrombosis. The impact and management of this condition is still controversial. This study aims to evaluate the incidence of pulmonary embolism (PE) in patients with distal DVT in comparison to proximal DVT and evaluate the correlation between DVT and PE extension.
100 patients with acute lower limb DVT diagnosed with whole leg Doppler ultrasound from January 2006 to December 2014 were retrospectively analyzed. Active investigation for PE was carried out in all patients using multislice computed tomography angiography. Classification of DVT and PE was based on the proximal extension of the thrombus.
The overall incidence of PE in our sample patients was 72%. In the subgroup analysis, incidence of PE was equal in both the proximal and distal DVT groups (77%, p > 0.99). PE was detected in 43% of the patients with isolated calf vein thrombosis (ICVT). No statistical difference was observed between the distribution of lobar, segmental and subsegmental PE in the 3 DVT subgroups (p = 0.665); however, truncular PE was only observed in the proximal DVT group.
Distal DVT is associated with a high incidence of PE compared to proximal DVT. Distal DVT and ICVT can provoke PE with involvement of proximal vessels in the pulmonary arterial tree, even in asymptomatic patients. Our study arises discussion in the controversial debate regarding the need for routine anticoagulation in distal DVT.
CHA2DS2-VASc score has been validated in risk prediction for stroke and thromboembolism in patients with atrial fibrillation (AF). Association of CHA2DS2-VASc score with higher risk of venous thromboembolism and pulmonary embolism (PE) has also been shown. In this study, we investigated the long-term prognostic value of CHA2DS2-VASc score in patients with acute pulmonary embolism (APE).
Consecutive patients with APE presenting to our emergency department were retrospectively recruited. Patients with AF and who died secondary to causes other than PE were excluded from the study. The CHA2DS2-VASc score and pulmonary embolism severity index (PESI) were calculated.
Two hundred seventy seven participants were included in the study. The mortality rate was 18.7%. Twenty-two cases died within 30 days, and 30 cases died during the follow-up period (median: 13 months). The mean CHA2DS2-VASc score was significantly higher in dead patients compared to survivors (3.61 ± 1.35 vs 1.95 ± 1.52, P < .01). In multivariate regression analysis, systolic pulmonary artery pressure (hazard ratio [HR]: 1.03, 95% confidence interval [CI]: 1.01-1.06, P = .02), PESI score (HR: 1.010, 95% CI: 1.004-1.017, P < .01), and CHA2DS2-VASc score (HR: 1.67, 95% CI: 1.19-2.16, P < .01) were found to be independently correlated with mortality. The patients whose CHA2DS2-VASc score was between 1 and 3 had 5.67 times and patients whose CHA2DS2-VASc score was ≥4 had 16.8 times higher risk of mortality compared to patients with CHA2DS2-VASc score = 0.
Patients with higher CHA2DS2-VASc scores had higher rates of mortality after APE.
In-stent restenosis (ISR) is a common clinical problem in patients with coronary artery disease treated with percutaneous coronary intervention. Inflammatory process plays a pivotal role in the development of ISR. Both lymphocytes and monocytes are associated with inflammatory status. Recently, it has been shown that the lymphocyte-to-monocyte ratio (LMR) is a novel inflammatory marker. We aimed to investigate the association of serum LMR levels and ISR in patients undergoing bare-metal stent (BMS) implantation. The study included 273 patients (aged 61 ± 11 years, 66.5% men) with a history of BMS implantation and a further control coronary angiography due to stable angina pectoris. Patients were divided into 2 groups: patients with and without ISR. The LMR levels were significantly lower in patients with ISR than in those without ISR (2.50 ± 0.95 vs 3.87 ± 1.51, respectively, P < .001). On multivariate logistic regression analysis, the LMR was independently associated with ISR (odds ratio [OR]: 0.310, 95% confidence interval: 0.166-0.579, P < .001) together with high-sensitivity C-reactive protein (OR: 1.244, P = .008), reason for stent implantation (OR: 6.566, P = .003), stent diameter (OR: 0.015, P < .001), and stent length (OR: 1.137, P = .007). In conclusion, LMR levels are inversely related to ISR in patients treated with BMS implantation.
Active cancer is a poor prognostic factor for survival after pulmonary embolism (PE). This retrospective cohort study was performed to investigate how accurately the pulmonary embolism severity index (PESI) predicts 30-day mortality in patients with active cancer. Whether the treatment setting (palliative vs curative) could predict mortality in these patients was also investigated.
All consecutive patients with active cancer and PE who visited the emergency department of Asan Medical Center in January 2007 to June 2014 were identified. The covariates for predicting 30-day mortality were PESI classification, treatment setting (curative vs palliative), brain natriuretic peptide ≥ 150 ng/L, troponin I ≥ 0.10 ng/mL, right ventricular dysfunction, deep vein thrombosis, and anticoagulants used. Cox proportional hazards regression analysis was used to assess the association between treatment setting and 30-day mortality.
The PESI classification and 30-day mortality did not associate significantly. Area under the receiver–operating curve of the PESI was 0.565 (95% confidence interval [CI]: 0.453-0.677). Palliative treatment setting associated with an increased risk of 30-day mortality, regardless of the PESI classification (adjusted hazard ratio: 3.72, 95% CI: 1.49-9.26). Treatment setting predicted mortality 30 days, 3 months, and 6 months after PE presentation better than PESI.
The PESI did not accurately predict mortality in patients with active cancer. Treatment setting was the most important determinant of clinical outcome in these patients. When stratifying patients with active cancer and PE, palliative treatment setting should be considered as it is predictive of high mortality.
Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.
The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L x min) than in either myeloma (866.2 ± 241.3 nmol/L x min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L x min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.
To evaluate the contribution of rs5918ITGB3 on the incidence and recurrence of deep venous thrombosis (DVT) in women and the relationship with body mass index (BMI) and smoking and to compare with data in men.
Rs5918(C) polymorphism in ITGB3 gene was assessed in 224 patients diagnosed with DVT and 216 controls. Thrombophilic genetic variant rs5918(C) was significantly pronounced in women (2 =7.565, P = .008) and total patients (2 = 9.266, P = .002) but not in men. Women patients (<45 years) who were carriers of rs5918ITGB3 polymorphism had an early onset of DVT (34.5 vs 39.4 years, 2 = 7.027, P = .008) as analyzed by Kaplan-Meier and a higher risk of the recurrent event (2 = 3.405, odds ratio = 2.581, P = .044). The period before recurrent venous thromboembolism event was related to smoking status and BMI in young female who were carriers of rs5918 polymorphism but not in the males.
Carriage of genetic variant rs5918(C) polymorphism in ITGB3 gene in women contributes to higher risk of single and recurrent DVT events at younger age.
Oral anticoagulation therapy with vitamin K antagonists (VKA) such as warfarin and acenocoumarol is recommended in patients with atrial fibrillation (AF) and risk factors for embolism. The quality of anticoagulation control with VKA may be assessed by the time in therapeutic range (TTR). In our country, there are no data available about the quality of anticoagulation in patients with AF. The primary goal of our study was to assess the level of effective anticoagulation in a multicenter network of anticoagulation clinics in Argentina, which included patients with nonvalvular AF (NVAF) treated with VKA oral anticoagulants.
The TERRA trial is a multicenter, cross-sectional study involving 14 anticoagulation clinics that were invited to participate and recruit 100 consecutive patients with NVAF treated with VKA for more than 1 year. The international normalized ratio (INR) values were retrospectively obtained from patient charts, and TTR was calculated using the Rosendaal method.
A total of 1190 patients were included in the analysis. Mean age was 74.9 ± 9.9 years, and 52.5% of the patients were male. Median TTR was 67.5% (interquartile interval 54-80). During 55% of the TTR, INR was >3. Interinstitution variability was substantial, with a range of 57.7% ± 17% to 87.7% ± 17%, P < .001. The 10th percentile of TTR was 41%, the 20th percentile was 50%, the 30th was 58%, and the 35th percentile was 60%. In 40% of patients, TTR was <70%.
In this multicenter study, mean TTR values in patients with AF under VKA were similar to those in international therapeutic clinical trials (55%-65%). Marked variations among institutions were observed and, although average results obtained were high, one third of the patients exhibited a TTR below 60%. This cutoff value is conservative according to current recommendations, and guidelines suggest that when management with VKA cannot be improved, patients should be switched to direct oral anticoagulants. The addition of TTR calculation to clinical practice may help improve the quality of oral anticoagulation in patients with AF, thus improving anticoagulation outcomes.
Transfusion of blood products occurs frequently in ruptured abdominal aortic aneurysm surgery (rAAA). The aim of this study is to establish the impact of packed red blood cell (PRBC), fresh frozen plasma (FFP), and platelet (PLT) transfusion on the 30-day mortality and morbidity (thrombotic versus non thrombotic complications) of rAAAs.
A retrospective study of 90 consecutive rAAAs from November 2007 to June 2015 was conducted. Multivariable regression models were produced to determine blood products associated with 30-day morbidity and mortality post-rAAA.
The overall mortality was 14.6%. At multivariable analyses, transfusion with FFP (>3 units) was independently associated with an increased risk of mortality (odds ratio [OR]: 11.27, 95% confidence interval [CI]: 1.13-96.72, P = .027). The overall morbidity was 26.8%, and subgroup analysis (thrombotic vs nonthrombotic complications) demonstrated transfusion of PLTs (>1 pool) to be independently associated with thrombotic events (OR: 4.3, 95% CI: 1.37-13.6, P = .012). Thrombotic events were responsible for 50% (n = 11 of 22) of all morbidities and mortalities (n = 6 of 12).
Transfusion of FFP and PLTs may be associated with an increased risk of postoperative morbidity and mortality. The use of these blood components should be considered in the context of the patient’s clinical and laboratory data as opposed to a fixed ratio to PRBCs. This may result in the reduction in thrombotic complications emerging in rAAA cohort.
The soluble form of CD40L (sCD40L) is a platelet-derived mediator that links inflammation, hemostasis, and vascular dysfunction. Indeed, blockade of CD40L by neutralizing antibodies or genetic disruption in mice prevents atherosclerosis and atherothrombosis. Until recently, it was believed that CD40 and αIIbβ3 were the only receptors on platelets responsible for binding sCD40L, leading to platelet activation and initiation of thrombotic events. Recent findings showed α5β1 integrin as a novel platelet sCD40L receptor, with an unknown function. For the first time, using anti-α5β1 blocking antibodies, we show that sCD40L/α5β1 interaction leads to platelet activation as evaluated in the human whole blood. Establishing α5β1 integrin’s role in platelet activation, and therefore thrombosis will help further shed light on the etiology of thrombotic disease.
Limited data are available on atrial fibrillation (AF) and its clinical management and outcomes from an Australian perspective. This study was designed to examine the patient characteristics and antithrombotic treatment patterns among patients with AF in Tasmania, Australia. This retrospective observational study reviewed and followed patients with AF admitted to Tasmania’s 3 major hospitals between January 2011 and June 2012. Patients were excluded if they had only 1 episode of AF that reverted spontaneously or upon cardioversion without any documented recurrences. We reviewed the records of 2502 patients (≥18 years), and1469 were subsequently included in the study. The mean (±standard deviation [SD]) age of the patients was 76 (±12.3) years. The mean (± SD) CHADS2 score was 2.1 (±1.3), and 65.7% had a score ≥2. In total, only 55.6% of patients with CHADS2 score ≥2 were receiving anticoagulation and 9.9% were not receiving any antithrombotic treatment, whereas 85.4% of those at low risk (score 0) were on antithrombotic therapy. Hospitalization was associated with a significant increase in the rate of combination (antiplatelet plus anticoagulant) therapy (P < .001). Suboptimal use of antithrombotic therapy highlights the need to improve AF management in our jurisdiction.
Phenotypic resistance to activated protein C (APC) is a complex mechanism associated with increased thrombosis risk. Activated protein C resistance (APCR) is mainly influenced by FVLeiden mutation, and various other single nucleotide polymorphisms (SNPs) in FV gene are known to be associated with APCR. The aim of present study was to investigate the incidence and assess possible mechanisms of APCR in Indian patients with deep vein thrombosis (DVT). Three hundred and ten Doppler-proven patients with DVT were screened for APCR, and 50 APCR positive patients and 50 controls were typed for FVLeiden, Hong Kong, Cambridge, HR2 haplotype, Glu666Asp, Ala485Lys, and Liverpool using either polymerase chain reaction (PCR)–restriction fragment length polymorphism or allele specific PCR. FVLeiden was commonest cause of APCR (50%) in Indian patients with DVT being statistically significant (P = .001) compared to controls. FV Liverpool, FV Glu666Asp and FV Ala485Lys were studied for the first time in Indian population. FV Liverpool, FV Glu666Asp, Hong Kong, and Cambridge were found to be absent. High frequency of Ala485Lys in patients shows that it might be a risk factor contributing to APCR in Indian patients with DVT. HR2 haplotype was not associated with APCR; however, presence of homozygous HR2 haplotype in patients only indicates the role it might play in Indian APCR population. In conclusion, contribution of FVLeiden causing APCR in Indian population is not as strong as previously reported in Western countries. The presence of other SNPs observed in the present study requires such studies on larger sample size to understand the molecular basis of defect.
This study assessed the long-term benefits and side effects of low-to-medium dose of danazol therapy in primary immune thrombocytopenia (ITP).
The retrospective analysis included 319 patients with ITP who accepted danazol therapy. Patients accepted danazol alone or in combination with glucocorticoids. Clinical outcome and tolerance were assessed in all patients.
Among patients with persistent or chronic ITP, the overall response rate of danazol therapy was 65.0%. Sixty-five (63.1%) of the 103 patients reached remission with danazol alone, and 93 (48.7%) of the 191 patients who accepted combination therapies acquired remission and discontinued glucocorticoids successfully. Age and previous treatments were 2 risk factors for response rate. In newly diagnosed patients with ITP, the response rate and median response time did not differ significantly with or without danazol. However, the relapse rate was significantly lower in patients administered danazol combined with glucocorticoids than those accepted glucocorticoids alone. Totally, 21.1% of the patients experienced mild or moderate side effects, and 1.2% of the patients discontinued treatment due to intolerable side effects.
Low-to-medium dosage of danazol is better tolerated and effective in patients with ITP, even in those refractory to other treatments. Combination of danazol and glucocorticoids for initial treatment may decrease relapse rates to achieve well-tolerated long-term remission.
Many risk factors may contribute to renal disease in patients with hemophilia A.
We aimed to evaluate functional and structural renal abnormalities among a group of Egyptian children with severe and moderate hemophilia A using technetium-99m diethylene triamine pentaacetic acid (99mTc-DTPA) and technetium-99 m dimercaptusuccinic acid (99mTc-DMSA) scan. We also aimed to determine the relation between these abnormalities and different risk factors and disease severity.
Forty male patients, 16 with severe and 24 with moderate hemophilia A, were enrolled in this study. Their mean age was 10.2 ± 4.3 years (range, 5-17 years). Full history taking, clinical examination, laboratory, and radionuclide investigations including serum creatinine, blood urea nitrogen (BUN), urine analysis, creatinine clearance, 24-hour urinary protein, 99mTc-DTPA scan, and 99mTc-DMSA scan were performed to all enrolled patients.
Serum creatinine and BUN were normal in all patients, and corrected creatinine clearance was diminished in 2 patients. However, 99mTc-DTPA results yielded 19 (47.5%) patients with diminished glomerular filtration rate (GFR). Moreover, it showed that 14 (35%) had obstructive uropathy, 15 (37.5%) had obstructive nephropathy, while 11 (27.5%) patients showed normal scan. One patient had atrophy of 1 kidney on 99mTc-DMSA scan. Among our cohort, 5 (12.5%) patients were hypertensive. Microscopic hematuria was detected in 14 (35%) patients while 72.5% had proteinuria. We found an association between hematuria and hypertension with diminished GFR.
Despite normal kidney functions (serum creatinine and BUN), we found a high rate of diminished GFR and obstructive uropathy and nephropathy as detected by 99mTc-DTPA scan among children with hemophilia A.
We compared thrombophilia in 67 cases (59 men and 8 women) with thrombotic events after starting testosterone therapy (TT) versus 111 patient controls having unprovoked venous thrombotic events without TT. In the 67 patients, thrombosis (47 deep venous thrombosis–pulmonary embolism, 16 osteonecrosis, and 4 ocular thrombosis) occurred 6 months (median) after starting TT. Cases differed from controls for factor V Leiden heterozygosity (16 of the 67 [24%] vs 13 [12%] of the 111, P = .038) and for lupus anticoagulant (9 [14%] of the 64 vs 4 [4%] of the 106, P = .019). After a first thrombotic event and continuing TT, 11 cases had a second thrombotic event, despite adequate anticoagulation, 6 of whom, still anticoagulated, had a third thrombosis. Screening for thrombophilia before starting TT should identify men and women at high risk for thrombotic events with an adverse risk–benefit ratio for TT. When TT is given to patients with familial and acquired thrombophilia, thrombosis may occur and recur in thrombophilic men despite anticoagulation.
Four direct oral anticoagulants (DOACs) have been licensed for the treatment of atrial fibrillation (AF); efficacy and safety have been shown in clinical trials, but its real use in elderly and very elderly people is still unclear.
To evaluate the impact of DOACs in our patients (pts) aged ≥75 years and switched from other treatments.
From September 2013 to May 2015, all consecutive pts aged ≥75 years, males and females, in treatment for AF and switched to DOACs are considered in this study. Follow-up (FU) was scheduled after 3 and 6 months by phone and after 12 months by visit.
Two hundred thirty-two pts in treatment for AF were switched to DOACs, among these 143 (61.6%) pts aged ≥75 years (mean age, 81 years). The medium FU was 9.6 months, during which 4 minor bleedings in 4 different pts and 1 clinically relevant nonmajor bleeding were reported, all treated with temporary cessation or reduction in DOACs. Two strokes occurred in pts in treatment with dabigatran 110 mg, both resolved without serious sequelae; 2.8% of pts had nausea, itching, vomiting, or discomfort, half of these returned to acenocumarol, and the remaining switched to other DOAC. Four pts died, but the deaths were not related to anticoagulation.
As reported for general people, also in our elderly population, DOACs resulted in a good alternative to old antithrombotic therapies. Efficacy and safety associated with a higher compliance by pts bring these drugs to be the first choice for long-term anticoagulation.
Interleukin 17F (IL-17F) is an inflammatory cytokine that plays an important role in autoimmune disease by inducing the expression of multiple chemokines, cytokines, and adhesion molecules. In vitro functional analysis revealed that IL-17F rs763780 polymorphism is associated with IL-17 expression and activity. Thus, considering the abnormal percentage of T helper 17 cells in patients with primary immune thrombocytopenia (ITP), we speculated there was a possible association between the IL-17F rs763780 polymorphisms and genetic susceptibility to ITP in a Chinese Han population. A total of 165 patients with ITP and 149 healthy controls were included in this study, and IL-17F rs763780 polymorphisms were analyzed by a polymerase chain reaction–restriction fragment length polymorphism system. The results showed that the frequency of the IL-17F rs763780 G allele in total patients with ITP or patients with chronic ITP was significantly lower than in normal controls (total ITP 3.6% vs controls 7.7%, P = .026; chronic ITP 3.5% vs controls 7.7%, P = .031). However, no significant difference in genotype frequencies was found among total patients with ITP, patients with chronic ITP, and normal controls. We further analyzed the association of IL-17F polymorphisms with clinical parameters of patients with ITP, and no association revealed between gene distribution and first onset age, clinical therapy response to glucocorticoids, or disease course. What’s more, an evident discrepancy with allelic frequencies was observed between female patients with ITP and gender-matched controls. In conclusion, IL-17F rs763780 polymorphisms may be associated with the development of ITP in a Chinese Han population.
The aim of this study was to investigate the relationship between endocan levels with the presence of slow coronary flow (SCF).
In this cross-sectional study, a total of 88 patients, who admitted to our hospital, were included in this study. Of these, 53 patients with SCF and 35 patients with normal coronary flow were included in the final analysis. Coronary flow rates of all patients were determined by the Timi Frame Count (TFC) method.
In correlation analysis, endocan levels revealed a significantly positive correlation with high sensitive C-reactive protein and corrected TFC. In multivariate logistic regression analysis, the endocan levels were found as independently associated with the presence of SCF. Finally, using a cutoff level of 2.3, endocan level predicted the presence of SCF with a sensitivity of 77.2% and specificity of 75.2%.
In conclusion, our study showed that higher endocan levels were significantly and independently related to the presence of SCF.
Sheikh Khalifa Medical City’s (SKMC) surgery institute was identified as a high outlier in the incidence of venous thromboembolism (VTE; deep vein thrombosis [DVT] and pulmonary embolism [PE]) based on the semiannual report of the American College of Surgeon’s National Surgical Quality Improvement Program (ACS NSQIP) in June 2010.
To report our rates of VTE at SKMC, the results, and 5-year follow-up after an ACS NSQIP quality improvement program.
A multidisciplinary VTE task force was established in June 2010. We instituted a compulsory risk assessment for VTE and utilized the ACS NSQIP best practice guidelines to review cases of VTE. We prospectively evaluated the observed/expected (O/E) ratio for DVT/PE after implementing the action plan.
The O/E ratio for PE/DVT in general and general/vascular (GV) surgery was 6.00 and 4.86 in June 2010. Our compliance with ordering antithrombotic prophylactic measures was as low and it improved to 100% and our O/E ratio decreased to 1.18 and 1.5 in July 2011 and stabilized for the next 4 years. Currently, our compliance with ordering antithrombotic prophylactic measures is 100%, and our last 2 O/E ratio for DVT/PE are 0.74 and 0.75 in GV surgery and 0.82 and 0.78 in the entire surgery institute, respectively, and we are considered an exemplary site of the ACS NSQIP in GV surgery.
A compulsory risk assessment for VTE has led to an overall improvement in DVT/PE rates in the surgery institute and for GV surgery to become an exemplary site for the ACS NSQIP.
Many genetic risk factors have been identified for causing venous thromboembolism (VTE). Most of them affect the function of natural anticoagulant pathways, particularly the protein C system, although recent studies suggest a role of components of the hematopoietic pathway in the etiology of venous thrombosis. In this case–control study, we aimed to determine the frequency of prothrombin G20210A and factor V Leiden (FVL) G1691A polymorphisms and protein C, protein S, and antithrombin III deficiencies in the East Algerian population and to investigate whether these genetic factors are associated with VTE. On the other hand, our study tends to evaluate the status of JAK2V617F and calreticulin (CALR) mutations among these cases. The participants consisted of 121 cases with VTE and 146 healthy controls. Polymorphisms of FVL G1691A and prothrombin G20210A were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. JAK2-V617F and calreticulin mutations were analyzed by quantitative PCR and PCR followed by capillary electrophoresis sequencing, respectively. Protein C, protein S, and antithrombin levels were determined and then hereditary deficiencies were identified. Of all cases and controls, none was a carrier of the antithrombin III deficiency, prothrombin gene G20210A, and CALR mutations. Only 1 case reported having a positive JAK2 mutation (mutant allele burden was 15%). The FVL mutation (GA/AA) was found in 14 (11.6%) cases and 2 (1.4%) controls and it was significantly different between both the groups (P = .001). Deficiencies of protein S and protein C were detected in 17 (18.8%) cases. The univariate analysis resulted in a significant impact of FVL (odds ratio [OR] = 9.4, 95% confidence interval [CI] = 2.1-42.3; P = .003) and of protein S deficiency (OR = 16.9, 95% CI =2.1-132.8, P = .007) on the VTE status. Both factors stayed significant after adjustment for sex and age. The OR of the protein C deficiency was slightly elevated (OR = 6.4, 95% CI = 0.7-55.5), but it did not reach the level of statistical significance (P = .091), and it was therefore not considered as a risk factor. In conclusion, coagulant factor V gene G1691A mutation and protein S deficiency constitute important genetic risk factors in patients with VTE in Eastern Algeria. The somatic mutation of JAK2 V617F and CALR mutations are less frequent causes of VTE, thus routine testing for these mutations is not recommended.
Disseminated intravascular coagulation (DIC) is a thrombohemorrhagic disorder characterized by hyperactivation of coagulation and secondary fibrinolysis.
The primary aim of this prospective study was to evaluate and compare the diagnostic performance of fibrin monomer (FM) and
The patients were categorized into 3 groups: overt DIC, nonovert DIC, and non-DIC based on the International Society of Thrombosis and Hemostasis scoring for overt DIC and the modified nonovert-DIC criteria. Coagulation tests were performed on freshly obtained plasma. Quantitative determination of FM and DD was done by immunoturbidimetric assay.
Median DD and FM levels in patients with overt DIC were significantly higher in comparison to the other 2 groups. Interestingly, unlike DD, the difference in FM levels was also found to be statistically significant between patients with nonovert DIC and non-DIC patients (P = .0001). At receiver–operator characteristic curve-generated cutoff values, FM had higher specificity and negative predictive value than DD for predicting onset of overt DIC. Multivariate analysis showed that only FM was as an independent predictive factor useful in differentiating patients with overt DIC from non-DIC patients (odds ratio [OR]: 43.3; confidence interval [CI] 4.61-406.68; P value = .001) as well as in distinguishing nonovert DIC from non-DIC patients (OR:18.3; CI 3.45-97.19; P value = .001).
Fibrin monomer is a better indicator than DD in distinguishing patients with overt and nonovert DIC from non-DIC patients, raising the possibility for its diagnostic utility as a marker for impending overt DIC, aiding in early diagnosis and prompt therapeutic intervention.
We aimed to examine the cross-sectional associations of plasma total homocysteine (tHcy) concentrations and methylenetetrahydrofolate reductase (MTHFR) C677T genotype with dyslipidemia. A total of 231 patients with mild-to-moderate essential hypertension were enrolled from the Huoqiu and Yuexi communities in Anhui Province, China. Plasma tHcy levels were measured by high-performance liquid chromatography. Genotyping was performed by TaqMan allelic discrimination technique. Compared with MTHFR 677 CC + CT genotype carriers, TT genotype carriers had higher odds of hypercholesterolemia (adjusted odds ratio [OR] [95% confidence interval (CI)]: 2.7 [1.4-5.2]; P = .004) and higher odds of abnormal low-density lipoprotein cholesterol (adjusted OR [95% CI]: 2.3 [1.1-4.8]; P = .030). The individuals with the TT genotype had higher concentrations of log(tHcy) than those with the 677 CC + CT genotype (adjusted β [standard error]: .2 [0.03]; P < .001). Patients with tHcy ≥ 10 μmol/L had significantly higher odds of hypercholesterolemia (adjusted OR [95% CI]: 2.4 [1.2-4.7]; P = .010). Furthermore, patients with both the TT genotype and the tHcy ≥ 10 μmol/L had the highest odds of hypercholesterolemia (adjusted OR [95% CI]: 4.1 [1.8-9.4]; P = .001) and low-density lipoprotein cholesterol (adjusted OR [95% CI]: 2.4 [1.0-6.0]; P = .064). This study suggests that both tHcy and the MTHFR C677T gene polymorphism may be important determinants of the incidence of dyslipidemia in Chinese patients with essential hypertension. Further studies are needed to confirm the role of tHcy and the MTHFR C677T mutation in the development of dyslipidemia in a larger sample.
Heart failure (HF) is the leading cause of in-hospital morbidity and mortality in the elderly population. Coexistence of HF and atrial fibrillation (AF) increases the risk of thromboembolic events. Oral anticoagulant therapy reduces the risk of thromboembolic events in patients with AF. Novel oral anticoagulants (NOACs) have been introduced as an alternative drug for prevention from thromboembolic events in patients with nonvalvular AF. The primary aim of this study is to investigate the clinical effects of warfarin, dabigatran, and rivaroxaban in patients with nonvalvular AF. The secondary aim of this study is to reveal the predictors of all-cause mortality in patients with nonvalvular AF undergoing NOACs therapy. The study population consisted of 171 patients with nonvalvular AF. Patients were divided into 3 groups according to the usage of oral anticoagulant therapy including coumadin (51 patients), dabigatran (52 patients), and rivaroxaban (68 patients). Although CHA2DS2-VASc score was similar between groups, HAS-BLED score was significantly higher in patients using rivaroxaban. Dyspepsia and itching were more common in patients using dabigatran. Heart failure and vascular disease were more common in the nonsurviving group (10 patients) than in the surviving group (110 patients) in patients using NOACs. Among age, sex, HF, hypertension, vascular disease, and CHA2DS2-VASc, which were included in the regression model, only the presence of HF was an independent predictor of all-cause mortality in patients using NOACs. In conclusion, the mortality rate is significantly higher in patients with HF using NOACs. Moreover, HF is an independent predictor of all-cause mortality in patients using NOACs.
The role of anticoagulants in the prevention of pregnancy complications, including recurrent miscarriage, late fetal loss, and preeclampsia, continues to be an area of active research and debate. Although prophylactic anticoagulation with heparin and aspirin is considered the standard of care in some conditions, such as obstetric antiphospholipid antibody syndrome, the optimal management of pregnant women with factor V Leiden mutation, prothrombin G20210A mutation, and other inherited thrombophilias without a history of thrombosis remains unknown. Some studies suggest a benefit of heparins in preventing late-term losses but not earlier miscarriages in the inherited thrombophilias. In the following review, we will discuss the recent literature regarding anticoagulation and pregnancy complications and conclude with our suggested approach to the management of these challenging patients.
There are conflicting reports about the protective effect of hemophilia on the occurrence of ischemic heart disease. This study focuses on evaluation of heart function in patients with hemophilia. Cross-sectional, case–control study was done on all patients with hemophilia A or B who came to hemophilia center, and data were compared to controls. The data were collected from their charts, and heart function was evaluated by 2-dimensional, Doppler and pulse tissue Doppler. The serum troponin I level was measured in all patients as a marker of myocardial damage. Fifty patients with hemophilia took part in this study. All of them were male with mean age 29.1 years. Systolic blood pressure (mean = 121.52 ± 11 vs 115.61 ± 9.81, P = .038) and diastolic (mean = 81.94 ± 4.51 vs 75.21 ± 3.95, P = .042) blood pressure were higher in the patients. Five (10%) patients had systolic hypertension and 7 (14%) patients had diastolic hypertension. The M-mode echocardiography results showed that interventricular septum in diastole in patients with hemophilia (mean 1.143 ± 0.29) was significantly thicker than the control group (mean 0.828 ± 0.22, P < .001). Tissue Doppler echocardiography showed that late diastolic velocity of septum (Aa; P = .030), systolic velocity (S) of lateral mitral valve (P = .006), late diastolic velocity of lateral mitral (Aa) annulus (P = .038), and late velocity of (Aa) tricuspid (P = .004) had significant difference compared with the control group (P < .05). Troponin enzyme level was < 0.1 in all patients. Patients with hemophilia had higher blood pressure and more hypertension. Echocardiographic study of patients with hemophilia showed some increase in septal thickness and changes in diastolic dysfunction
Inappropriate use of oral anticoagulants (OACs) have not been well investigatedand, however, may be frequent in real-world practice in patients with nonvalvular atrial fibrillation (NVAF). This study was designed to evaluate the prescription patterns and appropriateness of OACs in patients with NVAF in real-world clinical settings.
We performed a prospective, observational study (NCT02366338). A total of 148 patients with NVAF were screened for OAC prescription. Appropriateness of prescribing was evaluated using 9 criteria of the Medication Appropriateness Index (MAI): indication, choice, dosage, modalities and practicability of administration, drug–drug interactions, drug–disease interactions, duplication, and duration. For each criterion, the evaluator has to rate whether the medication is (A) appropriate, (B) inappropriate but with limited clinical importance, and (C) inappropriate.
Of 148 patients, 73 (50%) were on warfarin (group 1), 39 (26%) were on rivaroxaban (group 2), and 36 (24%) were on dabigatran therapy (group 3). The MAI showed that 83% of group 1, 28% of group 2, and 47% of group 3 patients had at least 1 inappropriate criterion. Moreover, according to the choice criterion, 37% of group 1, 8% of group 2 and 5% of group 3 were rated as inappropriate, and dosage was not appropriate in 77% of group 1, 23% of group 2, and 42% of group 3.
Inappropriate drug use is frequent among patients with NVAF not only for warfarin but also for NOACs. Although there is an apparent improvement in thromboprophylaxis of NVAF, much more effort is needed for appropriate use of OACs.
Venous thromboembolism (VTE) is a frequent and potentially lethal condition. Venous thrombi are mainly constituted of fibrin and red blood cells, but platelets also play an important role in VTE formation. Information about VTE in patients with thrombocytopenia is, however, missing.
To identify VTE risk factors and describe treatment and outcome (bleeding episodes and mortality) in patients with thrombocytopenia.
Patients with thrombocytopenia (platelet count <100 x 109/L) admitted to Odense University Hospital, Denmark, between April 2000 and April 2012 were included. Fifty cases had experienced VTE. Controls without VTE were matched 3:1 with cases on sex and hospital department. Medical records were examined, and data were analyzed using conditional logistic regression.
In multivariate analysis, platelet count <50 x 109/L (odds ratio [OR] 0.22, P < .05) and chronic liver disease (OR 0.05, 95% confidence interval [CI] 0.01-0.58) reduced the risk of VTE. Surgery (OR 6.44, 95% CI 1.37-30.20) and previous thromboembolism (OR 6.16, 95% CI 1.21-31.41) were associated with an increased VTE risk. Ninety-two percent of cases were treated with anticoagulants. There was no difference in bleeding incidence between cases and controls.
Several known VTE risk factors also seems to apply in patients with thrombocytopenia. Also, patients with thrombocytopenia may be VTE risk stratified based on platelet count and comorbidities. Finally, patients having thrombocytopenia with VTE seem to be safely treated with anticoagulants without increased occurrence of bleeding.
The impact of fat distribution, muscle mass, and muscle strength on no-reflow and severity of coronary artery disease in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear.
To investigate association between muscle strength and fat and muscle mass and severity of coronary atherosclerosis.
We included 218 patients with STEMI who had undergone primary percutaneous coronary intervention. We evaluated the no-reflow phenomenon in infarct-related artery and calculated Gensini scores from initial angiograms as indicative of coronary atherosclerosis severity. The patients were divided into 2 groups as patients with no-reflow and with thrombolysis in myocardial infarction grade 3 flow and patients with low (<55) Gensini and with high (≥55) Gensini. Patients’ total fat, muscle mass, visceral fat mass, and muscle strength were measured via body composition analyzer and handgrip dynamometer.
High Gensini patients had a greater body mass index (BMI) and lower handgrip strength and more visceral fat (P = .05, P = .017, and P < .001, respectively). The patients with no-reflow had significantly lower handgrip strength and more visceral fat (both, P < .001). In multivariate regression analysis, visceral fat and handgrip strength were associated with high no-reflow rate and high Gensini scores in patients with STEMI (P = .001, P = .014, P = .022, and P = .010; respectively).
Increased visceral fat and lower handgrip strength may be related to increased no-reflow rate and coronary plaque burden in STEMI. Visceral fat and muscle strength may be better prognostic markers than weight, BMI, total fat, and muscle mass in coronary artery disease.
Few studies have identified patterns and predictors of use of direct oral anticoagulants for venous thromboembolism (VTE).
To describe the use of anticoagulants and assess predictors associated with the prescription of rivaroxaban over vitamin K antagonist (VKA) for the subsequent treatment of VTE.
This cross-sectional study was built with all consecutive patients newly diagnosed with acute VTE admitted between February 18, 2013, and September 18, 2013, in an academic tertiary care center in Quebec, Canada. Patient characteristics and VTE treatments were described. Univariate analyses and a multiple forward stepwise logistic regression were performed to assess predictors of rivaroxaban use over VKA for the subsequent treatment of VTE.
The study included 256 patients, 36.7% with a diagnosis of deep vein thrombosis (DVT) and 63.3% with pulmonary embolism (PE). Mean age was 63.1 years, and 28.1% of patients had cancer-associated VTE. Overall, rivaroxaban was prescribed in 1.6% of patients for the initial treatment and in nearly 20% of patients for the subsequent treatment of VTE. Low-molecular-weight heparin and VKA were mostly prescribed. Independent predictors associated with the prescription of rivaroxaban over VKA were as follows: age < 65 years (OR: 2.86, 95% CI 1.29-6.37), a diagnosis of DVT versus PE (OR 2.54, 95% CI 1.20-5.40), and an emergency department visit rather than a hospitalization (OR 2.24, 95% CI 1.06-4.71).
Several months following its availability, rivaroxaban was rarely prescribed for acute VTE disease. It also appears to be prescribed in different patient populations than VKA.
We investigated the risk of stroke associated with renal dysfunction and the impact of warfarin therapies in Chinese patients with nonvalvular atrial fibrillation (NVAF). Information was collected on age, sex, height, weight, type of atrial fibrillation, and serum creatinine within the previous 6 months, together with the variables needed to calculate the CHADS2 score. For patients not taking warfarin, reasons why not were recorded. Three thousand seventeen eligible patients with NVAF, mean (1 standard deviation [SD]) age of 67.7 (13.0) years, from 50 Chinese hospitals were included from May 2012 to October 2012, with a mean (1SD) CHADS2 score of 2.0 (1.5). Of these, 58.3% were male and 86.2% were at high risk of stroke with a CHADS2 score ≥1. Only 42.6% were on warfarin, and 22.5% of the patients had moderate or severe renal impairment (estimated glomerular filtration rate < 60 mL/min/1.73 m2). After adjustment for the CHADS2 score, renal dysfunction remained moderately but significantly associated with the risk of stroke/TIA (odds ratio = 1.005, 95% confidence interval: 1.002-1.009, P = .002). There was, however, no significant difference in anticoagulant usage between patients with or without impaired renal dysfunction. The most common anticoagulant concerns were the low proportion of patients with regular international normalized ratio monitoring (43.0%) and the risk of bleeding (33.3%). Renal impairment was common and independently associated with the risk of cerebrovascular embolism in Chinese patients with NVAF but not independently related to underuse of anticoagulant treatment.
The outcomes of thrombolytic therapy (TT) in elderly patients with prosthetic valve thrombosis (PVT) have not been evaluated previously. We investigated the outcomes of low-dose and slow infusion TT strategies in elderly patients with PVT.
Twenty-seven (19 female) patients aged ≥65 years (median: 70 years, range: 65-82 years) were treated with repeated TT agents for PVT. The TT regimens included 24-hour infusion of 1.5 million units of streptokinase in 2 patients, 6-hour infusion of 25 mg recombinant tissue plasminogen activator (t-PA) in 12 patients, and 25-hour infusion of 25 mg t-PA in 13 patients. Treatment success and adverse event rates were assessed.
The initial and cumulative success rates were 40.7% and 85.2%, respectively. Adverse events occurred in 6 (22.2%) patients including 4 (14.8%) major (1 death, 1 rethrombosis, and 2 failed TT) and 2 (7.4%) minor (1 transient ischemic attack and 1 access site hematoma) events. Higher thrombus burden (thrombus area ≥1.1 cm2 by receiver operating characteristics analysis, sensitivity: 83.3%, specificity: 85%, area under the curve: 0.86, P = .008) and New York Heart Association class (0% vs 15.4% vs 25% vs 100% for classes I-IV, respectively, P = .02) predicted adverse events. By multiple variable analysis, thrombus area was the only independent predictor of adverse events (odds ratio: 13.8, 95% confidence interval: 1.02-185, P = .04).
Slow infusion of low doses of TT agents (mostly t-PA) with repetition is successful and safe in elderly patients with PVT. However, excessive thrombus burden may predict adverse events.
Thrombelastography (TEG)/thromboelastometry (ROTEM) devices measure viscoelastic clot strength as clot amplitude (A). Transformation of clot amplitude into clot elasticity (E with TEG; CE with ROTEM) is sometimes necessary (eg, when calculating platelet component of the clot). With TEG, clot amplitude is commonly transformed into shear modulus (G; expressed in Pa or dyn/cm2) as follows: G = (5000 x A)/(100 – A). Use of the constant "5000" stems from Hartert’s 50-year-old calculation of G for a normal blood clot. We question the value of calculating G as follows: (1) It may be questioned whether TEG/ROTEM analysis enable measurement of elasticity because viscosity may also contribute to clot amplitude. (2) It has been suggested that absolute properties of a blood clot cannot be measured with TEG/ROTEM analysis because the strain amplitude applied by the device is uncontrolled and changes during the course of coagulation. (3) A review of the calculation of G using Hartert’s methods and some updated assumptions suggests that the value of 5000 is unreliable. (4) Recalculation of G for the ROTEM device yields a different value from that with Hartert TEG, indicating a degree of inaccuracy with the calculations. (5) Shear modulus is simply a multiple of E/CE and, because of the unreliability of G in absolute terms, it provides no additional value versus E/CE. The TEG and ROTEM are valuable coagulation assessment tools that provide an evaluation of the viscoelastic properties of a clot, not through measuring absolute viscoelastic forces but through continuous reading of the clot amplitude relative to an arbitrary, preset scale.
The incidence of neonatal hypoxic–ischemic encephalopathy (HIE) is reportedly high in countries with limited resources. Its pathogenesis is multifactorial. A role for thrombophilia has been described in different patterns of preterm and full-term perinatal brain injury.
This study aims to identify risk factors associated with neonatal HIE and also to determine the contributions of genetic thrombophilia in the development of neonatal HIE.
Sixty-seven neonates with HIE and 67 controls were enrolled in the study. Clinical history and examination were undertaken. Patients and controls were tested for the presence of factor V G1691A and prothrombin G20210A mutations. In addition, protein S, protein C, and antithrombin III levels were assessed.
Parental consanguinity and performing emergency cesarean section (CS) were significant risk factors for neonatal HIE (odds ratio [OR] 6.5, 95% confidence interval [CI] 2.6-15.3, P < .001, OR 12.6, 95% CI 2.52-63.3, P = .002, respectively). No significant difference was found regarding maternal age and parity. About 33% of cases and 6% of controls were found to have at least 1 thrombophilic factor (P < .001). Factor V G1691A mutation significantly increased the risk of neonatal HIE (OR 4.5, 95% CI 1.4-14.5, P = .012), while prothrombin G 20210A mutation and protein C deficiency were not.
Parental consanguinity, emergency CS, and factor V mutation may contribute to the higher risk of developing neonatal HIE.
Previous studies have demonstrated optimized diagnostic accuracy in utilizing higher antiheparin–platelet factor 4 (PF4) enzyme-linked immunosorbent assay (ELISA) optical density (OD) thresholds for diagnosing heparin-induced thrombocytopenia (HIT). We describe the incidence of positive serotonin release assay (SRA) results, as well as performance characteristics, for antiheparin–PF4 ELISA thresholds ≥0.4, ≥0.8, and ≥1.0 OD units in the diagnosis of HIT at our institution.
Following institutional review board approval, we conducted a single-center retrospective chart review on adult inpatients with a differential diagnosis of HIT evaluated by both antiheparin–PF4 ELISA and SRA from 2012 to 2014. The major endpoints were to assess incidence of positive SRA results, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy at antiheparin–PF4 ELISA values ≥0.4 OD units when compared to values ≥0.8 and ≥1.0 OD units. Clinical characteristics, including demographics, laboratory values, clinical and safety outcomes, length of stay, and mortality, were collected.
A total of 140 patients with 140 antiheparin–PF4 ELISA and SRA values were evaluated, of which 23 patients were SRA positive (16.4%) and 117 patients were SRA negative (83.6%). We identified a sensitivity of 91.3% versus 82.6% and 73.9%, specificity of 61.5% versus 87.2% and 91.5%, PPV of 31.8% versus 55.9% and 63.0%, NPV of 97.3% versus 96.2% and 94.7%, and accuracy of 66.4% versus 86.4% and 88.6% at antiheparin–PF4 ELISA thresholds ≥0.4, ≥0.8, and ≥1.0 OD units, respectively.
Our study suggests an increased antiheparin–PF4 ELISA threshold of 0.8 or 1.0 OD units enhances specificity, PPV, and accuracy while maintaining NPV with decreased sensitivity.
Ankaferd Blood Stopper (ABS) is a new promising local hemostatic agent, and its mechanism on hemostasis has been shown by many studies. However, the effects of ABS on skin superoxide dismutase (SOD) and catalase (CAT) activities have not been investigated before. The aim of this study was to evaluate the effects of this new generation local hemostatic agent on warfarin-treated rats focusing on its the antioxidant potential in short-term soft tissue healing.
Twelve systemically warfarin treated (warfarin group) and 12 none treated Wistar Albino rats (control group) were selected for the trial. Rats in the warfarin group were treated intraperitonally with 0.1 mg/kg warfarin, and rats in the control group were given 1 mL/kg saline 3 days earlier to surgical procedure and continued until killing. All rats had incisions on dorsal dermal tissue, which was applied ABS or no hemostatic agent before suturing. Six of each group were killed on day 4, and the other 6 were killed on day 8. Blood and skin samples were taken. Prothrombin time (PT) in blood samples, CAT, and SOD activities in skin samples were determined.
Warfarin treatment dose was found to be convenient and warfarin treatment increased the PT levels as expected. Warfarin treatment decreased CAT activity significantly compared to the control group. The ABS treatment significantly increased SOD activities in the warfarin group at the end of the eighth day.
Ankaferd Blood Stopper acted positively in short-term tissue healing by increasing SOD activity in warfarin-treated rats. Therefore, ABS may be suggeted as a promoting factor in tissue healing.
Plasma-soluble platelet glycoprotein VI (sGPVI) levels were examined in patients undergoing living donor liver transplantation (LDLT), and the relationship between platelet activation and thrombocytopenia was evaluated to understand the mechanism of thrombocytopenia in LDLT. Platelet counts were significantly higher in the donors compared to the recipient, and the plasma sGPVI levels increased in both groups after the operation. Regarding the relationship between the platelet counts and the sGPVI levels, the slope varied on different days, and it became negative on day 3, suggesting that the plasma sGPVI levels are related to platelet activation in LDLT. The frequency of complications was high in the nonsurvivors. The platelet counts were higher in the survivors than in the nonsurvivors on days 14 and 28. Although the plasma levels of sGPVI in the survivors increased after the operation, those in the nonsurvivors were high only on day 3. Although the ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 domain, member 13) levels were markedly reduced, von Willebrand factor (VWF) and VWF propeptide (VWFpp) were markedly elevated during LDLT. The antithrombin activity was significantly lower (day 14) and VWFpp (day 28) was significantly higher in the nonsurvivors than in the survivors. These findings suggest that platelet activation first occurs after LDLT, and it is high in the nonsurvivors on day 3. Thereafter, the hemostatic abnormality and vascular endothelial cell injuries may appear on days 14 and 28.
To investigate all cases of isolated factor VII (FVII) deficiency as gathered from personal files or by a PubMed search.
Personal files dealing with patients studied in Padua during the years 1970 to 2010 were reevaluated. The PubMed search was time unlimited and was carried on 2 occasions during 2014. Cross-checking of the references, listed in every article, was also carried out to avoid omissions. Inclusion criteria were isolated FVII defect of less than 40% of normal, negative coagulation pattern in the family, normal level of other vitamin K-dependent clotting factors, and normalization of the clotting factor after the therapeutic procedures, unless the patient died.
Twenty-nine patients met the inclusion criteria (18 male and 9 female, in 2 cases gender was unreported). This number included 1 personal case. Mean age was 37.9 (range 3-80). Underlying diseases were the following: neoplasia, infections, polytrauma, penicillin administration, nephrotic syndrome Wiskott Aldrich syndrome, and left heart failure (1 case, each); 2 patients had no underlying disease. Bleeding was variable but usually mild. There were 11 fatalities.
Isolated FVII deficiency is a rare defect, which appears to be a finding associated with several morbid conditions, especially sepsis and tumors. This indicates the need for a careful investigation of even a mild prolongation of prothrombin time, especially when fibrinogen and partial thromboplastin time are normal.
Anticoagulation therapy is central to the management of thromboembolic disorders, and the use of direct oral anticoagulants offers several advantages over standard therapy with parenteral heparins and vitamin K antagonists. In phase III clinical trials, the direct oral anticoagulants (given once or twice daily) all demonstrated favorable benefit–risk profiles compared with conventional standard therapy for the treatment and secondary prevention of venous thromboembolism and for stroke prevention in patients with nonvalvular atrial fibrillation. In clinical practice, many factors may influence overall clinical outcomes in patients receiving anticoagulant therapy, including adherence and persistence to the prescribed therapy, which becomes particularly important during long-term therapy. When choosing an anticoagulant for an individual patient, the pharmacological and clinical profile of the anticoagulant, its dosing regimen, and the patient’s clinical characteristics (eg, renal function and comorbidities) and preferences should be considered. This review examines the rationale for and clinical evidence of the selected dosing regimens of the direct oral anticoagulants for the treatment of venous thromboembolism and stroke prevention in nonvalvular atrial fibrillation. The potential influence of dosing strategies (eg, once- or twice-daily dosing) and other factors on patient adherence and therapy persistence are also discussed.
Obstructive sleep apnea syndrome (OSAS) is a risk factor for arterial thrombosis and cardiovascular morbidity. Activated platelets play key roles in the development of atherothrombosis, thus may be involved in these complications of OSAS. Herein, we evaluated the relationship between severity of OSAS and the degree of platelet aggregates as a marker of activated platelets in 64 patients with OSAS. Platelet aggregations were determined by means of optical aggregometry, using adenosine diphosphate (ADP) as an agonist. Compared with the control group, ADP-induced platelet aggregability was increased in patients with total OSAS, severe OSAS, and in mild to moderate OSAS. Moreover, ADP-induced platelet aggregation was correlated with the Epworth sleepiness scale (ESS) in patients with severe OSAS. Obstructive sleep apnea syndrome is associated with enhanced platelets aggregations, which may predispose the cardiovascular sequels. The ESS may be important in predicting platelet activation and thus atherothrombotic complications in those with OSAS.
We hypothesized that patients taking warfarin require frequent hospital follow-up and they are at higher risk for complications, so the incidence of depression and anxiety is higher in patients with atrial fibrillation (AF) in the period of taking warfarin compared to the period of taking dabigatran. Fifty patients having AF without valvular diseases under treatment of warfarin in whom a transition to dabigatran was planned were consecutively enrolled in this study and followed up prospectively between July 2013 and July 2014. All patients completed Beck Depression Inventory and Hamilton Anxiety Scale (HAS) at the initiation of study and 6 months after initiation of study. Of the patients enrolled in the study, age, gender, smoking status, and comorbidities were questioned. A total of 50 patients (28 women; mean age 74.6 ± 8.7 years) treated with warfarin in whom a transition to dabigatran was planned were included. Basal mean value of BDS (15.6 ± 7.8 vs 11.5 ± 4.8, P < .001) and HAS (16.8 ± 10.4 vs 12.6 ± 8.1, P < 0.001) was significantly higher in patients when they used warfarin than when they switched to dabigatran. In categorical analysis, frequency of patients with depression (mild, moderate, and severe) was significantly higher in period of warfarin use than after dabigatran transition (n = 24, 48% vs n = 14, 28%, P = .039). Our study demonstrates that patients with nonvalvular AF under treatment of dabigatran had lower BDS and HAS scores compared to warfarin. These findings suggest that dabigatran may increase quality of life and decrease morbidity and mortality due to reduction in anxiety and depression.
Assessment of venous thromboembolism (VTE) risk is important to determine optimal primary prophylaxis in hospitalized patients. The Padua score helps to recognize patients with high VTE risk, but quantifying a VTE risk is often challenging in medical patients. Thrombin generation assay (TGA) reflects the pro-/anticoagulant balance and thus could help to better quantify VTE risk in medical hospitalized patients.
To analyze the relation between TGA and VTE risk according to Padua score in medical hospitalized patients.
Between May and October 2013, 105 patients were included in an unselected cohort group of patients admitted to an internal medicine department in a large, university hospital. Within the 36 hours after admission and before any anticoagulant therapy, Padua score was calculated and sample for TGA was collected for each patient. Thrombin generation assay (velocity, peak, and endogenous thrombin potential [ETP]) was performed with 1 and 5 picomol/l (pM) tissue factor (TF) reagent.
In patients with high Padua score (n = 29), velocity, peak, and ETP differed from patients with low Padua score. This difference was present at 1 and 5 pM TF, in ETP (P < .0001 and P = .003 respectively), in peak (P < .0001 in both conditions), and in velocity (P < .0001). According to multivariate analysis, myeloid disorders, older age, higher body mass index, myocardial infarction, C-reactive protein >5 mg/L, reduced mobility with bed rest significantly increased velocity 1 pM TF value.
Single thrombin generation measurement could help to identify patients at risk of VTE in medical hospitalized patients.
Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare entity with no standard of care and high mortality, despite the use of plasma exchange.
Using specific search terms, all cases having TA-TMA treated with eculizumab and indexed in MEDLINE (English language only) by November 2014 were reviewed.
A total of 26 cases, 53% men, had a median age of 33 years (range 2-61). Transplant-associated thrombotic microangiopathy occurred after stem-cell transplant (35%) or solid-organ transplant (65%), frequently associated with the use of cyclosporine or tacrolimus (96%). A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS 13) level was always >10%. After TA-TMA diagnosis, the following drug adjustments were made: discontinuation of cyclosporine or tacrolimus in 45%, dose reduction in another 27%, continuation of the drugs in 23%, and switch from cyclosporine to tacrolimus in remaining 5%. Plasma exchange was performed in ~43%. The median interval between transplant and initiation of eculizumab was 63 days (range 11-512). A median of 5.5 doses (range 2-21) of eculizumab was utilized with 92% response occurring after a median of 2 doses (range 1-18). At a median follow-up of 52 weeks (range 3-113), the survivors (92%) were doing well.
Within the limits of this retrospective analysis, our study demonstrates that eculizumab use may result in high response rate and 1-year survival in patients with TA-TMA refractory to discontinuation of calcineurin inhibitor and plasma exchange.
Elderly patients intrinsically have higher bleeding risks, deterring clinicians from prescribing them oral anticoagulants. Setting a narrow international normalized ratio (INR) target range might potentially mitigate some of these risks. This study sought to compare the outcomes of elderly patients who were assigned to either a narrow INR target range or the conventional INR target range in a real-world environment.
This was a retrospective cohort study with the primary and secondary outcomes being the mean percentage time above INR 3.0 and the mean percentage time below INR 2.0 and the incidents of bleeding and thromboembolism associated with oral anticoagulant therapy, respectively. Patients and health care workers managing them had no prior knowledge of this study.
Data of 150 patients with a narrow INR target range (2.0-2.5) and 164 patients with a conventional INR target range (2.0-3.0) were collected and analyzed. The narrow INR group had significantly higher underlying risks of bleeding than the conventional INR group. Patients in the narrow INR group had a significantly lower percentage time above INR 3.0 but no significant difference in the percentage time below INR 2.0. Adjusted incidence rate ratio (IRR) for bleeding events was significantly lower for the narrow INR group, while the adjusted IRR for thromboembolic events between both groups was similar.
Patients assigned to a narrow INR target range in real-world practice spent a significantly lower amount of time below an INR of 3.0 compared to conventional INR target range with lower incidents of bleeding complications and no increase in subtherapeutic INRs.
Emergency physicians frequently deal with patients on vitamin K antagonists (VKAs) suffering major bleeding events, and rapid reversal of anticoagulation in this setting is of paramount importance. In Italy, given the absence of specific national guidelines, local policies are likely to differ, possibly impacting on clinical outcomes. We decided to perform a telephone survey among Italian emergency physicians to evaluate management strategies for VKAs reversal in patients with major bleeding.
We conducted a computer-assisted, 10-minute telephone survey of 15 questions, focusing on the local prevalence, assessment, and management strategies of major and intracranial hemorrhage (ICH) occurring in patients on VKAs. We planned to interview a sample of 320 Italian emergency physicians. Institutions from all geographic areas of Italy were to participate in the survey.
Of the 320 physicians contacted, 150 (47%) completed the survey, 95% being employed in public hospitals. Focusing on ICH, only 29% of the responders stated they would reverse anticoagulation irrespective of the international normalized ratio value, and only 27% would use prothrombin-complex concentrate as first-line agent. In patients needing urgent neurosurgical operation, less than 50% would administer prothrombin-complex concentrate before surgery.
The average knowledge of management strategies for reversal of anticoagulation displayed by Italian emergency physicians appears to be unsatisfactory. The need for an extensive educational program and for the implementation of specific guidelines, possibly endorsed by Scientific Societies, cannot be underemphasized.
Fibrinogen and fibrin formation have a key role in perioperative hemostasis. The aim of this study is to examine the association of postoperative hemostasis with a combined evaluation of the fibrinogen level and fibrin polymerization in cardiac surgery. We retrospectively classified 215 consecutive cardiac surgery patients into 4 groups (Fuji-san classification) that were divided by fibrinogen level <150 mg/dL (ie, hypofibrinogenemia) and fibrinogen thromboelastometry value at 10 minutes with rotational thromboelastometry <6 mm (ie, low fibrin polymerization) at the warming of cardiopulmonary bypass. Four groups resulted; group I, the acceptable range (n = 85); group II, only hypofibrinogenemia (<150 mg/dL, ≥6 mm, n = 63); group III, hypofibrinogenemia and low fibrin polymerization (<150 mg/dL, <6 mm, n = 60); and group IV, only low fibrin polymerization (≥150 mg/dL, <6 mm, n = 7). The risk of chest tube drainage volume greater than 500 mL within the first 24 hours after surgery (with group I as the reference) was increased in group II (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.5-7.4; P < .01) and group III (OR, 8.5; 95% CI, 3.5-21.7; P < .01), and the risk greater than 1000 mL (with group I as the reference) was increased in group III (OR, 4.0; 95% CI, 1.1-17.3; P = .03) and group IV (OR, 23.1; 95% CI, 3.2-201.0; P < .01). Intraoperative blood transfusions were decreased by 24.5%, after stratifying the starting amount of fresh frozen plasma by the 4-group classification in the recent consecutive 65 (30.2%) patients (P < .01). The 4-group classification is associated with postoperative bleeding and may improve the quality of perioperative blood transfusion in cardiac surgery.
Peripherally inserted central venous catheters (PICCs) are widely used in patients with cancer. Catheter usage is one of the risk factors for venous thromboembolism. We aimed to scrutinize the incidence and risk factors for PICC-related upper extremity venous thrombosis (UEVT) in patients with lung cancer receiving chemotherapy.
We performed a retrospective cohort study of patients with lung cancer with PICC insertion undergoing chemotherapy. Symptomatic PICC-UEVT was diagnosed by ultrasound. The relationship between chemotherapeutic agent exposure and PICC-UEVT was evaluated. Patient-, catheter-, and insertion-related factors were analyzed in univariable and multivariable logistic regression to identify significant independent risk factors for PICC-UEVT in patients with lung cancer.
A total of 328 patients with lung cancer having PICC undergoing chemotherapy were included, for a total of 34 895 catheter days. Seventeen (5.2%) patients developed PICC-related UEVT, with an incidence of 0.49 per 1000 catheter days. In multivariable logistic analysis, advanced disease was shown to be a significant risk factor for PICC-UEVT (odds ratio [OR]: 4.9; 95% confidence interval [CI]: 1.4-16.7; P = .011). Patients treated with etoposide had a higher risk of PICC-related UEVT (OR: 3.6; 95% CI: 1.1-12.1; P = .042). Patients were followed up after PICC removal for a median duration of 246 days. None of the patients developed pulmonary embolism.
Patients with lung cancer harboring an advanced disease or treating with etoposide were at higher risk of PICC-UEVT.
Warfarin, which is a widely used oral anticoagulant, has a narrow therapeutic window and requires regular international normalized ratio (INR) monitoring to maintain optimal anticoagulation. Recently, several portable coagulometers have been developed to measure INR levels.
To compare the INR results obtained by a portable coagulometer (CoaguChek XS) and a standard laboratory method (STAGO STA-R).
Overall, 433 consecutive patients (male: 191, median age: 61 [44-86] years) who were admitted to outpatient anticoagulation clinic were enrolled in this study. Each patient was tested for INR using portable CoaguChek XS and STAGO STA-R automatic laboratory coagulometer. Correlation between methods was assessed using the Pearson correlation test and Cohen test. Bland-Altman plot was used to identify mean difference and 95% limits of agreement.
The mean INR values for CoaguChek XS and STAGO STA-R were 2.54 ± 1.17 and 2.79 ± 1.39, respectively. There was a strong positive correlation between the 2 methods (r = .966; 95% confidence interval [CI]: 0.95-0.97, P < .001). The Bland-Altman analysis gave a mean difference of 0.26 ± 0.40 between the 2 methods, with a 95% limit of agreement of –0.54 to 1.05. In patients with INR values >5.0, there was only a moderate correlation (r = .676; 95% CI: 0.38-0.89, P = .002), and the mean difference of INR tended to increase as mean INR values increased. There was a high overall agreement between the 2 methods ( = .751; 95% CI: 0.69-0.80; P < .001).
There was good consistency between traditional laboratory testing and CoaguChek XS coagulometer, which provides rapid and reliable INR analysis.
Angelica shikokiana is a Japanese medicinal plant that is used traditionally in several ailments of cardiovascular diseases. However, there is no report regarding its anticoagulant or antiplatelet activities. So this study was designed to screen for such activities (anticoagulant by prothrombin time [PT], activated partial thromboplastin time, and thrombin time assays and antiplatelet activities against adenosine 5'-diphosphate [ADP] and arachidonic acid-induced platelet aggregations) for the methanol extract of the aerial part (Angelica methanol extract [AME]), its isolated coumarins, flavonoids, and flavonoid metabolites. The AME had potent anticoagulant and antiplatelet activities, and the flavonoid compounds were evidenced to be responsible for such activities. Among coumarins compounds, hyuganin C showed significant prolongation of only PT, while other coumarins were inactive. Similarly, hyuganin C and bergapten were the only active coumarins against ADP-induced platelet aggregation. Compared to the parent compounds, colonic metabolites of the flavonoids had similar anticoagulant and antiplatelet activities, while glucuronides showed sharp decreases in all studied activities. This is the first report showing that the medicinal plant A shikokiana has potent antiplatelet and anticoagulant activities.
Bone involvement is a frequent cause of acute morbidity in sickle cell disease (SCD). Tartrate-resistant acid phosphatase 5b (TRACP 5b), a bone resorption marker, is produced specifically by activated osteoclasts. We assessed bone mineral density (BMD) in 30 young patients with SCD and 17 asymptomatic patients with sickle cell trait (SCT) compared with 32 healthy controls and determined TRACP 5b levels in relation to vascular complications. Serum ferritin, alkaline phosphatase (ALP), and TRACP 5b were measured. Echocardiography was performed with assessment of BMD using dual energy X-ray absorptiometry (DXA). The BMD was decreased in patients with SCD compared with SCT and controls (P = .005), with no significant difference between the latter 2 groups. Patients with SCD had higher incidence of bone complications than SCT group and controls (P = .03). The SCD group with abnormal DXA scan had higher ferritin and ALP than normal BMD. Serum TRACP 5b was significantly higher in patients with SCD than SCT and controls (P = .003). The TRACP 5b levels were associated with severe vaso-occlusive crisis (P = .022). Patients treated with hydroxyurea and those on chelation therapy had lower TRACP 5b levels than untreated patients. The TRACP 5b level was positively correlated with lactate dehydrogenase, while there was no relation with ferritin, ALP, or BMD. We suggest that bone complications frequently occur in SCD as reflected by low BMD and high ALP and TRACP 5b. Hemolysis and iron overload may be involved in the occurrence of these complications. The lack of correlation between abnormal DXA scan and high TRACP 5b suggests that bone disease in SCD is multifactorial.
We analyzed a cohort of 36 females with pregnancy loss. In addition to 11 patients with antiphospholipid antibody syndrome and 2 patients with congenital antithrombin (AT) or protein C deficiency, we identified 5 patients with low fibrinogen levels (median 110 mg/dL) prior to 10 weeks of gestation. Four of these 5 patients underwent a fibrinogen gene analysis, and all 4 were found to be heterozygotes for the α-fibrinogen (FGA) Thr321Ala polymorphism. One female without hypofibrinogenemia with a history of 8 pregnancy losses was found to be homozygous for the same polymorphism, and she also showed hypercoagulability without thrombosis. In conclusion, there was a relatively high frequency of pregnancy loss in the setting of hypofibrinogenemia and/or the FGA Thr312Ala polymorphism, and this may be an important risk factor for pregnancy loss and a hypercoagulable state in later pregnancy.
For the present study, the authors hypothesized that the
Doppler ultrasonography of lower limbs was performed pre- and postoperatively to evaluate for deep vein thrombosis in 150 patients who underwent open reduction and internal fixation (ORIF). Plasma
Plasma
Using a threshold of 3 mg/L, the
In a 24-hour porcine model of liver injury, we showed that fibrinogen supplementation does not downregulate endogenous fibrinogen synthesis. Here we report data from the same study showing the impact of fibrinogen on coagulation variables.
Coagulopathy was induced in 20 German land race pigs by hemodilution and blunt liver injury. Animals randomly received fibrinogen concentrate (100 mg/kg) or saline. Coagulation parameters were assessed and thromboelastometry (ROTEM) was performed.
Fibrinogen concentrate significantly reduced the prolongations of EXTEM clotting time, EXTEM clot formation time, and prothrombin time induced by hemodilution and liver injury. A decrease in clot strength was also ameliorated. Endogenous thrombin potential was significantly higher in the fibrinogen group than in the control group, 20 minutes (353 ± 24 vs 289 ± 22 nmol/L·min; P < .05) and 100 minutes (315 ± 40 vs 263 ± 38 nmol/L·min; P < .05) after the start of infusion. However, no significant between-group differences were seen in other thrombin generation parameters or in
This study suggests that, in trauma, fibrinogen supplementation may shorten some measurements of the speed of coagulation initiation and produce a short-lived increase in endogenous thrombin potential, potentially through increased clotting substrate availability. Approximately 12 and 24 hours after starting fibrinogen concentrate/saline infusion, all parameters measured in this study were comparable in the 2 study groups.
Thrombocytopenia is common among surgical critically ill patients. The relationship between the duration of thrombocytopenia and mortality is not well studied. This retrospective 12-month cohort study was designed to evaluate the association between persistent thrombocytopenia and mortality among surgical critically ill patients to determine the risk factors for persistent thrombocytopenia. The study included adult patients consecutively admitted to the surgical intensive care unit (SICU) at our institution. Patients with a diagnosis of thrombocytopenia were identified from a prospective critical care database. We defined patients with persistent thrombocytopenia as those with thrombocytopenia lasting more than 7 consecutive days. The primary outcome of this study was 28-day mortality and the secondary outcomes were lengths of SICU stay and hospital stay. Fifty-one patients experienced persistent thrombocytopenia and 71 experienced nonpersistent thrombocytopenia. Among patients with persistent thrombocytopenia, mortality was significantly higher, and SICU and hospital stays were longer than those with nonpersistent thrombocytopenia. Risk factor analysis failed to predict which patients with thrombocytopenia would develop into persistent thrombocytopenia. Persistent thrombocytopenia is a clinically significant disorder and is associated with poorer outcomes. Future studies are needed to further define this process.
There is accumulating evidence that the coagulation system is involved in the process of fibrogenesis in chronic liver disease. Recent studies postulated a possible connection between plasmatic hypercoagulability and progression of fibrosis. The aim of the study was to investigate disorders of the coagulation system in patients with chronic hepatitis C having different extent of hepatic fibrosis well defined by liver histology. A total of 62 patients with chronic hepatitis C were recruited and categorized into 2 groups according to their histological fibrosis stage : mild/moderate fibrosis group (F0-F3 group, n = 30) and extensive fibrosis/cirrhosis group (F4-F6 group, n = 32). The control group consisted of 31 healthy individuals. The following hemostatic assays were evaluated: antithrombin III (AT), protein C (PC) activity, activated partial thromboplastin time, prothrombin time, plasma fibrinogen as well as conventional liver function test. The PC level exhibited a significant reduction in both patient groups when compared to the normal control group (89.25% ± 10.05% and 48.33% ± 15.86% vs 111.86 ± 10.90; P < .001 and P < .001). The PC was found to be the strongest associated factor to histological fibrosis stage (r = –.834; P < .0001). Univariate and multivariate analysis showed that AT (P = .003) and PC (P = .0001) were the most important factors associated with advanced fibrosis. The PC (P = .001) was found to be the only predictor of mild fibrosis. In conclusion, PC deficiency occurs in an early stage of liver fibrosis. The severity of deficiency is proportional to extent of fibrosis. The PC may have a key role in linking hypercoagulability with hepatic fibrogenesis in chronic liver disease.
The purpose of the research was to study the influence of several genetic factors, especially the -1693 G>A polymorphism of the VKORC1 gene, on the risk of acute unprovoked lower extremity deep vein thrombosis (DVT).
The study included 127 patients (median age 63 [53.2; 72] years; 61 [48%] women and 66 [52%] men) who were diagnosed with acute lower extremity DVT and 114 controls (median age 62 [53; 73] years; 64 [56.1%] women and 50 [43.9%] men) without DVT. We recorded data regarding the history of DVT and the presence of varicose veins. We determined the genotypes for factor V Leiden (FVL) mutation, prothrombin G20210A mutation, VKORC1 -1639 G>A mutation, and PAI-1 -675 4G/5G polymorphism.
Varicose veins were found in 67 (52.8%) patients and 29 (25.4%) controls (P < .001). FVL was present in 29 (22.8%) patients and 10 (8.8%) controls (P = .005). The VKORC1 (-1693 G>A) GG genotype was found in 42 (33.1%) patients and 41 (36%) controls, the GA genotype in 71 (55.9%) patients and 47 (41.2%) controls, and AA genotype in 14 (11%) patients and 26 (22.8%) controls (P = .020). Multivariate analysis showed that the presence of varicose veins, FVL, and VKORC1 -1639 G>A was independently associated with the risk of DVT. The VKORC1 (-1693 G>A) AA genotype was associated with fewer cases of DVT (odds ratio = 0.435; 95% confidence interval 0.205-0.991; P = .031).
The Asian population with atrial fibrillation (AF) have a higher risk of stroke than the caucasian population and a higher risk of intracranial bleeding when anticoagulated with warfarin. There are few real-world studies comparing the efficacy of non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin among Asian patients to assess its outcomes of ischemic stroke and hemorrhagic stroke.
A retrospective cohort study of 1000 patients on dabigatran and warfarin from 2009 to 2013.
Data were available for 500 patients on dabigatran and 500 patients on warfarin. The average follow-up duration was 315 ± 280 days in the dabigatran group and 355 ± 232 in the warfarin group. The time in therapeutic range (TTR) was 53.2% in the warfarin-treated group, with 32.8% of patients in the subtherapeutic international normalized ratio range of <2. None of the patients in the dabigatran group had ischemic cerebrovascular accident (CVA) compared to 4 (0.8%) patients in the warfarin group, hazard ratio (HR) 0.13, P = .3. There was 1 (0.2%) patient in both dabigatran and warfarin groups with hemorrhagic CVA (HR 1.16, P = .92). There were 3 (0.6%) patients with major bleeding in the dabigatran group compared to 2 (0.4%) patients in the warfarin group (HR 1.57, P = .59).
There were similar rates of efficacy for outcomes of ischemic CVA, hemorrhagic CVA, and bleeding when comparing dabigatran with warfarin. Our study shows that despite similar efficacy, suboptimal TTR rates and inconveniences with warfarin demonstrate that NOACs are preferred for stroke prevention in AF.
In a prospective setting, we aimed to find associations between biomarkers of the hemostatic system and the occurrence of central venous catheter (CVC)-related thrombosis in patients with hematological malignancies undergoing intensive chemotherapy.
The study was conducted between July 2006 and August 2010 at the University Hospital Maastricht, the Netherlands. Consecutive adult patients with hematological malignancies who were going to receive a CVC for intensive chemotherapy were included. The primary end points were (a) symptomatic CVC-related thrombosis and (b) CVC-related infections. Blood samples were taken directly after catheterization, and easy to determine biomarkers (platelet count, leukocyte count, and hemoglobin level) in combination with blood group, factor VIII (FVIII), plasminogen activator inhibitor 1 (PAI-1), activated protein C (APC) resistance, and free protein S antigen were determined.
Blood was collected and analyzed from 168 patients. The incidence of symptomatic CVC-related thrombosis was 9%. In univariate analysis, white blood cell count >10.6 x 109/L, mean FVIII activity, and PAI-1 >12.2 IU/mL were found to be associated with the development of symptomatic CVC-related thrombosis.
Elevated leukocyte count, high PAI-1, and high FVIII were associated with an increased incidence of symptomatic CVC-related thrombosis. We hope in future that simple, easy to determine laboratory tests that reflect the hemostatic and fibrinolytic activity in combination with clinical parameters may help to identify hematological patients at highest risk of CVC-related thrombosis and help to tailor the management of thromboprophylaxis in hematological patients undergoing CVC placement.
Dabigatran and rivaroxaban are novel nonvitamin K antagonist oral anticoagulants (NOACs) approved for thromboprophylaxis in atrial fibrillation (AF). In Turkey, like other countries, the efficacy of translation of the clinical trial results and current guideline recommendations into daily clinical practice is yet to be discovered. Using data from medical records of three tertiary care cardiology centers, we identified patients with nonvalvular AF on dabigatran or rivaroxaban treatment. Baseline characteristics and utilization trends were compared between dabigatran and rivaroxaban groups. Secondarily, clinical events including ischemic stroke and/or transient ischemic attack, systemic embolism, and bleeding were evaluated. Among 294 patients with AF included, dabigatran was utilized in 177 (60.2%) and rivaroxaban in 117 (39.8%). Overall, 76% of patients had received long-term warfarin therapy. The use of 110 mg twice a day (55.4%) was the prevailing strategy in dabigatran group, whereas in rivaroxaban group 20 mg every day (67.5%) was the preferred option. Of the patients, 37.3% had severe valvular disease in which mitral regurgitation was the predominant valve abnormality. Scores of CHADS2, CHA2DS2VASc, and HAS-BLED were similar in both the groups. Of the patients, 24% in dabigatran group and 13.7% in rivaroxaban group were prescribed the lower dose inappropriately. The two NOACs did not differ significantly in terms of clinical events. The results of this study indicate that in daily practice, the physicians’ behavior in utilizing the NOACs is shaped by the clinical trials and the guideline recommendations. On the other hand, in dose selection, this adherence is not of high quality.
The hypercoagulable state accompanying inflammatory bowel diseases (IBDs) is still poorly understood. The aim of this study was to assess antiphospholipid antibodies (APAs) and a large panel of inherited and acquired thrombotic markers simultaneously in a sample of Tunisian patients with IBD. In total, 89 consecutive patients with IBD (mean age 38 ± 15 years; 48 with Crohn disease and 41 with ulcerative colitis) and 129 controls were prospectively evaluated for immunoglobulin (Ig) G, IgM, and IgA antibodies against cardiolipin (aCL), β2glycoprotein I (aβ2GPI), and prothrombin (aPT); IgG and IgM antibodies against phosphatidic acid (aPA), phosphatidylinositol (aPI), and annexin V (aAnnV); lupus anticoagulant (LA); coagulation factors; natural inhibitors; and thrombotic genetic polymorphisms. Levels of fibrinogen, factors II, V, and VIII and von Willebrand factor, antithrombin, and protein C were significantly higher in patients with IBD than in controls (P < .05 for all comparisons). At least 1 APA subset was detected in 54 patients. The frequencies of antibodies against anionic phospholipids—aCL, aPI, and aPA—in patients with IBD were 15.9%, 21.3%, and 14.6%, respectively. The frequencies of antiphospholipid cofactor antibodies were 39.8% for aβ2GPI and 15.7% for both aAnnV and aPT. Isolated aβ2GPI IgA was detected in 22 patients, and 12 (13.5%) patients had LA. The IgA aβ2GPI antibodies were frequently detected in Tunisian patients with IBD. These results are of potential diagnostic, prognostic, and therapeutic interest.
Thromboelastography (TEG) has long been available for routine monitoring of perisurgical and postpartum hemostasis, especially at point of care. The purpose of this study is to retrospectively compare TEG parameters to concomitant standard clotting test results in an unselected cohort of patients with Gaucher disease to ascertain whether TEG values are specific and sensitive enough to substitute for classic coagulation tests for decision making. This remains a cogent concern because of high incidence of thrombocytopenia in patients with Gaucher disease. Thromboelastography values were compared to concomitant platelet counts, partial thromboplastin time, international normalization ratio, and plasma fibrinogen. Demographic characteristics were collected from patients’ files. There were 22 patients with Gaucher disease (2 children; 12.5%) for whom there were 24 TEG results at the same time as classic coagulation test results and 30% performed platelet function tests. The current study shows linear and/or monotonic relationships between platelet counts and several TEG values that were significant over a range of platelet counts including severe thrombocytopenia. The fibrinogen component, correlating only with the rate of clot lysis, played a lesser role. Based on these preliminary results albeit in a small cohort with only 1 case of hemorrhage, there is putative support for the intention to treat patients with Gaucher disease based on TEG results using the same TEG protocol as for other patients undergoing comparable procedures in our institution.
The aim of this study was to investigate the effects of different paclitaxel concentrations on platelet aggregation induced by adenosine diphosphate (ADP). This experiment involved platelet suspensions that were obtained from fasting morning blood specimens from healthy adult male volunteers aged 22 to 28 years. The effect of paclitaxel on platelet aggregation induced by ADP and the inhibition rate of platelet aggregation were calculated in 6 groups with varying concentrations of paclitaxel, respectively. The optimal incubation time and concentration of ADP were 10 minutes and 10 μmol/mL, respectively. When the concentration of paclitaxel increased, platelet aggregation induced by ADP increased accordingly. When the concentration of paclitaxel exceeded 0.1 ng/mL, the ability of ADP to induce platelet aggregation increased significantly with increasing paclitaxel concentrations. In all the 3 experimental groups, that is A, C, and AC groups, the ability to inhibit platelet aggregation was weakened as paclitaxel concentration increased. Paclitaxel can enhance platelet aggregation induced by ADP, and this ability was observed to increase as paclitaxel concentration increased. In conclusion, paclitaxel can reduce the ability of aspirin, clopidogrel, and aspirin combined with clopidogrel to inhibit platelet aggregation. Furthermore, the ability to inhibit platelet aggregation was weakened as paclitaxel concentration increased in all 3 experimental groups.
The pathological consequences of decreased protein Z (PZ) and/or Z-dependent protease inhibitor (ZPI) levels remain as yet unclear, despite a growing body of evidence which supports their involvement in an increased thrombotic risk. The purpose of the present study was 2-fold: to evaluate plasma concentrations of protein Z and ZPI in patients with essential thrombocythemia (ET) and to determine their significance in thrombotic complications. The median (range) plasma concentrations of PZ in our patients with ET were lower, but not significantly, than in healthy individuals: PZ (1.42 µg/mL, 0.36-3.14 µg/mL vs 1.6 µg/mL, 0.75-2.56 µg/mL, P = .08). On the other hand, the median (range) plasma concentrations of ZPI in the said patients with ET were meaningfully lower than in the reference group: ZPI (3.22 µg/mL, 0.85-6.97 µg/mL vs 4.41 µg/mL, 1.63-7.83 µg/mL, P = .0004). More importantly, the study revealed a statistically significant lower concentration of PZ and ZPI in patients with the presence of the JAK2V617F mutation relative to patients without the mutation, for PZ: 1.38 µg/mL, 0.36-2.6 µg/mL versus 1.63 µg/mL, 0.88-3.14 µg/mL, P = .03, and ZPI 2.89 µg/mL, 0.85-5.91 µg/mL versus 3.61 µg/mL, 1.53-6.97 µg/mL, P = .002. Additionally, significant differences between the concentrations of PZ and ZPI were found in patients with venous thrombotic episodes compared to healthy individuals, for PZ: 1.23 µg/mL, 0.82-1.99 µg/mL versus 1.6 µg/mL, 0.75-2.56 µg/mL, P = .043, and ZPI: 2.42 µg/mL, 0.85-4.21 µg/mL versus 4.41 µg/mL, 1.63-7.83 µg/mL, P < .0001. To recapitulate, our results suggest that the deficiency of PZ may increase tendency to thrombosis in patients with ET.
The frequency of patients diagnosed with cerebral venous sinus thrombosis (CVST) has increased due to the expanded use of noninvasive brain imaging methods. The aim of this study was to assess the correlations between the location and extent of venous sinus impairment, clinical presentation during the acute phase, recanalization, the presence of parenchymal lesions, and clinical outcome after 3 to 4 months in patients with CVST. In a retrospective study, clinical and magnetic resonance imaging data from a cohort of 51 consecutive patients with CVST (mean age 33.1 ± 15.4 years) were collected and analyzed. Good clinical outcome after 3 to 4 months, which was assessed using the modified Rankin scale, significantly negatively correlated with a thrombosis location in the left transverse, left sigmoid, or superior sagittal sinus (P = .022, P = .045, and P = .046, respectively) and positively correlated with recanalization (P = .048). The clinical outcome was significantly more favorable in the females with gender-specific risk factors than in the males (P = .029). In conclusion, successful recanalization substantially helps to achieve good clinical outcome in patients with CVST.
Postpartum hemorrhage (PPH) remains a leading cause of maternal mortality and morbidity worldwide. This retrospective observational study describes patient characteristics and hemostatic therapies administered to 352 parturients experiencing PPH and analyzes risk factors for developing severe PPH. During the study period, bleeding was controlled in all cases and 99.4% survived. The majority (98%) of patients received packed red blood cells. The most frequent hemostatic therapies administered were fibrinogen concentrate (56%), fresh frozen plasma (49%), and platelets (30%). A total of 124 (35%) women experienced severe PPH. Significant independent predictors for evolution to severe PPH were age, obstetric comorbidity, and plasma fibrinogen concentration. The latter was based on records from 267 (76%) patients. Plasma fibrinogen concentration before labor was the only modifiable prepartum risk factor independently associated with severe PPH, indicating that fibrinogen monitoring is warranted in these patients.
Venous thromboembolism (VTE) is the most common preventable cause of hospital death; the burden of VTE includes the management of the acute event (deep vein thrombosis [DVT]/pulmonary embolism) and the chronic subsequents such as postthrombotic syndrome and recurrent DVT. All experts agree that despite the abundance of knowledge available on VTE and how to prevent it, it is still underused, and since the first step in prophylaxis is to identify those who are at high risk of VTE, several risk assessment models have been developed to identify these patients and provide appropriate prophylaxis. In our study, the institutional guideline in a tertiary educational hospital is the Caprini score (2006), a comparison was conducted between the institutional guideline and the American College of Chest Physicians guideline (ACCP ninth edition [ACCP-9]) in terms of the degree of agreement of the actual prophylaxis with the institutional guideline and the ACCP-9 and the differences in risk levels. The concordance with the ACCP-9 guideline was higher than with the institutional guideline, specifically in those patients receiving prophylaxis, and there was an overestimation of the risk levels in the institutional guideline, especially in medical patients. The replacement of the existing Caprini-2006 with the ACCP-9 is prudent, since it agrees with the physicians’ clinical judgment and may result in reduced use of pharmacologic prophylaxis which could lead to lower costs and fewer adverse effects.
Hemoglobin Eβ thalassemia is a major public health problem in India, especially in the state of West Bengal. Various thromboembolic events are common, especially in splenectomized patients. Platelet hyperactivity most likely plays a pathogenetic role. To investigate the role of platelets in hypercoagulability, platelet aggregation tests were undertaken in the present study. Platelet-rich plasma from 30 patients with Eβ thalassemia (15 splenectomized and 15 nonsplenectomized) were studied and compared with 15 healthy participants. The 4 agonists used were adenosine 5-diphosphate, adrenaline (epinephrine), collagen, and ristocetin. The current study shows both splenectomized and nonsplenectomized patients had abnormal aggregation compared to normal healthy controls. Splenectomized patients had higher platelet aggregation than nonsplenectomized patients for all 4 agonists; but statistically significant difference among 2 groups was found only for collagen. The present study confirms a role of splenic absence in platelet hyperaggregation.
The association between hereditary thrombophilia and venous thrombosis is well established but controversial data exist with respect to arterial thrombosis. We performed a pilot study on 31 patients with acute myocardial infarction (AMI), 21 patients with unstable angina (UA), and 20 healthy volunteers to investigate the role of various hemostatic gene polymorphisms in young Egyptian patients, who survived their first ischemic heart disease (IHD). Thrombophilic gene polymorphisms were tested using multiplex polymerase chain reaction and reverse-hybridization technique. We showed an increased risk of AMI with factor V (FV) Leiden and prothrombin G20210A heterozygosity. The increased risks of UA was associated with GA and A allele of fibrinogen β-455G->A polymorphism. Conversely, factor XIII (FXIII) Val34Leu GT and T allele were protective in the UA group. Nevertheless, the prevalence of FV H1299R, plasminogen activator inhibitor 1 4G/5G, glycoprotein IIIa C1565T, 5,10-methylenetetrahydrofolate reductase C677T, and A1298C mutations did not differ between patients with IHD and controls. The data have clinical implications regarding screening and thromboprophylaxis in high-risk individuals younger than 40 years.
Expression and peptide immunoreactivity of apelin messenger RNA have been described in a variety of tissues, including gastrointestinal tract, adipose tissue, brain, kidney, liver, cardiovascular system, and lungs. This study aimed to investigate the possible involvement of the endogenous apelin in the pathophysiological events that occur in patients with pulmonary embolism (PE).
In total, 53 patients with PE and 35 healthy volunteers were included the study. This cross-sectional study was conducted at a tertiary care university hospital and among patients diagnosed as having PE. The control group consisted of healthy volunteers who applied to hospital for a routine checkup examination. Serum apelin 13 levels were measured in both the groups and their results were compared.
The median ages were 57 and 53 years, and female–male ratios were 30/23 and 20/15, in the PE and control groups, respectively. The mean serum apelin 13 levels were found to be significantly higher in the PE group (76.94 ± 10.70 ng/mL) than in the control group (50.01 ± 7.13 ng/mL; P < .001).
This study demonstrated that apelin 13 levels are elevated in patients with PE. These results suggest that apelin may be a novel biomarker and a potential therapeutic target in patients with acute PE in the future.
Genetic variants of cholesteryl ester transfer protein (CETP) and endothelial nitric oxide synthase (eNOS) influence high-density lipoprotein cholesterol (HDL-C) metabolism and nitric oxide (NO) synthesis, respectively, and might increase the risk of coronary artery disease (CAD). This study is to investigate the relationship between genetic polymorphisms and the risk of CAD and to evaluate their potential interactions. A total of 237 patients with CAD and 101 controls were genotyped. The association of the polymorphism with the risk of CAD varied among the ethnic groups. Moreover, the concomitant presence of both CETP B1 and eNOS 4a alleles significantly increased the risk of CAD in the Malay group (OR = 33.8, P < .001) and the Indian group (OR = 10.9, P = .031) but not in the Chinese group. This study has identified a novel ethnic-specific gene–gene interaction and suggested that the combination of CETP B1 allele and eNOS 4a allele significantly increases the risk of CAD in Malays and Indians.
In the present study, in vivo thrombolysis efficiency of Brevithrombolase, a nontoxic fibrinolytic enzyme purified from Brevibacillus brevis strain FF02B, was affirmed by significant inhibition of thrombus formation in the k-carrageenan-induced rat tail, in a dose-dependent manner. Brevithrombolase at a dose of 600 µg/kg showed an efficacy that was comparable to streptokinase and plasmin, in dissolving in vivo thrombus of k-carrageenan-treated rats under identical conditions. The in vivo anticoagulant property of Brevithrombolase was demonstrated by its prolongation of activated partial thromboplastin time, prothrombin time, and thrombin time in Wistar rats. However, the Brevithrombolase-treated rats demonstrated an insignificant decrease in fibrinogen (Fg) level of plasma compared with Fg level of control group of rats corroborating in vivo as well as in vitro anticoagulant activity of Brevithrombolase is due to its hydrolytic action on thrombin. These findings unequivocally suggest that Brevithrombolase may serve a promising alternative to the commercial thrombolytic drugs.
Although the rate of bleeding among patients with atrial fibrillation (AF) taking novel oral anticoagulants in randomized controlled trials is described, the rate of bleeding with "real-world" use is uncertain.
We conducted a retrospective electronic medical record interrogation and subsequent chart review among patients within Intermountain Healthcare between October 2010 and November 2012. Patients were included if they had a diagnosis of AF and were receiving either dabigatran or rivaroxaban. Rates of major bleeding were calculated.
Among 2579 patients, 13 (0.5%) experienced major bleeding (95% confidence interval [CI] 0.23-0.77), 5 (0.19%) experienced intracranial hemorrhage (95% CI 0.02-0.36), and 2 (0.08%) experienced fatal bleeding. Of the 13 patients experiencing a major bleed, 8 (61.5%) would have been excluded from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) clinical trials.
We observed a rate of major bleeding similar to that reported in randomized clinical trials among patients with AF prescribed dabigatran or rivaroxaban.
Chronic thromboembolic pulmonary hypertension (CTEPH) is an ominous disease leading to progressive right heart failure. Selected patients can be treated by pulmonary endarterectomy (PEA). We assessed long-term clinical outcome of patients with CTEPH who underwent PEA and patients who remained on medical treatment alone. A total of 112 consecutive patients with CTEPH referred between 1998 and 2008 to one center were followed for a mean of 35 (range 0-128) months after diagnosis. All the patients had advanced pulmonary hypertension at baseline. The operated group had higher World Health Organization functional class compared to the nonoperated group. No other differences in hemodynamic, echocardiographic, or biochemical parameters were observed at baseline. Despite the perioperative mortality rate of 9.1%, patients who underwent PEA had significantly lower long-term mortality compared to nonoperated patients (12.7% vs 34.8%; P = .003), and PEA survivors showed sustained clinical improvement. All efforts should be undertaken to perform PEA in all patients with operable CTEPH.
To assess the impact of preanalytical variables of time and temperature on prothrombin time (PT), activated partial thromboplastin time (aPTT), dilute Russell viper venom time (DRVVT), activated protein C resistance (APCR), and
Markers of platelet activity (P-selectin), fibrinolysis (
The aim of this study was to evaluate the relationship between hematologic indices and the Global Registry of Acute Coronary Events (GRACE) score in patients with ST-segment elevation myocardial infarction (STEMI). A total of 800 patients who consecutively and retrospectively presented with STEMI within 12 hours of symptom onset. After accounting for exclusion criteria, a total of 379 patients remained in the study. We enrolled 379 patients with STEMI (mean age 61.7 ± 13.6 years; men 73%). Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), red cell distribution width (RDW), and monocyte count were associated with increased worse GRACE risk score (P = .008, P = .012, P = .005, P = .022, respectively). In multivariate linear regression analysis, NLR, PLR, RDW, and monocyte count were found to be independent predictors of GRACE risk score. We demonstrate for the first time that PLR, RDW, and monocyte were associated with the GRACE score in patients with STEMI.
The aim of this study is to evaluate the incidence and predictors of silent neuronal injury (SNI) after coronary angiography (CAG) and intervention by serial measurement of serum neuron-specific enolase (NSE) in patients presented with acute coronary syndrome (ACS). Ninety-eight consecutive patients presented with ACS and underwent CAG and intervention were included in the study. The NSE levels significantly increased after CAG and intervention compared to baseline levels (22.03 ± 27.70 and 10.08 ± 3.15 consecutively). Left ventricular ejection fraction in the SNI+ group was significantly lower than that in the SNI– group (43.71% ± 12.51%, 50.84% ± 9.34%, P = .002). Maximal creatinine kinase myocardial band, troponin I, and SYNTAX score of the SNI+ group were significantly higher than those of the SNI– group (103.83 ± 99.22, 51.92 ± 78.33, P = .006; 50.04 ± 66.18, 19.18 ± 30.50, P = .002; 103.83 ± 99.22, 51.92 ± 78.33, P = .006; and 50.04 ± 66.18, 19.18 ± 30.50, P = .002 successively). SYNTAX score and performing percutaneous coronary intervention were the independent predictors of SNI (P = .009, odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.014-1.107, P = .036, OR = 4.262, 95% CI = 1.097-16.56). Percutaneous coronary intervention and coronary artery lesion complexity may increase the risk of SNI in patients with ACS.
Registro Informatizado de Enfermedad TromboEmbólica (RIETE) database was used to investigate whether neurosurgical patients with venous thromboembolism (VTE) were more likely to die of bleeding or VTE and the influence of anticoagulation on these outcomes.
Clinical characteristics, treatment details, and 3-month outcomes were assessed in those who developed VTE after neurosurgery.
Of 40 663 patients enrolled, 392 (0.96%) had VTE in less than 60 days after neurosurgery. Most patients in the cohort (89%) received initial therapy with low-molecular-weight heparin, (33% received subtherapeutic doses). In the first week, 10 (2.6%) patients died (8 with pulmonary embolism [PE], no bleeding deaths; P = .005). After the first week, 20 (5.1%) patients died (2 with fatal bleeding, none from PE). Overall, this cohort was more likely to develop a fatal PE than a fatal bleed (8 vs 2 deaths, P = .058).
Neurosurgical patients developing VTE were more likely to die from PE than from bleeding in the first week, despite anticoagulation.
The aim of this open, observational registry was to evaluate the effects of antithrombotic treatment on the development of postthrombotic syndrome (PTS): the effects of "standard management" (SM; according to International Union of Angiology guidelines) were compared to SM in association with sulodexide or aspirin.
Postthrombotic syndrome occurrence was observed in 3 nonparallel groups after deep venous thrombosis (DVT); the registry started after the end of the anticoagulation period. The target was to observe the occurrence of PTS in 5 years. Three possible options were suggested to the patients, and the patients and their caregivers defined the type of management. A group of 167 patients was involved in the SM with reevaluation every 6 months; the sulodexide group included 124 patients and the aspirin group included 48 patients.
The 3 groups were clinically similar and comparable for age and sex distribution. Of the 167 patients in the SM group, 154 patients completed 60 months of follow-up. The percentage of patients with PTS in the SM group ranged from 14.9% (1 year after the end of anticoagulation) to 19.5% (60 months). In the nonparallel group using sulodexide (124 comparable patients at inclusion; 115 at 60 months), the percentage of PTS was variable from 8.8% (1 year after anticoagulants) to 12.17% at 60 months. These percentages are significantly lower than those observed with SM. In the nonparallel aspirin group (48 patients at inclusion and 34 at 54 months), there was a PTS incidence of 23.5% at 54 months (vs 12.17% in the sulodexide group and 18.23% in the SM group). The incidence of PTS was significantly higher in comparison with the other 2 groups. The incidence of PTS was lower in the sulodexide group in comparison with the 2 other groups.
Sulodexide administration after DVT appears to be effective in preventing PTS in association with recommended management and a number of recurrent DVTs. Modalities of treatment, dosages, and timing of administration should be explored in more comprehensive and complete studies.
The plasminogen activator system controls intravascular fibrin deposition; besides, it also participates in a wide variety of physiologic and pathologic processes, including cancer.
In this study, we examined the levels of plasminogen activator inhibitor 1 (PAI-1) and vitronectin in 32 newly diagnosed pediatric patients with malignancies, determined by enzyme-linked immunosorbent assay between January 2009 and January 2010 and compared them to 35 age-matched healthy children, using SPSS 16.0 software.
The mean level of PAI-1 was 23.02 ± 15 (8.2-71.19) ng/mL and vitronectin was 83.10% ± 23.77% (12%-126%) in the tumor group. Thirty-five healthy children in the same age range were enrolled in the control group. The levels of PAI-1 and vitronectin were 23.63 ± 10.44 (11.67-58.85) ng/mL and 85% ± 20.85% (39%-126%), respectively. No significant difference was found between the 2 groups by independent sample t-test (P = .86 and P = .69).
This is a preliminary study done in children with malignancies, investigating PAI-1 and vitronectin. Further study is needed, including larger trials and tumor tissue with histopathological examination as in adults.
Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count has emerged as a marker of inflammation that is widely available in clinical practice. Since inflammation plays a key role in atherosclerosis and its end results, discovering new biomarkers of inflammation becomes important in order to help diagnostic accuracy and provide prognostic information about coronary cardiac disease. In acute coronary syndromes and percutaneous coronary intervention, elevated levels of almost all subtypes of white blood cell counts, including eosinophils, monocytes, neutrophils, and lymphocytes, and neutrophil–lymphocyte ratio and eosinophil–leukocyte ratio constitute independent predictors of adverse outcomes. Eosinophil count and eosinophil–leukocyte ratio, in particular, emerge as novel biomarkers for risk stratification in patients with coronary artery disease. Since the presence of eosinophils denotes hypersensitivity inflammation and hypersensitivity associated with Kounis syndrome, this reality is essential for elucidating the etiology of inflammation in order to consider predictive and preventive measures and to apply the appropriate therapeutic methods.
We aimed to investigate the 6-month efficacy and safety of postprocedural 12-hour tirofiban administration versus 24-hour tirofiban administration in patients with ST-segment elevated myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI).
This retrospective study enrolled 349 patients with STEMI who underwent primary PCI. Following the administration of bolus tirofiban after primary PCI, those receiving a 12-hour tirofiban infusion as the maintenance dose were classified as group 1 (n = 123) while those receiving a 24-hour infusion were classified as group 2 (n = 226). In-hospital and 6-month major adverse cardiac events were recorded.
There were no statistically significant differences between the 2 groups regarding in-hospital efficacy (in-hospital death: 4.4% vs 5.7%, P = .600 and stent thrombosis 1.8% vs 1.6%, P = .921) and in-hospital safety (2.6% vs 1.6% for major bleeding and 5.3% vs 4.1% for minor bleeding, P = .562). During the 6-month follow-up period, the incidence of the recurrent revascularization (16.1% vs 15.5%, odds ratio [OR] = 1.05 [0.47-3.67]), the repeated nonfatal acute coronary syndrome and/or stent thrombosis (27% vs 24.4%, P = .598, OR = 1.02 [0.42-2.48]), and the cardiovascular deaths (6.6% vs 6.5%, P = .943, OR = 1.03 [0.43-2.43]) were comparable between group 1 and group 2.
Our study revealed that 12-hour tirofiban administration versus 24-hour tirofiban administration in STEMI who underwent primary PCI was similar with respect to in-hospital efficacy and safety and major adverse cardiac events during 6-month follow-up.
Women with mild bleeding disorders (MBDs) pose a diagnostic challenge and menorrhagia, the most common presenting symptom that remains underreported. We tested the hypothesis that screening apparently normal females using general and gynecological bleeding assessment tools and a global hemostatic assay together with platelet aggregation can help predict MBDs. We assessed 47 women using electronic bleeding assessment tools; e-bleeding questionnaire; and e-Pictorial Bleeding Assessment Chart (e-PBAC) based on previously validated methods, thrombelastography (TEG), and platelet aggregation together with basic coagulation testing. Three women had elevated bleeding score with von Willebrand disease diagnosis confirmed in one case and eleven cases had elevated e-PBAC. We report normal ranges for TEG and platelet aggregation in women during the first half of the menstrual cycle and show 23.4% of apparently normal women may have general or heavy menstrual bleeding. This is a prelude to a larger study to determine the validity of bleeding assessment tools in screening for MBDs in women.
Hemophilia A (HA) is an inherited X-linked coagulation disorder caused by the deficiency of factor VIII (FVIII). Linkage analysis is a common indirect method for the detection of female carriers in families with HA. In the current study, 173 patients from 30 unrelated families with HA were recruited from the Azeri Turkish population of northwest Iran and analyzed for BclI and HindIII markers by polymerase chain reaction-restriction fragment length polymorphism. We investigated the potential of using these markers for the detection of mutation in carriers through linkage analysis, which would be of tremendous use in prenatal diagnosis. Among the tested women, 47% and 35% were found to be heterozygous for BclI and HindIII polymorphic markers, respectively. The BclI and HindIII markers were informative for the detection of 63% and 17% potential carriers, respectively, demonstrating the effectiveness of the BclI marker for the detection of HA carriers among the Azeri Turkish population.
Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Copenhagen, Denmark) is used to control bleeding in patients with hemophilia. A generic version of FVIIa was developed by AryoGen (Tehran, Iran). This study compared the composition and functional activities of AryoSeven and NovoSeven. Each product was compared at equigravimetric (1 mg/mL) stock solution for protein content. The proteomic profile was obtained using surface-enhanced laser desorption ionization mass spectrometry. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis was carried out to determine the protein profile and Western blotting was performed using a polyclonal rabbit antihuman FVIIa antibody. The FVIIa-related antigen was also measured using a commercially available enzyme-linked immunosorbent assay method. Functional assay included the prothrombin time correction in FVII-deficient plasma. The protein content was comparable in 2 products and the mass spectra analysis showed a single peak at 50 kDa in all products. The SDS-PAGE and immunoblotting studies were comparable. Both products exhibited similar coagulant properties in different assays.
In order to establish the efficacy and biosimilar nature of AryoSeven to NovoSeven in the treatment of congenital factor VII (FVII) deficiency, patients received either agent at 30 μg/kg, intravenously per week for 4 weeks, in a randomized fashion. The primary aim was to compare FVII:coagulation activity (FVII:C), 20 minutes after recombinant activated FVII (rFVIIa) injection, in the 2 groups. A secondary measure was self-reported bleeding. The median interquartile baseline range of the plasma level of activated FVII (FVIIa) activity in the 2 groups was 1.6 (1.1-14.0) IU/dL and 5.0 (1.1-25.5) IU/dL. All patients achieved levels of FVIIa (FVII:C) >30 IU/dL, 20 minutes after the injection of rFVIIa. Bleeding was similar between the 2 groups, with a comparable decrease in severity and frequency compared to the last month prior to treatment. AryoSeven is similar to NovoSeven in increasing postinjection FVIIa activity as well as in clinical safety and efficacy.
Both plasma- and recombinant activated factor VII (rFVIIa)-based algorithms can be used to correct coagulopathy in preliver transplant patients with acute liver failure requiring intracranial pressure monitor (ICPM) placement. A decision model was created to compare the cost-effectiveness of these methods. A 70-kg patient could receive either 1 round of plasma followed by coagulation testing or 2 units of plasma and 40 μg/kg rFVIIa. Intracranial pressure monitor is placed without coagulation testing after rFVIIa administration. In the plasma algorithm, the probability of ICPM placement was estimated based on expected international normalized ratio (INR) after plasma administration. Risks of rFVIIa thrombosis and transfusion reactions were also included. The model was run for patients with INRs ranging from 2 to 6 with concomitant adjustments to model parameters. The model supported the initial use of rFVIIa for ICPM placement as a cost-effective treatment when INR ≥2 (with incremental cost-effectiveness ratio of at most US$7088.02).
Immune thrombocytopenia (ITP) is a rare autoimmune disorder with an incidence of 3 to 5 per 100 000 individuals. In children, the disease is self-limited and is most commonly virus related (acute ITP) whereas in adults, the disease is typically chronic. The age distribution of adult ITP displays 2 peaks; the first in younger adults aged 18 to 40 with a female predominance and the second in people aged older than 60 with men and women affected equally. Our approach to ITP has evolved over the past several years: there has been a change in nomenclature and ITP now denotes "immune thrombocytopenia" (the "I" no longer denoting "idiopathic") and "purpura" no longer features in the name of the disease; new insights into the pathogenesis of ITP have revealed the importance of impaired megakaryocytopoiesis in the condition; underlying mechanisms of secondary ITP have been elucidated and finally novel thrombopoietic agents have been shown to be effective in the treatment of ITP in randomized clinical trials. In this article, we review important recent advances in the pathogenesis and treatment of ITP.
The aim of this study was to detect the genetic alterations in the Factor 8 gene in 26 patients from Western Algeria. We detected the presence of "intron 22 inversion" with long-range polymerase chain reaction (PCR). Negative patients for this inversion were analyzed for "intron 1 inversion" using multiplex PCR. Patients who were negative for both inversions were analyzed using a direct sequencing. Deleterious effects of novel mutations on protein were assayed with bioinformatics tools. Causing mutations were identified in 85.71% of the families, including 11 "intron 22 inversion," 1 "intron 1 inversion," and 6 different point mutations (2 nonsense, 1 splice site, and 3 missense mutations). Among these mutations, c.2189G > A (p.Cys711Tyr) and c.5219+1G > T are novel. This is the first study that reports spectrum of mutations in the Factor 8 gene in the Western Algerian population. Knowledge of these mutations is important for genetic counseling and medical care of affected families.
The use of flow-mediated dilation (FMD) as a surrogate indicator for the extent of coronary artery disease (CAD) remains largely unknown. We assessed FMD at the brachial artery in 89 consecutive patients undergoing coronary angiography.
Patients were classified in groups 0 to 3 according to the number of diseased vessels and the SYNTAX score was calculated. The FMD decreased significantly from groups 0 to 3 (P < .001). There was a significant linear relation between SYNTAX score and FMD (corrected r 2 = .64, P < .001). In multivariate analysis, a reduced FMD was the only significant independent predictor of the presence of CAD (odds ratio [OR] 1.78, P = .032) and of CAD severity (OR 1.85, P = .005).
This study confirms that FMD is reduced in patients with CAD and that such reduction in FMD is related to the extent of the disease. Therefore, FMD at the brachial artery is likely to represent a reliable indicator of CAD burden.
Retinal vein occlusion (RVO) is the second most common retinal vein disease and an important cause of blindness and visual morbidity. Many conditions are associated with RVO but the real role of the thrombophilic mutations is still unclear.
To evaluate the potential role of thrombophilic mutations in RVO.
We have evaluated 113 patients with RVO and compared with 104 volunteer controls. The controls were all healthy blood donors without previous venous thromboembolism episode or arterial thromboembolism episode. All patients were tested for 5 gene variants (here all named as mutations): factor V (FV) Leiden (G1691A), factor II (FII; G20210A), 5,1-methylenetetra-hydrofolate reductase (MTHFR; C677T), plasminogen activator inhibitor 1 (PAI-1; 4G/5G), and angiotensin-converting enzyme (ACE; Del/Ins). Statistical analysis were performed by the 2-tailed chi-square test.
Statistical test showed that TT homozygous patients of the MTHFR C677T mutation (P = .017) and heterozygous GA patients of the FII G20210A mutation (P = .018) were significantly higher than that in controls. For FV Leiden, even if the values were higher in patients than in controls, P value was not statistically significant. Conversely, for the ACE (Ins/Del) and PAI-1 (4G/5G) mutations, no difference was observed among genotypes of patients with RVO and control participants.
In our study, the FII G20210A and the MTHFR C677T mutations resulted significantly higher in patients than in controls; in contrast, thrombophilic mutation of FV, ACE, and PAI-1 genes was not statistically correlated with RVO. In spite of having found an association between some thrombophilic mutations and RVO, more studies with a major number of patients are necessary to determine the final role of these gene variants.
Background and Aim: Hepcidin has been shown to be an acute phase reactant, induced by infection and inflammation. Ongoing inflammation was shown in rheumatic valve disease (RVD). In this study we want to investigate whether there is a relationship between inflammation and impaired iron metabolism and the role of hepcidin on serum iron levels. Methods and Results: Fourty-six patients with RVD and 34 healthy individuals were included in the study. Serum hepcidin, high-sensitive C-reactive protein (hs-CRP), hemoglobin, hematocrit, iron, iron-binding capacity, ferritin levels were measured. Serum hepcidin levels were significantly increased in patients with RVD than in control group (316 ± 121 ng/mL vs 435 ± 126 ng/mL; P < .001). Serum hs-CRP levels were no significantly higher in the patient group in than in the control group (3.9 ± 3.6 mg/L vs 3.5 ± 3.7 mg/L; P = .521). Conclusion: Hepcidin levels are decreased independently from hs-CRP levels as a compensatory mechanism to increase the iron absorption in response to decreased serum iron levels in patients with RVD.
Recombinant human soluble thrombomodulin (thrombomodulin α [TM-α]) has been marketed as a novel anticoagulant for disseminated intravascular coagulation (DIC) in Japan since 2008. Postmarketing surveillance (PMS) has been conducted since its approval. As effectiveness and safety were not previously determined in pediatric patients, this study evaluated PMS data and examined the usefulness of TM-α in treating pediatric DIC. After excluding newborn infants, data for 210 pediatric patients were analyzed and compared to 3786 adult patients. The day after the last TM-α administration, DIC had resolved in 58.5% of the patients. At 28 days after the last TM-α administration, the survival rate was 71.6%. Nineteen episodes of adverse drug reactions were observed in 11 patients but no significant differences were noted for effectiveness and safety. Although this study was limited by its retrospective design, including selection biases and no limitation on concomitant use of other anticoagulants, TM-α appears to be useful for the treatment of DIC in both pediatric and adult patients.
The diagnosis of mild bleeding disorders is not easy as most of the "healthy" individuals also report bleeding symptoms. In order to get a precise bleeding history, Pediatric Bleeding Questionnaire (PBQ) has been developed. In our study, Turkish children diagnosed with Von Willebrand disease (VWD), platelet function defect (PFD), and healthy children without any symptoms (control group 1) and healthy children with symptoms but found hemostatically normal (control group 2) were analyzed with PBQ. The cut off level for "positive bleeding score" was found to be ≥2 (area under the curve [AUC]: 0.785, 95% confidence interval [CI]: 0.718-0.852). The sensitivity, specificity, positive predictive value, and negative predictive value of PBQ to define VWD versus control group 1 was 100%, 97.4%, 96.4%, and 100%; VWD versus control group 2 was 100%, 53.1%, 64.3%, and 100%; PFD versus control group 1 was 93.3%, 53.1%, 73.7%, and 85%; and PFD versus control group 2 was 93.3%, 53.1%, 73.7%, and 85%, respectively.
Our aim is to present the etiology and risk factors for cerebral sinovenous thrombosis (CSVT) and the radiological findings, anticoagulant therapy used, and treatment outcome of patients with CSVT. This study included 12 patients who were treated for CSVT at the Ankara University, School of Medicine, Department of Pediatric Neurology. This study included 5 girls (41.7%) and 7 boys (58.3%) with a mean age of symptom onset of 5.2 ± 6.29 years (range: 0-18 years), who were followed at our institution for a mean of 1.8 ± 1.73 years (range: 0-6.5 years). Among the patients, 3 had no risk factors, 2 had 1 risk factor, and 7 had multiple risk factors. Anticoagulant therapy was administered to 4 patients, of which 1 had neurological sequelae; neurological sequelae or exitus occurred in 4 of the 8 patients who did not receive anticoagulant therapy. The present findings showed that appropriate prophylaxis in appropriately selected patients reduced the rate of recurrence of CSVT.
Objectives: The SYNTAX score (SXscore) has emerged as a reproducible angiographic tool to quantify the extent of coronary artery disease based on the location and complexity of each lesion. The aim of this study was to evaluate whether the SXscore is an independent predictor of long-term cardiovascular outcomes in patients treated with primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI).Methods: A total of 2993 patients with acute STEMI who underwent primary PCI were stratified into the 4 groups according to the SXscore quartiles; quartile 1(Q1, SXscore ≤ 9, n = 819), Q2 (9 < SXscore < 16, n = 715), Q3 (16 ≤ SXscore < 20, n = 710), and Q4 (SXscore ≥ 20, n = 749).Results: There were significant differences among the quartiles with respect to age, basal creatinine and glucose levels, and the incidences of diabetes mellitus, Killip ≥2, and anemia. From Q1 to Q4, there were increasing rates of culprit left anterior descending lesion (P < .001), multivessel disease (P < .001), chronic total occlusion (P < .001), and proximal lesion localization (P < .001). At long-term follow-up, all-cause mortality, nonfatal myocardial infarction, stroke, rehospitalization due to heart failure, and the need of revascularization were significantly more frequent among the patients in the highest SXscore quartile. In multivariate analysis, after including the SXscore as a numerical variable into the model, every point of increase was determined as an independent predictor for long-term mortality (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.01-1.05, P = .008) and for overall major adverse cardiac events (MACEs; HR 1.02, 95% CI 1.01-1.04, P < .001).Conclusion: The SXscore is an independent predictor of both in-hospital and long-term mortality and MACE in patients with acute STEMI undergoing primary PCI.
Myeloma has a well-described association with venous thromboembolism (VTE). There are few dedicated studies investigating the incidence and risk factors. Many assessment scores have been suggested to estimate the risk of VTE in patients with cancer but these have been validated in solid organ tumors. The records of patients with myeloma attending a university hospital between January 2007 and December 2012 were reviewed to investigate the incidence of VTE and the associated risk factors. In all, 217 patients with a mean (standard deviation) age at diagnosis of 65 (12) years were included. Of 217 patients, 12% had an episode of VTE, 69% received at least 1 immunomodulatory agent, and 95% had low or intermediate risk of VTE according to the Khorana score. Venous thromboembolism was a frequent occurrence in this cohort. Patients had many risk factors for VTE but no one was predictive. As myeloma outcomes continue to improve, a dedicated prospective study is warranted to investigate the most appropriate thromboprophylaxis strategy.
We aimed to investigate the association between the neutrophil–lymphocyte ratio (NLR) and coronary artery ectasia (CAE). The study included 198 patients who had undergone coronary angiography for suspected coronary artery disease (CAD). The patients were divided into the following 4 groups: group 1, 44 patients with normal coronary arteries; group 2, 61 patients with CAD; group 3, 40 patients with isolated CAE; and group 4, 53 patients with CAE coexisting with CAD. Neutrophil–lymphocyte ratio was significantly lower in group 1 than the other groups and significantly higher in group 4. Patients in group 1 had significantly lower neutrophil counts and significantly higher lymphocyte counts than the patients in group 4. The isolated CAE and CAD groups were similar in terms of NLR, neutrophil count, and lymphocyte count. In addition, we found significant positive correlations between presence of ectasia, number of ectatic vessels, and NLR. Our findings provide additional evidence for the role of NLR in CAE.
Generally, recurrent spontaneous abortions (RSAs) have no identifiable cause; yet, vascular alterations during pregnancy may be associated with pregnancy loss. Therefore, we evaluated the association between thrombophilic mutations and RSAs. This case–control study was conducted in 112 patients who had RSAs and 98 health control women. Genomic DNA was extracted from whole blood, and polymorphism genotyping was conducted using polymerase chain reaction. The following 6 genetic variants were analyzed: factor V Leiden, prothrombin mutation, methylenetetrahydrofolate reductase C677T and A1298C, plasminogen activator inhibitor type 1 (4G>5G), and factor XIII G103T (V34L). No correlations were found in any of the investigated polymorphisms. Moreover, 35.0% of cases and 25.5% of controls had at least 2 mutations in combination, and 4.8% of cases and 5.1% of controls had 3, but these combinations were not associated with additional risk. In conclusion, we found no association between the polymorphisms studied and the occurrence of RSAs.
Hemodynamic fluctuations and thromboembolic complications are significant areas of concern during the postoperative management of patients with univentricular hearts. The objective of this study is to review the incidence and risk factors associated with thrombosis and thromboembolic complications following total cavopulmonary anastomosis, the third stage of the palliative surgical procedure. A literature search of published evidence was conducted on OvidSP MEDLINE(R) and Embase followed by paired title, abstract, and full-text screening based on specific inclusion criteria. High risks of thromboembolic outcomes were identified across studies, with variable incidences between 3% and 20%, high mortality rates up to 38%, and an inverse relationship with prophylaxis treatment administration. Several risk factors for thrombotic complications, including chronic systemic venous hypertension, protein-losing enteropathy, passive blood flow, atrial arrhythmias, conduit stenosis, prosthetic material use, coagulation factor abnormalities, and several patient characteristics were identified. Based on these findings, a prophylactic anticoagulation algorithm has been proposed.
Objective: To evaluate the performance of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in predicting hyperhomocysteinemia (HHcy) in Chinese patients with hypertension. Methods: We measured plasma total homocysteine tHcy level and C677T genotype in 1058 Chinese patients with hypertension from 4 previous studies. We used 10, 15, and 20 μmol/L as cutoff values for the definition of mild, modest, and severe HHcy, respectively. Logistic models for HHcy were built from the study sample using the C677T genotype as well as age and gender as predictors. The receiver–operating characteristics of the models were evaluated. Results: Our major findings are that (1) C677T TT genotype is consistently associated with a higher tHcy across the 4 studies, with an increase in size ranging from 38% to 68% in the 4 studies and 51% overall. The C677T polymorphism independently explained about 14% of the total variance of the normalized tHcy. (2) The TT genotype is associated with a large increase in odds ratio (OR) for HHcy. Overall, the multivariate-adjusted ORs for the TT genotype are 3.9 (95% confidence interval [CI]: 2.4-6.4), 6.5 (95% CI: 4.0-10.6), and 17.9 (95% CI: 8.4-38.1) for mild, modest, and severe HHcy, respectively. (3) Overall, the predicting performance increased with HHcy severity, with sensitivity improving from 31.0% for mild HHcy to 70.3% for severe HHcy, and with specificity slightly decreasing from 85.4% to 80.3%. Inclusion of gender and age as predictors significantly improves the sensitivity, especially for predicting mild HHcy. Conclusion: With an excellent sensitivity and a modest specificity, C677T could be a useful screening marker for severe HHcy.
Atherosclerosis and venous thromboembolism (VTE) share common risk factors. We set to assess the strength of the association between atherosclerosis risk factors and disease manifestation, and VTE, in patients with coronary artery disease undergoing percutaneous coronary intervention. We pooled data from 6 global randomized controlled trials assessing coronary stenting (ENDEAVOR and SIRIUS programs), developed separate risk scores to predict major adverse cardiac and cerebrovascular events (MACCEs: cardiac death, myocardial infarction, and stroke) and VTE, and compared their performance. The 5-year rates of MACCE and VTE were 10.8% and 2.04%, respectively. Selected predictors for MACCE performed equally well in predicting VTE (area under the receiver–operating characteristic curve [AUC] 0.651 vs 0.672), and selected predictors for VTE performed equally well in predicting MACCE (AUC 0.699 vs 0.620). Ejection fraction and age were associated with both MACCE and VTE. These findings support the concept of overlapping pathophysiology of VTE and atherothrombosis.
The aim of the study was to evaluate the utility of the preprocedural platelet–lymphocyte ratio (PLR) for predicting no reflow in patients undergoing primary percutaneous intervention (PCI) for the treatment of ST-segment elevation myocardial infarction. The thrombolysis in myocardial infarction (TIMI) flow grades of 287 patients treated with primary PCI were assessed retrospectively. Patients were divided into 3 tertiles based upon preprocedural PLR. Pre- and postprocedural TIMI flow grades were evaluated. No reflow developed in 6, 14, and 43 patients in the lower, middle, and higher tertiles, respectively (P < .001). After multivariate analysis, PLR remained a significant predictor of no reflow together with neutrophil–lymphocyte ratio (NLR). A cutoff value of 160 for PLR and 5.9 for NLR predicted no reflow with sensitivities and specificities of 75% and 71% and 74% and 70%, respectively. In conclusion, high preprocedural PLR and NLR levels are significant and independent predictors of no reflow in patients undergoing primary PCI.
There is little data regarding the diagnostic ability of neutrophil–lymphocyte ratio (NLR) in acute coronary syndrome. Therefore, we aimed to assess the predictive value of NLR in the discrimination of troponin-positive patients. We enrolled 244 patients (mean age 61.3 ± 11.7 years, 70.5% male) who presented to the emergency service with acute chest pain. Patients were divided into 2 groups based upon the troponin positivity in the 12- to 24-hour follow-up. The admission NLR was significantly higher in the troponin-positive group (5.49 ± 4.01 vs 2.40 ± 1.36, P < .001). A cutoff point of 2.80 for NLR measured on admission had 79% sensitivity and 73% specificity in predicting follow-up troponin positivity. After multivariate analysis, admission NLR and glucose levels remained significant predictors of follow-up troponin positivity. In conclusion, NLR may be an early diagnostic marker in emergency service for discriminating patients who will have a positive troponin test in the follow-up.
Background: In this study, our aim is to examine the role of the neutrophil to lymphocyte ratio (NLR) in the predictions of recurrence under long-term follow-up in patients whose sinus rhythms (SRs) were restored with amiodarone in acute atrial fibrillation (AF).Methods: Retrospectively, patients with acute AF, which successfully converted to the SR with amiodarone treatment, were recruited into the study. Patients experiencing the first AF attack were enrolled to the study and followed up for 5 years (median 23 months, 25-75 percentiles 12-24 months). Neutrophil to lymphocyte ratio was computed as absolute neutrophil count divided by lymphocyte count.Results: A total of 218 patients were recruited into the study and followed up for 21.6 ± 13.9 months; 87 (40%) patients had ≥1 recurrent AF attack within this period. The follow-up of 131 (60%) patients resulted in persisted SR without any other AF attack. Groups were similar in terms of age and gender. Left atrium (LA) diameter and NLR were increased, and platelet count and lymphocyte count were decreased in patients with AF recurrence in univariate analysis (P < .05 for all). Only LA diameter (for per mm, 1.077 [1.021-1.136], P = .006) and NLR (1.584 [1.197-2.095], P = .001) were independent predictors of AF recurrence in the multivariate analysis.Conclusion: Increased NLR is a marker of increased inflammation and may serve as simple, cheap, and readily available predictors of recurrence in the long-term follow-up of patients admitted with acute AF and successfully converted to SR with amiodarone.
The purpose of the study was to analyze a systemic activation of hemostasis and concentration of matrix metalloproteinase 10 (MMP-10) in patients with primary varicose veins (PVVs). A study group consisted of 41 patients with noncomplicated PVVs. A control group consisted of 30 age- and sex-matched healthy individuals without varicose veins. The concentration of <sc>d</sc>-dimers (DD), prothrombin fragments 1 and 2 (F1+2), antigen of von Willebrand factor (vWF), and activity of plasminogen activator inhibitor (PAI-1) in plasma and concentration of MMP-10 in serum were analyzed. In patients with PVVs, higher concentrations of DD (P < .001), F1+2 (P < .001), vWF (P = .027), MMP-10 (P = .006), and higher activity of PAI-1 (P < .001) were observed. However, no correlation between the concentrations of MMP-10 and prothrombotic markers was found. Noncomplicated PVVs are associated with systemic, prothrombotic activation of hemostasis and increased concentration of MMP-10, suggesting a prothrombotic and proinflammatory state.
In this randomized trial, we compared the hemodynamic effects of 2 different methods of bilateral sequential pneumatic compression (Simultaneous compression with Fixed cycling rate [SF] vs Alternate compression with Adjusted cycling rate [AA]) and investigated whether venous flow augmentation influenced deep vein thrombosis (DVT) development in patients undergoing total knee arthroplasty. Pneumatic compression was started on the operation day and applied to discharge. A total of 108 limbs was evaluated by computed tomographic angiography and duplex ultrasound. Augmented peak volume flow (P = .008), expelled total volume (P < .001), and expelled peak volume (P < .001) were significantly larger in group SF. The DVT developed in 35 (32.4%) limbs, and they were neither symptomatic nor ileofemoral in location. The enhanced hemodynamic parameters did not influence the DVT development. In conclusion, group SF showed superior hemodynamic efficacy, but this superiority may not be a surrogate for better thromboprophylaxis.
Acute traumatic coagulopathy (ATC) is commonly seen among patients with severe injury and will lead to uncontrolled bleeding diathesis, which is an important contributor to trauma death. During the past 10 years, the understanding of the mechanism causing ATC has changed rapidly. The mechanisms for ATC are complicated. To date, the possible mechanisms include activation of protein C, shedding of endothelial glycocalyx, catecholamine release, platelet dysfunction, primary, and secondary fibrinolysis, with tissue injury and hypoperfusion as the triggers. Classic factors such as dilution, acidosis, and hypothermia can further aggravate the coagulopathy. Inflammation may have a potential effect on the onset and prognosis of ATC. With the aid of diagnostic device, the outcome can be improved through early and customized treatment. Antifibrinolytics such as tranexamic acid has some benefits in patients with bleeding trauma, especially in the early time. This review presents the current understanding of ATC mechanisms and management.
This study compared the incidence of M2/ANXA5 haplotype carriage, a documented repeated miscarriage risk factor, in patient groups with normal and elevated lipoprotein(a) (Lp(a)) levels. A total of 138 women with ≥2 consecutive, idiopathic recurrent miscarriages, categorized in patients with elevated (≥30 mg/dL, n = 44) and normal Lp(a) level (<30 mg/dL, n = 94) were recruited at the recurrent pregnancy loss (RPL) clinic of Munich Großhadern University Hospital. A total of 500 fertile women served as controls. All patients were genotyped for ANXA5 promoter haplotypes, genetic frequencies were compared, and odds ratios (ORs) and relative risks of M2 carriers were calculated. Women with M2 haplotype had an almost 2 times higher relative risk of RPL (OR 2.6, 95% confidence interval 1.5-4.6, P = .001) than fertile controls. Furthermore, risk rises to 2.47 in patients having normal Lp(a) levels (OR 3.2, 95% confidence interval 1.7-5.9, P = .001), whereas women with high Lp(a) levels exhibit notably lower apparent RPL risk of 1.39 (OR 1.4, 95% confidence interval 0.5-4.1, P = .659).
Background: Factor V (FV) Leiden mutation-related activated protein C resistance (APCR) is one of the common inherited risk factors for venous thromboembolism (VTE) in caucasian population. Although APCR could be identified in some of the Chinese healthy people and patients with VTE, it was not related to FV Leiden mutation. In 2008, we have identified a novel FV mutation (FV E666D) in exon 13 in a hereditary APCR family. And we presumed that the novel mutation might be a genetic defect of APCR in the Chinese population. The aim of our study was to evaluate the prevalence of FV E666D mutation and its correlation with APCR in the Chinese population in a larger series.Methods: From June 2009 to January 2011, 163 consecutive patients who underwent thrombophilia tests in our hospital were recruited. The clinical data were retrospectively reviewed. Thrombophilia tests included APCR, anticoagulant proteins, and antiphospholipid antibodies. Factor V E666D mutation was detected.Result: Of the 163 patients, 6 (3.7%) were identified as APCR positive, 2.9% for patients without thrombosis and 5.1% for patients with thrombosis or thrombosis history. Factor V E666D mutation was not detectable in all the 163 patients including 6 APCR-positive patients.Conclusions: The prevalence of APCR either in the nonthrombotic patients or in the patients with thrombosis was lower than that reported in other Chinese studies. Our study couldn’t provide illustration whether FV E666D mutation is correlated with APCR in the Chinese population.
The aim of the study is to investigate the association between the severity of rheumatic mitral valvular disease (RMVD) and the neutrophil–lymphocyte ratio (NLR). A total of 227 patients were enrolled in the study and divided into 3 groups. Patients in group 1 had rheumatic mitral stenosis (RMS), those in group 2 had RMVD without stenosis, and those in group 3 served as the control group. Group 1 was further divided into 2 groups, severe mitral stenosis (MS) and mild to moderate MS. The NLR was significantly higher in patients with severe MS when compared to those with mild to moderate MS (P = .002) while lymphocyte count was lower (P = .034). Using a cutoff level of 2.56, the NLR predicted severe RMS with a sensitivity of 75% and specificity of 74%. In conclusion, as an inexpensive, simple, and accessible marker of inflammation, the NLR may be useful in predicting the presence and severity of MS in patients with RMVD.
Retinal vein occlusion (RVO) and retinal artery occlusion (RAO) cause significant visual impairment. The role of thrombophilia and cardiovascular testing is uncertain, and optimal treatment strategies have not been determined. We reviewed medical records of 39 patients with RVO and RAO (23 women and 16 men). Thrombophilia and cardiovascular evaluations were performed and outcomes were reviewed. In all, 24 (61.5%) patients had at least 1 thrombophilia. Elevated factor VIII levels were found in RVO (n = 5) but not in RAO. There are no other significant differences in thrombophilias in RVO compared to those in RAO. Most patients had hypertension(41.2% RAO and 55% RVO) and hyperlipidemia (35.5% RAO and 81.8% RVO). In all, 4 women were using oral contraceptives, 2 were pregnant or postpartum. Follow-up data was available for 28 patients (13 RAO, 15 RVO). Nineteen were treated with aspirin, four with warfarin, and one with low molecular weight heparin. Eight patients reported improvement in vision at time of follow-up (5 RAO, 3 RVO). Multiple risk factors are associated with RVO and RAO, and a complete assessment should include thrombophilia and cardiovascular studies.
This study presents the demographics, clinical spectrum, and outcome of patients with congenital factor VII (FVII) deficiency at a tertiary care center over a period of 12 years. Of the 49 patients, 27 (55%) patients were males. Consanguinity was found in 92% of the patients. The median age of symptom onset was 2.4 (interquartile range [IQR]: 1.1-6.5) years with a median age of 5.8 (IQR: 3.1-10) years at diagnosis. Life-threatening complications like intracranial bleeding (ICB) and intra-abdominal bleeding (IAB) were observed in 8 (16.4%) patients. We found that 11 (55%) of the 20 patients with FVII coagulant activity (FVIIc) <1% were either asymptomatic or showed mild phenotype. In contrast, 9 (53%) of the 17 patients with FVIIc >5% were affected by severe symptoms. Age <1 year was the only identified risk factor associated with development of life-threatening bleeding episodes (P = .042; odds ratio 6.46). Overall, 4 (8.2%) died as a consequence of ICB (3 patients) and IAB (1 patient).
Objectives: In this study, we aimed to investigate the relationship between neutrophil to lymphocyte ratio (NLR) and infarct-related artery (IRA) patency in patients with ST-segment elevation myocardial infarction (STEMI).Methods: A total of 349 patients with STEMI were recruited to this retrospective study. Baseline characteristics were reviewed. Patency of IRA was evaluated by thrombolysis in myocardial infarction flow grade.Results: Of all patients, 293 patients formed the occluded IRA group and 56 patients formed the patent IRA group. The NLR was significantly higher in occluded IRA group (4.4 ± 4.1 vs 1.9 ± 1.1, P < .001). Glucose levels were also higher in occluded IRA group (171.3 ± 78.0 vs 144.7 ± 49.7, P = .022). Regression analysis demonstrated admission NLR and plasma glucose levels as independent predictors of IRA patency.Conclusion: In this study, we found that admission NLR and glucose levels were higher in patients with occluded IRA than in patients with STEMI. We also found that NLR and glucose levels were independent predictors of IRA patency. Because hemogram is a cheap, fast, and widely available test, it can be used in daily practice as a predictor of IRA patency.
Polymyxin B is a cationic peptide that inhibits phospholipid-dependent coagulation tests including activated partial thromboplastin time and to a lesser degree prothrombin time. Thrombin clotting time is insensitive to polymyxin B. β2-glycoprotein 1 (β2GP1) is a cofactor of antiphospholipid antibodies. Antiphospholipid autoantibodies also poses lupus anticoagulant activity through interactions with β2GP1. Using affinity chromatography, polymyxin B can effectively decrease the binding of β2GP1 to immobilize phosphatidylserine. Since then, anticoagulant effect of polymyxin B is most likely due to the binding to negatively charged phospholipids, preventing formation of coagulation complexes.
Thromboelastography (TEG) is drawing more attention for clinical and laboratory studies of hemostasis. It has been applied to evaluate the effects of both psychological and physiological stress on whole blood coagulation from the onset of the coagulation cascade through clot formation, to the end with fibrinolysis. We conducted a comprehensive review on the applications of TEG for assessment of different stressors, ranging from physical exercise to emotional situations. The methodology is unique in terms of instrumentation, the methods to activate blood coagulation, the type of blood (citrated vs fresh blood), and study settings (in vitro vs in vivo vs clinical trials). Thromboelastography has most often been used to study the effects of physiological stress. The author’s own work and future directions are discussed as well. The review would facilitate future development of TEG for evaluating hemostasis and potential pathological pathways in response to various forms of stress.
Early diagnosis is the key point in the management of acute pulmonary thromboembolism (PTE). There are no reports in the literature comparing the serum cystatin C levels in patients with acute PTE and normal volunteers. Therefore, in this study, we analyzed 50 patients with acute PTE and 45 healthy volunteers with normal renal function. The serum cystatin C level was significantly higher in the PTE group than in the non-PTE group (1.08 mg/dL [interquantile range (IQR) 0.79-1.56] and 0.85 mg/dL [IQR 0.77-1.03], respectively, P = .017). When determining the presence of PTE, the highest value of sensitivity and specificity was set at a cutoff value of 1.15 mg/dL with 93.3% specificity, 46.0% sensitivity, 88.5% positive predictive value, and 60.9% negative predictive value. In the multivariate model, cystatin C was significantly associated with the presence of PTE (odds ratio: 12.34, 95% CI 2.64-57.75). In conclusion, cystatin C may be an indicator of acute PTE in patients with normal renal function.
Objective: This study was planned to compare the efficacy of bolus regimens of tenecteplase (TNK) and 24 hours infusion of streptokinase (STK) in acute pulmonary embolism (APE) in a resource-poor setting. Interventions: In all, 25 patients received injection of TNK, and 75 patients received infusion of STK over 24 hours. Results: Pulmonary artery systolic pressure and right ventricular function were improved separately and significantly (P = .01) in both the study groups of patients from baseline at 24 hours or at seventh day and was comparable among the TNK and STK groups of patients. Mean duration of stay in intensive care unit was significantly less (2.2 ± 0.8 vs 3.2 ± 1.3 days; P = .04), and bleeding risk was also found to be nonsignificantly less in the TNK group. Conclusion: These results suggest that a 24-hour infusion regimen of STK is as effective as bolus TNK in the treatment of patients with APE in countries with limited resources.
The purpose of this study was to characterize differences in the prevalence of hereditary and acquired thrombophilia in patients with splanchnic vein thrombosis (SVT). A total of 88 consecutive patients with SVT, including Budd Chiari Syndrome (n = 47) and portal extrahepatic portal vein obstruction (n = 41), underwent comprehensive thrombophilia testing, including testing for heritable and acquired causes. In 33 (37.5%) patients, etiology could be explained by at least 1 of the heritable etiologic factors, and 31 (35.2%) patients could be explained by at least 1 of the acquired causes studied. The combination of multiple concurrent factors was present in 9 (11.4%) patients. Among the heritable causes, the risk of SVT was found increased in the presence of thrombophilia resulting from the deficiencies of the naturally occurring anticoagulant proteins, and the acquired thrombogenic factors were significantly associated with causation of thrombosis in adult patients with SVT.
Inflammatory mediators and hemostatic markers were evaluated in patients enrolled in a phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with sepsis and suspected disseminated intravascular coagulation (DIC). In contrast to controls, patients with sepsis and suspected DIC showed an increase in the circulating levels of inflammatory and fibrinolytic markers. The levels of procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), anaphylatoxin C5a, plasminogen activator inhibitor 1 (PAI-1), and myeloperoxidase were higher in the patients with sepsis and suspected DIC, whereas protein C (PrC) exhibited a significant decrease. When the patients with overt and nonovert DIC were compared, the PrC level was lower, and PCT, PAI-1, IL-6, and IL-10 levels were higher in the patients with overt DIC. These results indicate that inflammation is elevated in sepsis and suspected DIC, and inflammation, impairment of fibrinolysis, and overconsumption of PrC may play a key role in the pathogenesis of DIC.
In this study, lymphocyte subgroups including blood CD3, CD4, CD8, CD4/CD8, CD19, and CD16.56 values were analyzed in children with Down syndrome (DS). The study includes 85 children with DS, followed at Department of Pediatrics, Faculty of Medicine, Yüzüncü Yil University and 64 healthy age-matched control participants. Blood CD3, CD4, CD8, CD4/CD8, CD19, and CD16.56 values were examined in both the groups. Significantly decreased blood CD3, CD4, and CD19 values were found in the study group (P < .05) when compared with the control group. In conclusion, we would like to emphasize that blood CD3, CD4, and CD19 levels were found to be decreased in children with DS. Based on these finding, we think that these decreased lymphocyte subgroups might be responsible for increased susceptibility to infections in children with DS.
Objective: The aim of this study was to evaluate the relationship between vitamin D levels and hemostatic factors like tissue factor pathway inhibitor (TFPI).Methods: Patients who had 25-hydroxyvitamin D3 (25(OH)D3) levels measured were included. Coagulation and hemostatic parameters were evaluated. Patients were divided into 3 groups based on 25(OH)D3 levels as group 1 (25(OH)D3 < 10 ng/mL, n = 25), group 2 (25(OH)D3 = 10-19.9 ng/mL, n = 22), and group 3 (25(OH)D3 ≥ 20 ng/mL, n = 28).Results: A total of 75 patients with a mean age of 39 (range 18-57) years were included in the study. Prothrombin time was longer in group 3 than in group 2 (P = .043). The TFPI levels were higher in group 3 than in the other groups (P < .001). There was a strong positive correlation between 25(OH)D3 and TFPI levels (r = .47, P < .001).Conclusion: Further studies are needed for evaluation of the role of TFPI in hemostasis and thrombotic process in patients with vitamin D deficiency.
Leukocytes are reported as crucial not only for plaque activation but also in thrombus formation in acute coronary syndromes (ACSs). Among the markers of inflammation, in coronary artery disease neutrophil–lymphocyte ratio (NLR) has been reported to have the greatest predictive power of poor outcomes. Our aim was to evaluate the association of NLR with coronary thrombus in patients with non-ST-segment elevated ACSs (NST-ACSs). A total of 251 patients were hospitalized with a diagnosis of NST-ACS including non-ST-segment elevated myocardial infarction and unstable angina pectoris. Coronary angiographies were performed. In 167 patients, coronary thrombus was detected. Between the patient groups with and without coronary thrombus, neutrophil count, platelet count, and NLR are significantly increased, and lymphocyte count is significantly decreased in the group with coronary thrombus as compared to patient group without coronary thrombus. Leukocyte count and NLR may give an indication about the presence of coronary thrombus. In NST-ACS, blood parameters may give valuable information about the status of the coronary arteries.
To study the production of anti-platelet factor 4 (anti-PF4)/heparin complex antibodies of Ig (immunoglobulin) G/IgA/IgM using enzyme-linked immunosorbent assay (ELISA; heparin-induced thrombocytopenia [HIT] antibodies) in 79 patients undergoing cardiovascular surgery, we employed optical density (OD) as a marker of HIT-antibody production. The ODs were calculated from the differences in the ODs using ELISA. Patient were classified into 3 OD ranges: OD ≥ 1.0, OD ≥ 0.4 to <1.0, and OD < 0.4. The underlying disease, time course of the postoperative platelet count, <sc>d</sc>-dimer level, postoperative brain magnetic resonance imaging (MRI), use of cardiopulmonary bypass and postoperative thrombocytosis were not considered for the 3 OD classifications. None of the 6 patients with OD ≥1.0 and a positive functional assay was diagnosed with HIT due to the absence of HIT-derived thrombocytopenia. In conclusion, HIT-antibody production increased until day 7 after heparin cessation and reached a trace level on day 14. It was demonstrated that HIT-antibody production is in remission unless there is any evidence of a further increase during the second week postsurgery.
Background: Biomarkers of endothelial dysfunction are not recommended for routine laboratory investigation of the outcome prognosis and prediction of the course of sepsis.Methods: A total of 60 patients who fulfilled the criteria for diagnosis of sepsis were included in our study. Development of multiorgan dysfunction syndrome (MODS) in the first 48 hours was assessed. Differences between groups of patients with sepsis were assessed by Mann-Whitney U test and by Kruskal-Wallis test. Logistic regression analysis was performed to test the joint effect of different predictors.Results: Level of thrombomodulin was significantly higher in group of patients with MODS than without MODS (P = .015). Levels of antithrombin (P = .026) and protein C (P = .035) were significantly lower in patients with MODS. Level of thrombomodulin was the strongest predictor in MODS development in first 48 hours (P = .028).Conclusion: The level of thrombomodulin not only was able to distinguish the severity of sepsis but also was a significant predictor of MODS development.
Inflammation has recently emerged in the pathogenesis of several cardiovascular disorders, including arrhythmias. The neutrophil–lymphocyte ratio (NLR) is a simple marker for the assessment of inflammatory status. Therefore, we aimed to investigate the relationship between the NLR and the ventricular premature contraction (VPC) existence. Patients aged between 18 and 40 years who were referred to the cardiology clinic were enrolled in the study. All patients’ complete blood counts and 24-hour Holter recordings were analyzed. The NLR was higher within the VPC group compared to the control group (P < .001). According to the NLR tertiles, VPCs were more common in the higher NLR tertile (P < .001). A cutoff point of 1.80 for the NLR had 71% sensitivity and 60% specificity in predicting VPC in apparently healthy individuals. After multivariate analysis, only the NLR remained significant predictor of presence of VPC. In conclusion, the NLR is independently and significantly associated with VPC existence.
Objectives: We aimed to investigate the relationship between the platelet-lymphocyte ratio (PLR) and coronary collateral circulation (CCC) in patients with stable angina pectoris (SAP) and chronic total occlusion (CTO). Methods: A total of 294 patients with both SAP and CTO were classified according to their Rentrop collateral grades as either poor (Rentrop grades/0-1) or good (Rentrop grades/2-3). Results: The PLR values were significantly higher in patients with poor CCC than in those with good CCC (156.8 + 30.7 vs 132.1 + 24.4, P<0.001). In regression analysis, PLR (unit=10) [odds ratio 1.48, 95% confidence interval (CI) 1.33 -1.65; P<0.001] and high-sensitivity C-reactive protein were found to be the independent predictors of poor CCC. In receiver operator characteristic curve analysis, optimal cut-off value of PLR to predict poor CCC was found as 138.1, with 76% sensitivity and 65% specificity. Conclusion: PLR may be an important, simple, and cost effective tool predicting the degree of collateralization in patients with SAP and CTO.
Traditional anticoagulants, such as low-molecular-weight heparin and vitamin K antagonists, have been the mainstay for the treatment of venous thromboembolism (VTE) in the hospital setting and after discharge. These anticoagulants are effective but are associated with some limitations that may lead to their underuse. Based on the results of the EINSTEIN clinical trial program, the oral, direct factor Xa inhibitor rivaroxaban is approved for the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) and for the prevention of recurrent VTE. The single-drug approach with rivaroxaban is now available in both the hospital and the outpatient settings and may overcome some of the limitations of traditional agents. This review provides hospital physicians with an overview of the practical management of rivaroxaban and a critical evaluation of its use for the treatment of DVT and PE, including in specific clinical settings and special patient populations.
Hospitalized acutely ill patients face high risk for venous thromboembolism (VTE) unless appropriate thromboprophylaxis is applied. This study aimed to determine VTE prophylaxis practices for inpatients in Turkey and to evaluate the impact of physicians’ training via a modified "Standard Medical Patients’ VTE Risk Assessment Model (MERAM)." A total of 607 inpatients included in this national multicenter noninterventional observational registry were evaluated in terms of demographics, VTE risk, and preventive measures at 2 consecutive cross-sectional visits. Physicians were asked to complete a questionnaire on current VTE method risk assessment and other models including MERAM. The VTE prophylaxis rates significantly increased from 49.4% to 62.4% between visits (P < .05). The lack of risk evaluation decreased from 74.6% to 19.5% (P < .001). Percentage of physicians using prophylaxis and use of MERAM increased between visits. Physician training proved effective for providing general "awareness" of VTE prophylaxis and led to higher rates of risk assessment model-based appropriate VTE prophylaxis.
The AVERROES trial name is the following: The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial demonstrated that apixaban reduced the risk of stroke relative to aspirin, without significantly increasing major bleeding risk in patients with atrial fibrillation (AF) considered unsuitable for warfarin therapy. Based on AVERROES trial results, this study compared the medical costs for clinical end points among patients with AF treated with either apixaban or aspirin.
Medical costs per patient-year for clinical events were determined. Based on clinical event rates for patients in the AVERROES trial, medical costs excluding drug costs were estimated for apixaban- and aspirin-treated patient groups.
Based on AVERROES trial results, among patients with AF unsuitable for warfarin therapy, apixaban use was estimated to be associated with a mean medical cost avoidance of US$735 in a patient-year relative to aspirin. The primary driver was the significant reduction in ischemic stroke rate. The medical cost reduction associated with apixaban use was consistent in sensitivity analyses.
Introduction: Inferior vena cava filters (IVCF) are used liberally in clinical practice and have been associated with multiple complications. Herein, we present results from our institution. Methods: Records of consecutive patients discharged between January 1, 2009 and 2012 were reviewed. Indications were subcategorized under absolute, relative, and prophylactic. Student t test and Kaplan-Meier survival analysis were employed. Results: During this period, 254 vena cava filters (VCF) were placed. Of these, 65 were placed for absolute indication, 28 for relative, and 161 for prophylaxis. Follow-up imaging was available for 96 patients of which 15 showed complications. Successful retrieval of 19 filters was achieved. Conclusion: The study demonstrates that most IVCF are being placed for prophylaxis with low retrieval rate. This contradicts current recommendations. Moreover frequent migration and penetration of IVCF can lead to serious complications. Strict enforcement of IVCF placement guidelines and setting up of filter clinics for timely retrieval is suggested.
Background: Diagnosing cerebral venous sinus thrombosis (CVST) in patients referring to emergency service or neurology outpatient unit with complaints of headache is a challenging task. Magnetic resonance (MR) venography is the gold standard, but there are limitations regarding its use. Aim: To evaluate the validity of red cell distribution width (RDW) in CVST diagnosis in patients presenting with headache. Methods: A total of 138 patients comprising 37 patients with CVST and 101 control primer headache cases were included in this retrospective cross-sectional study. Control group consists of hospitalized patients with primary headache. Venous blood hemoglobin (Hb), platelet, mean corpuscular volume (MCV), RDW, fibrinogen, and vitamin B12 levels of the patients were recorded at the first referral. Diagnosis of CVST was established by MR venography. Results: The RDW ratio of patients with a diagnosis of CVST was significantly higher than that in patients with primary headache (15.3 ± 1.4 vs 13.3 ± 0.5; P <.0001). Fibrinogen and vitamin B12 levels were not significantly different between the 2 groups. In a total of 11 patients, there was more than 1 thrombosis. In 21 of the patients with CVST, gene mutation was detected. There was no significant difference between the patients with and without mutations regarding RDW values. Diagnostic validity of RDW was found to be excellent in differentiating patients with CVST and primary headache (area under the curve = 0.996; 95% CI: 0.990-1.000). Optimum RDW cutoff value was determined as 14.1% (sensitivity: 91.9%, specificity: 99%, positive predictive value: 92.8, negative predictive value: 0.082). Conclusion: We suppose that among patients presenting with the complaint of headache, RDW value may lead to diagnose CVST.
In this study, we aimed to investigate the association of the neutrophil-to-lymphocyte ratio (NLR) with Global Registry of Acute Coronary Events (GRACE) risk score in patients with ST-segment elevated myocardial infarction (STEMI). We analyzed 101 consecutive patients with STEMI. Patients were divided into 3 groups by use of GRACE risk score. The association between NLR and GRACE risk score was assessed. The NLR showed a proportional increase correlated with GRACE risk score (P < .001). The occurrence of in-hospital cardiac death, reinfarction, or new-onset heart failure was significantly related to NLR at admission (P < .001). Likewise, NLR and GRACE risk score showed a significant positive correlation (r = .803, P < .001). In multivariate analysis, NLR resulted as a predictor of worse in-hospital outcomes independent of GRACE risk score. Our study suggests that the NLR is significantly associated with adverse in-hospital outcomes, independent of GRACE risk score in patients with STEMI.
The aim of this study is to assess the in vivo hemostatic effect of Ankaferd Blood Stopper (ABS) on rats using a tail bleeding model. Wistar rats were randomized into 4 groups of 9 each: group 1, control, no pretreatment, irrigated with saline; group 2, no pretreatment, irrigated with ABS; group 3, control, heparin pretreatment, irrigated with saline; and group 4, heparin pretreatment, irrigated with ABS. To control bleeding, compressive dressings were placed after instilling 1 mL of either ABS or saline to the bleeding area. Without heparin pretreatment, ABS shortened hemostasis time by 1.57 minutes and reduced the amount of bleeding by 0.85 g. With heparin pretreatment, ABS shortened hemostasis time by 3.29 minutes and reduced the amount of bleeding by 1.32 g. The ABS was more effective than saline irrigation for treating tail tip bleeding in rats, with or without heparin pretreatment, while also using a compressive dressing.
Objective: Neutrophil–lymphocyte ratio (NLR) has been associated with poor outcomes in patients with cardiovascular diseases. We aimed to compare NLRs among patients with nonvalvular atrial fibrillation (AF) with or without left atrial (LA) thrombus.Methods: A total of 309 (70.1 ± 9.8 years, 49% male) patients with nonvalvular AF have undergone transoesophageal echocardiography (TEE) to assess the presence of LA thrombus. Baseline NLR was measured by dividing neutrophil count to lymphocyte count.Results: Left atrial thrombus was detected in 32 (10.3%) of 309 patients. Mean NLR (2.2 ± 1.0 vs 2.7 ± 1.1, P = .026) was significantly higher among patients with LA thrombus compared to patients without LA thrombus. On multivariate analysis, NLR (odds ratio 1.59, 95% confidence interval 0.87-4.18; P < .02) was an independent risk factor for the presence of LA thrombus in patients with nonvalvular AF.Conclusion: Neutrophil–lymphocyte ratio, an emerging marker of inflammation, was independently associated with the presence of LA thrombus in patients with nonvalvular AF.
Aim: The pathophysiology of cardiac syndrome X (CSX) has not been clearly identified, although multiple abnormalities including microvascular spasm, endothelial dysfunction, and atherothrombosis have been reported. It is known that eosinophils play an important role in vasoconstruction and thrombosis. We aimed to compare the eosinophil counts in patients with CSX versus controls. Materials and Methods This study included 50 patients with CSX (20 male, mean age 50.42 ± 9.6 years) and 30 control persons (10 male, mean age 49.16.11 ± 9.2 years). These participants underwent concurrent routine biochemical tests, and their eosinophil counts were obtained on whole blood count. These parameters were compared between groups. Results: Baseline characteristics of the study groups were comparable. Patients with CSX had a higher eosinophil count and mean platelet volume (MPV) value than the controls (339.4 ± 188 vs 132.7 ± 75 and 8.8 ± 0.2 vs 7.2 ± 0.1 fL; P < .001, respectively). Conclusion: As a result, our study revealed a relationship between eosinophil count and MPV in patients with CSX.
Introduction: The sticky platelet syndrome (SPS) is a common cause of thrombosis. There are no prospective studies concerning treatment. Objective: To analyze changes in platelet hyperaggregability of patients with SPS who were given antiplatelet drugs and to assess its association with rethrombosis. Methods: A total of 55 patients with a history of thrombosis and SPS phenotype were prospectively studied before and after treatment with aspirin and/or clopidogrel. Results: Patients were followed for 1 to 129 months, median 13. Of 55 patients, 40 received aspirin, 13 received aspirin + clopidogrel, and 2 received only clopidogrel. The platelet aggregation response to adenosine diphosphate and epinephrine significantly diminished after treatment, and only 2 patients developed rethrombosis 52 and 129 months after starting therapy, with the freedom from rethrombosis rate of the patients being 96.4% at 129 months. Conclusion: Using antiplatelet drugs, the platelet hyperreactivity of patients with the SPS phenotype was reverted; and this translated into a substantial decrease in the rethrombosis rate.
Background: Hemophilia A is a X-linked recessive bleeding disorder characterized by qualitative and quantitative deficiency of factor VIII resulting from heterogeneous mutations in the factor VIII gene located in the Xq28 region. Intron 22 inversion (Inv22) mutation is one of the major causes of the protein alteration in factor VIII; its frequency is 40% to 50% in severe patients. Long polymerase chain reaction (PCR) and inverse PCR (I-PCR) have been used for the detection of Inv22 mutation. Objective: Development of new protocol for detection of Inv22 mutation. Method: We have designed a new method for the detection of Inv22 mutation in complementary DNA (cDNA) of patients. Real-time PCR targeting exons 21 to 22, 22 to 23, and 23 to 24 of factor VIII gene were used in cases with hemophilia A. Samples that were inversion positive by this new method were cross-checked by the conventional I-PCR method. We observed that region between exons 22 and 23 could not be amplified, while in negative cases and controls a 480 bp product is obtained. Result: The method was validated in 20 cases with severe hemophilia A by the new cDNA method, and 8 cases were inversion positive, whereas 12 were negative cases. The findings were confirmed by standard I-PCR method. Complete correlation was observed. Conclusion: Conventional long PCR and I-PCR methods are work intensive, prolonged, and sometimes difficult to be standardize. The cDNA method is short, involves 3 short-segment amplifications, and is easy to reproduce.
The association between factor XIII-A (FXIII-A) Val34Leu polymorphism and myocardial infarction (MI) risk remained controversial. We performed a meta-analysis. Online databases were searched. Twenty-eight studies were included. The FXIII-A Val34Leu polymorphism was significantly associated with MI risk (odds ratio (OR) = 0.83, 95% confidence interval [CI] 0.76-0.91; P < .0001). This result remained statistically significant when the adjusted ORs were combined (OR = 0.77, 95% CI 0.65-0.92; P = .004). When stratifying for race, this polymorphism showed decreased MI risk in Caucasians. In the subgroup analysis by age group, significant associations were observed in early-onset patients and in late-onset patients. In the subgroup analysis by gender, there was a significant association in women but not in men. In the subgroup analysis stratified by smoking status, MI risk was decreased in both smokers and nonsmokers. This study suggested that FXIIIA Val34Leu polymorphism was a protective factor for MI in caucasians.
Neutrophil/lymphocyte ratio (NLR) has been proposed as a prognostic marker to determine systemic inflammatory response and atherosclerosis. Our aim was to determine the relationship between NLR and development of coronary collateral circulation (CCC) in patients with stable coronary artery disease (CAD). A total of 521 consecutive patients with stable CAD who underwent coronary angiography and documented total occlusion in one of those major coronary arteries were included in this study. Levels of fasting blood glucose, white blood cell, and NLR were significantly higher in patients with poor collateral than in those with good collateral. After multivariate analysis, high level of NLR was an independent predictor of CCC together with levels of fasting blood glucose. The receiver–operating characteristic analysis provided a cutoff value of 2.75 for NLR to predict poor CCC with 65% sensitivity and 68% specificity. We demonstrated an independent association between levels of NLR and development of CCC in patients with stable CAD.
Dysfunctional T-lymphocyte immunity plays an important role in the pathophysiology of immune thrombocytopenic purpura (ITP). Cytotoxic T-lymphocyte antigen 4 (CTLA-4)—a surface marker expressed on T regulatory cells and activated T lymphocytes—is a negative modulator of T-cell responses. Polymorphisms of the CTLA-4 may alter the level of antigen expression and hence may influence immune regulation. The study aimed to evaluate the possible contribution of CTLA-4 exon 1 49 A>G polymorphism to the pathogenesis of ITP and its relation to age of disease onset, clinical course, and response to therapy. Genotyping of CTLA-4 exon 1 49 A>G was performed in 100 pediatric patients with ITP and 259 healthy individuals by polymerase chain reaction–restricted fragment length polymorphism. No significant differences existed in genotype or allele distributions between patients and controls for the studied polymorphism. Comparable genotypes and allele frequencies were obtained between the 2 groups after their stratification by age of disease onset, clinical course, or response to therapy. In conclusion, CTLA-4 exon 1 49 A>G polymorphism is not associated with susceptibility to ITP in the Egyptian population; neither it affects the clinical picture of the disease.
Management of pulmonary embolism (PE) is still unclear. We summarized 16 kinds of evaluation factors of PE severity and prognosis, and we analyzed the single and joint value for short-term and long-term prognosis. Among them, biomarkers such as brain natriuretic peptide or N-terminal probrain natriuretic peptide, troponin, and heart-type fatty acid-binding protein are the best indicators of PE severity and short-term prognosis. They might replace imaging detections in evaluating PE severity. But the positive predictive value of all the biomarkers is low, and we need to improve each value through joint detection. The PE severity index and simplified PE severity index are more suitable for evaluating the overall risk and long-term prognosis. They could be used as complements of indicators of the PE severity, especially in identifying low-risk group. Integrated risk stratification and strategies of management should be established based on the 2 aspects mentioned previously.
No study has compared 2 different dosing strategies for argatroban titration nor has any published nomogram demonstrated improvement in outcomes. This study was conducted to evaluate the effectiveness of 2 argatroban nomograms on reaching therapeutic anticoagulation. Patients treated with argatroban were separated into 2 sliding scale groups, percentage adjustments (PAs) and predefined dose increments (PDIs). The primary outcome was the time to reach a therapeutic activated partial thromboplastin time (aPTT). The average initial dose and dose to achieve a therapeutic aPTT were similar between the groups. There was also no difference in the number of dose changes. The time to reach a therapeutic aPTT was 2 hours shorter in the PDI compared to the PA group, 8 ± 4 hours versus 10 ± 4 hours, P = .015. This study demonstrates a significant time advantage associated with a PDI nomogram compared to a PA nomogram but no difference with respect to the number of rate changes.
We aimed to investigate whether prolonged treatment with dalteparin could inhibit plaque progression. With C57BL/6J mice as the control, genetically deficient apolipoprotein E (apo E) male mice of C57BL/6J strain (apo E-/-) were randomly divided into 3 groups. The model group received no dalteparin, while the other 2 groups received dalteparin at 100 and 200 U/kg d, respectively. The aorta was harvested for hematoxylin and eosin staining to observe plaque formation and for immunohistochemical staining to detect the expression of oxidized low-density lipoprotein receptor 1 (LOX-1). The expression of LOX-1 messenger RNA was detected by reverse transcription polymerase chain reaction, while the expression of LOX-1 protein was detected by Western blotting. Dalteparin decreased aortic plaque volume and inhibited aortic LOX-1 protein expression in apo E-/- mice. The effect persisted 4 weeks after dalteparin treatment was discontinued. Dalteparin may inhibit atherosclerotic lesions by downregulating the expression of LOX-1 protein.
The aim of this study was to evaluate the relationship between red cell distribution width (RDW) and Global Registry of Acute Coronary Events (GRACE) risk score in patients with unstable angina pectoris (UAP) and non-ST elevation myocardial infarction (NSTEMI). We retrospectively enrolled 193 patients with UAP/NSTEMI (mean age 63.6 ± 12.6 years; men 57%) in this study. Higher RDW values were associated with increased in-hospital mortality (P = .001). There is a significant correlation between RDW and GRACE score (P < .001). In multivariate logistic regression analysis, RDW was found to be an independent predictor of high GRACE score (odds ratio: 1.513, 95% confidence interval: 1.116-2.051, P = .008). A cutoff value of >15.74 for RDW predicted high GRACE score, with a 64% sensitivity and 65% specificity. Our study results demonstrated that high RDW was an independent predictor of high GRACE score, and it is associated with in-hospital mortality in UAP/NSTEMI.
The novel oral anticoagulants (NOACs) apixaban, dabigatran, and rivaroxaban have been recently indicated for stroke prevention in patients with atrial fibrillation (AF) . Due to a lack of direct head-to-head trials comparing the NOACs, the current systematic review and network meta-analysis (NMA) were conducted to assess their relative efficacy and safety. Three phase III randomized controlled trials enrolling 50 578 patients were included. Results of the NMA show a clear trend favoring NOACs over warfarin with regard to the key outcomes of stroke/systemic embolism and all-cause mortality, with apixaban also showing a favorable response for major bleeding and total discontinuations. Although there were few significant differences among the NOACS with regard to efficacy outcomes, apixaban and dabigatran 110 mg were associated with significantly lower hazards of major bleeding compared with dabigatran 150 mg and rivaroxaban. The NOACs offer a therapeutic advance over standard warfarin treatment in stoke prevention in patients with nonvalvular AF.
Backgound/Aim: Preeclampsia (PE) is a multisystem disease resulting in high maternal–fetal morbidity and mortality. The aim of the study was to investigate antiangiogenesis-associated alterations in antiapoptotic and antioxidative proteins in PE. Method: Of the 46 patients with PE, 25 (54.3%) were with gestational hypertension (GH), 12 (26%) were with mild, and 9 (19.5%) were with severe PE. The serum levels of vascular endothelial growth factor receptor 1 (VEGFR-1), heme oxygenase 1 (HO-1), and B-cell lymphoma/leukemia (Bcl-2) levels were measured by enzyme-linked immunosorbent assay. Results: In the severe PE group, the VEGFR-1 serum levels (27.3 ± 16.8 vs 13.3 ± 10.7 ng/mL, P = .023) were higher, but the Bcl-2 levels (1.5 ± 0.2 vs 2.1 ± 1.7 ng/mL, P = .047) were lower than the levels in the GH-mild PE group (P = .047). Also, VEGFR-1/Bcl-2 ratio in the severe PE group was significantly higher (P = .003) than the ratio in the GH-mild PE group. Conclusion: The Bcl-2 and HO-1 proteins seem to have important roles in the antiangiogenic environment of preeclampsia.
In our study of 596 men hospitalized in the last 3 years for deep venous thrombosis-pulmonary emboli (DVT-PE), we determined the prevalence of exogenous testosterone (T) use with subsequent development of DVT-PE. Of the 596 men, 110 were now dead, 97 had cancer thought to cause DVT-PE, 250 could not be contacted, leaving 139, of whom 7 had taken T before and at the time of their admissions, 1.2% of the total cohort, a conservative estimate of the prevalence of T-associated DVT-PE. In all, 5 of the 7 DVT-PE events occurred within 3 months of initiation of T, with mean and median intervals between initiation of T and hospitalization with DVT-PE 6.7 and 2 months. Of the 7 men treated with exogenous T, all 5 men who had evaluation of thrombophilia–hypofibrinolysis were found to have previously undiagnosed familial or acquired thrombophilia or hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia–hypofibrinolysis.
Objectives: We evaluated the relationship between neutrophil to lymphocyte ratio (NLR) and slow coronary flow (SCF). Methods: A total of 180 participants were recruited to the present study. Of all the participants, 82 patients were with SCF and 98 participants were with normal coronary arteries. Basal characteristics were recorded. Coronary flow was quantified by thrombolysis in myocardial infarction frame count. Results: Basal characteristics were similar between the 2 groups. The NLR was significantly higher in the SCF group when compared to the control group (2.3 ± 0.8 and 1.5 ± 0.4 respectively, P < .001). In multiple logistic regression analysis, NLR remained as the independent predictor of SCF (P < 0.001). Conclusions: Our findings showed that NLR was significantly higher in the SCF group when compared to the control group with normal coronary arteries. We also showed that NLR was related to the presence of SCF rather than the extent of SCF. Besides these findings, we also showed the NLR as an independent predictor of SCF.
Background: Coagulation and anticoagulation systems are good targets of antiphospholipid antibodies. We assessed the contribution of the antiphospholipid antibodies to the thrombotic risk. Methods: Enzyme-linked immunosorbent assays on antibodies against phosphatidylserine and prothrombin (PS/PT), protein C, protein S, protein Z, and thrombomodulin were performed in 164 patients who showed positive results for lupus anticoagulant or anticardiolipin antibody. Results: Anti-β-2-glycoprotein I (β2GPI) and anti-PS/PT were significant risk factors for thrombotic events (P < .001, P = .049). However, there was no association between antiprotein C, antiprotein S, antiprotein Z, or antithrombomodulin and thrombosis. Coexistence of anti-β2GPI and anti-PS/PT antibodies was significantly associated with thrombotic events (P = .001). Interestingly, the absence of both anti-β2GPI and anti-PS/PT antibodies was a significant preventive factor for thrombosis (P = .003). Conclusion: Our data show a lack of association of antiprotein C, antiprotein S, antiprotein Z, and antithrombomodulin antibodies with thrombosis. However, the combination of conventional anti-β2GPI with anti-PS/PT antibody is expected to enhance the predicting power of thrombotic risk.
Postthrombotic syndrome (PTS) is a common complication of deep vein thrombosis. This study aims to assess the role of recurrent venous thrombosis and inherited thrombophilia in the pathogenesis of PTS. A series of 206 patients diagnosed with lower extremity venous thrombosis were retrospectively reviewed. The PTS was observed in 30.58% of the patients. Recurrent venous thrombosis was identified in 3.4% of the patients without PTS and in 33.3% of patients with PTS (P < .001). Inherited thrombophilia alone or in association with recurrent venous thrombosis was more commonly detected when PTS was moderate to severe (P = .04 and <.001) or severe (P < .001). Recurrent venous thrombosis increases the incidence of PTS significantly. The severity of PTS raises when an underlying thrombophilia is present either alone or in association with recurrent venous thrombosis.
A family with a novel c.717_del frameshift and a c.3655C > T missense mutation of a disintegrin and metalloproteinase with thrombospondin type I motif, member 13 protein (ADAMTS13) is described. Family members have been under observation for 44 years. Two double heterozygotes have severe early-onset Upshaw-Schulman syndrome and require prophylactic plasma infusions. Analysis reveals that 2 weekly plasma infusions are not sufficient in preventing laboratory evidence of a thrombotic thrombocytopenic purpura (TTP) attack. Both the double heterozygotes also have a heterozygous factor V Leiden G1291A mutation. One underwent splenectomy, which did not reduce the frequency of TTP episodes but resulted in a recurrent pulmonary embolism and has necessitated lifelong anticoagulant therapy. The other has mild chronic renal failure and has had episodes of atrial fibrillation and cerebral infarction. Of the 3 heterozygotes in the family, 1 has had episodes of mild thrombocytopenia.
The prevalence of the Factor V Leiden (FVL; G1691A) mutation and the methylenetetrahydrofolate reductase (MTHFR; C677T) mutation was determined in 180 patients with sickle cell (SS) disease (126 sickle homozygous and 54 sickle β-thalassaemia—age 1-47 years) and in 130 healthy controls. The FVL mutation in the heterozygous state was present in only 3 patients with SS disease and was absent in the controls. Genotyping of MTHFR 677C > T revealed increased frequency of the C allele than the T allele in patients as well as in controls. This suggests that these genetic markers may not be major risk factors for a hypercoagulable state in Indian patients with SS disease.
Introduction: Disturbances in cytokine networks are believed to be associated with increased risk of adverse pregnancy complications. Methods: Plasma samples collected from pregnant women with preterm deliveries, high-risk pregnancy complications including postpartum hemorrhage, hypertensive disorders, and multiple gestations, and normal pregnancies were analyzed at different periods throughout gestation and postpartum. Interleukin (IL) 1β , IL-6, IL-8, IL-10, tumor necrosis factor α, and antiprotein Z antibody levels were measured by enzyme-linked immunosorbent assay. Results: The IL-6 levels in preterm delivery patients were elevated during pregnancy with statistically significant differences observed at 21 to 32 weeks (P < .01) and 33+ weeks (P < .001). The IL-10 levels were increased in normal pregnancy at all time points compared to the other patient groups (P < .05). The TNF-α levels were elevated in the high-risk pregnancy group versus normal controls (P < .001 at <21 weeks and P < .05 at 21-32 weeks). Conclusion: Analysis of the maternal plasma for elevated IL-6 and reduced IL-10 levels may be of value in the early prediction of pregnancy complications.
Background: Rivaroxaban (Xarelto, Bayer HealthCare, Leverkusen, Germany) is a new oral anticoagulant drug. Anticoagulants may cause bleeding, thereby requiring reliable monitoring and efficient therapy. We investigated thromboelastometry versus routine coagulation tests to measure prophylactic and therapeutic concentrations of rivaroxaban and their reversal with prothrombin complex concentrate (PCC) and activated recombinant factor VII (rFVIIa) in vitro. Methods: Rivaroxaban was solubilized, and PCC and rFVIIa were added in 2 concentrations to the rivaroxaban-spiked blood samples, and thromboelastometry and measurements were performed. Results: Rivaroxaban increased tissue factor–activated clotting time (CTExTEM) dose dependently. Activated partial prothrombin time (aPTT), prothrombin time ratio (PTR), and prothrombin time (PT) were changed significantly in both concentrations. Reversal with PCC in both dosages caused no significant change in the measured parameters. For prophylactic rivaroxaban dosage, rFVIIa changed the PT significantly but not CTExTEM, aPTT, and PTR. For therapeutic rivaroxaban dosage, the CTExTEM was significantly reduced. The other parameters remained unaffected. Conclusions: Thromboelastometry can detect rivaroxaban effects. In vitro rFVIIa seems highly effective for reversal in contrast to PCC.
We aimed to investigate the relationship between the extent of venous thromboembolism (VTE) and nonspecific inflammatory markers such as neutrophil to lymphocyte ratio (NLR) and high-sensitivity C-reactive protein (hs-CRP). We retrospectively enrolled 77 patients with VTE (distal deep vein thrombosis [DVT], n = 19; proximal DVT, n = 32; and pulmonary thromboembolism [PTE], n = 26) and 34 healthy controls. In the performed analysis of variance, the levels of white blood cell, NLR, and hs-CRP were clearly different among the groups (control, distal and proximal DVT, and PTE) (P < .001). Especially, a significant increase from the control group to the DVT and PTE was observed in the analysis made for NLR. In the performed receiver–operating characteristic curve analysis, area under curve (AUC) = 0.849 and P < .001 were detected for NLR > 1.84. For this value, the sensitivity and specificity were determined as 88.2% and 67.6%, respectively. The NLR is an inexpensive and a readily available marker that may be effective in determining the extent of VTE, and it is useful for risk stratification in patients with VTE.
We assessed the rates, trends, and factors associated with venous thromboembolism (VTE) diagnosis among hospitalizations of adults ≥60 years of age during the period 2001 to 2010. Data from the National Hospital Discharge Survey were used for this study. During the period 2001 to 2010, the estimated annual number of hospitalizations in which a VTE diagnosis was recorded, among adults ≥ 60 years of age, ranged from approximately 2 70 000 in 2001 to 4 23 000 in 2010. The rate of such hospitalizations per 1 00 000 US population ≥60 years of age ranged from 581 in 2001 to 739 in 2010. During the period 2001 to 2004, there was a significant increasing trend in the rate of hospitalizations with VTE among women ≥60 years of age. The factors positively associated with an increased risk of VTE diagnosis were female sex, summer and autumn seasons (compared with spring), venous catheterization, cancer, and greater length of hospital stay.
Fagonia arabica (FA) is a deobstruent and blood purifier, which possesses thrombolytic and antioxidant activities. In this study, the anticoagulant effects of FA and its derived fractions were evaluated. Plasma recalcification was performed with multisolvent extracts of FA and then with extracts prepared successively with increasing polarity of the solvents. Aqueous extract was the most potent anticoagulant extract, which was fractionated by thin-layer chromatography and column chromatography. Five fractions collected were checked for their anticoagulation effect. The most potent fraction was screened for phytoconstituents. Aqueous extract of FA is the most active anticoagulant (31 minutes). Results were statistically significant when compared to heparin (38 minutes) and saline (4.04 minutes; P > .001). The Fifth fraction (FA5), the most potent fraction (27 minutes), was found positive for flavonoids, saponin, tannin, triterpenoids, carbohydrates, reducing sugar, and monosaccharides. Aqueous FA and fraction FA5 were most active in in vitro anticoagulation, and any of the phytochemicals identified could be considered the active component.
Some studies evaluated the association of factor V Leiden (FVL) with sepsis risk and mortality risk. However, the results were conflicting. Thus, we performed a meta-analysis to address the association between FVL and sepsis. PubMed and EMBASE databases were searched to find relevant studies. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random effects model. Five case–control studies and 3 cohort studies were included. Overall, no significant association between FVL and sepsis risk was observed (OR = 0.93; 95% CI 0.74-1.15; P = .49). In addition, there was no significant association between FVL and sepsis-related mortality (OR = 1.17; 95% CI 0.73-1.88; P = .52). In the subgroup analysis, no increased sepsis risk and mortality risk were found in caucasian population. This meta-analysis suggested that FVL was not a risk factor for sepsis and sepsis mortality.
Aim: We aimed to investigate the association between baseline red cell distribution width (RDW) level and the risk of stroke in patients with heart failure (HF). Methods: A total of 153 consecutive patients with HF (New York Heart Association [NYHA] I-III and left ventricular ejection fraction of <40%) were included in this prospective study. All the patients were followed up for 1 year, and during this period the cerebrovascular disease was questioned. Results: In matched population, using propensity score matching comparing patients with HF having stroke with patients without stroke, we found significantly increased basal RDW and serum uric acid. The receiver-operating characteristic curves of RDW for predicting stroke are performed. An RDW ≥15.2% measured on admission had 87% sensitivity and 74% specificity in predicting stroke in patients with HF (area under the curve: 0.923, 95% confidence interval: 0.852-0.994, P < .001). Conclusion: In conclusion, this study demonstrated that RDW may be important hematological indices for stroke in patients with HF using propensity score analysis.
Severe sepsis remains the most common cause of death in critically ill patients, and thrombin plays a crucial role in the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin–antithrombin complex (TAT), and <sc>d</sc>-dimer (DD) throughout the course of hospital stay in patients identified with sepsis. Plasma samples from patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized placebo-controlled trial were analyzed for various parameters using enzyme-linked immunosorbent assay methods. Plasma levels of F1.2, DD, and TAT were measured at several time points following administration of recombinant thrombomodulin or placebo, and the results were tabulated. In the group treated with thrombomodulin, the median F1.2 levels demonstrated a 16% decrease from the baseline to day 7, while the placebo group showed an 8% increase. Both the treatment groups showed a gradual decrease in the TAT and DD, with the group treated with thrombomodulin demonstrating twice the decrease over the 7-day period. Although the data were widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through targets such as DD, F1.2, and TAT may play an important regulatory role in the pathogenesis of sepsis-associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin downregulates the thrombin generation mediators/markers in sepsis-associated DIC.
Background: Periprocedural anticoagulation is primarily used in endovascular procedures to prevent acute reocclusion of the target vessel, but periprocedural anticoagulation might also have an impact on long-term outcome. Consecutive bleeding events are feared complications. Despite changes in peripheral endovascular revascularizations (EVRs), the periprocedural management has remained unchanged for years. Unfractionated heparin is still the treatment of choice during and immediately after EVR. Materials and Methods: We performed a prospective, single-center, open-label phase III study comparing 2 different regimes of enoxaparin peri-interventional to peripheral EVR stratified into low- and high-risk groups according to the acute and long-term reocclusion risk due to their vessel morphology. In both groups, 0.5 mg/kg of enoxaparin as a bolus was administered intravenously 10 to 15 minutes before the start of the procedure. In the low-risk group, 40 mg of enoxaparin were administered once daily for 7 days; whereas in the high-risk group, 1 mg/kg of enoxaparin was administered subcutaneously (sc) 2 times a day for 48 hours after the procedure and afterward 40 mg of enoxaparin was administered sc once daily for 5 days. Results: For the analysis of the per protocol population, 44 patients remained in the low-risk group and 140 in the high-risk group. Concerning the primary safety end point, a total of 25 (13.59%) bleeding events occurred until day 30; 5 (11.36%) of them in the low-risk group and 20 (14.29%) in the high-risk group (P = .809 for low vs high risk). None of the bleeding events observed were major according to Thrombolysis In Myocardial Infarction criteria. Concerning our primary efficacy end point, none of the patients showed an acute reocclusion classified as a significant decrease in ankle–brachial index (ABI) or elevated peak systolic velocity ratio confirmed by duplex sonography until day 30. Concerning the second end point of prevention of chronic reobstruction, at day 180 ABI has decreased in the low-risk group from mean 0.94 at day 30 to mean 0.89 and from 1.28 at day 30 to 0.85 after 6 months in the high-risk group. No significant reobstruction was found in the low-risk group, whereas 5 significant reobstruction events were objectified in the high-risk group, all of them in the femoropopliteal arterial segment at day 180. Conclusion: We conclude that low-molecular-weight heparin either in a low-dose or high-dose regime during a peripheral EVR is safe concerning bleeding complications and acute reobstructions. The long-term follow-up showed no significant difference between our high- and low-risk groups concerning reobstruction. The periprocedural anticoagulation seems to have no influence on the long-term patency rate after peripheral EVR.
Due to the pronounced hypercoagulable state in heparin-induced thrombocytopenia (HIT), alternatives to heparin that do not interact with HIT antibodies are needed for anticoagulation management. This study was designed to determine whether the oral factor Xa inhibitor apixaban could be used. Functional platelet activation with apixaban in the presence of HIT antibodies was evaluated by the 14C-serotonin release assay (SRA; washed platelets) and the heparin-induced platelet aggregation assay (PA-HIT; platelet-rich plasma). A consistent absence of platelet activation by apixaban (0.05-50 μg/mL) was observed: SRA (n = 35) 11 ± 4% and PA-HIT (n = 37) 8 ± 3% (mean ± standard error of the mean; positive is >20%) versus heparin (0.1 U/mL) 82 ± 3% SRA and 78 ± 6% PA-HIT (P < 0.01) versus enoxaparin (10 μg/mL) 73 ± 5% SRA and 62 ± 7% PA-HIT. Apixaban may provide an option for oral anticoagulation in patients with HIT, particularly for extended management and prevention.
Elderly individuals are prone to nonvalvular atrial fibrillation (AF) with associated risks of arterial thromboembolic disease. Despite definitive guidelines, oral anticoagulant therapy (OAC) is notoriously underutilized in patients with AF. Physicians cite excessive bleeding risk as one reason they omit OAC for their older patients with AF. Improved understanding of the pathophysiology of age-related bleeding may improve risk–benefit assessments for warfarin and newer antithrombotic agents. We reviewed the literature to identify age-related pathophysiological elements that can exacerbate the likelihood of bleeding. In the context of the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly (HAS-BLED) bleeding risk framework, we highlight age-related physiological dynamics that predispose to hemorrhage. The combination of increased age (>65 years) with the other elements of the risk factor stratification model identifies patients with AF who are especially susceptible to OAC-related bleeding, irrespective of the agent used. Empirically adjusting OAC dose relative to these common bleeding risks may help to achieve an improved risk–benefit therapeutic ratio.
The predictive value of leukocyte counts has been reported in patients with acute myocardial infarction (AMI). We aimed to evaluate the predictive value of the total leukocyte count and neutrophil–lymphocyte (N/L) ratio for mortality due to AMI. A total of 522 patients with acute ST-elevated MI were included in the study. The study population was divided into tertiles based on admission N/L ratio values. High (n = 174) and low N/L (n = 348) ratio groups were defined as patients having values in the third tertile (>5.77) and lower 2 tertiles (≤5.77), respectively. The high N/L ratio group had a significantly higher incidence of in-hospital cardiovascular mortality (13.8% vs 4.6%, P < .001). An N/L ratio >5.77 was found to be an independent predictor of in-hospital cardiovascular mortality (hazard ratio: 3.78, 95% confidence interval: 1.71-8.30, P = .001). A high N/L ratio is a strong and independent predictor of in-hospital cardiovascular mortality of AMI with ST elevation.
We compared hemorheological parameters in 42 male patients with acute myocardial infarction (AMI), with (n = 22) or without (n = 20) ST-segment elevation and in 20 controls. Plasma and blood viscosity (cP), plasma protein (g/dL) and fibrinogen (mg/dL) concentrations, red (106/µL) and white (103/µL) blood cell counts, hemoglobin concentration (g/dL), and hematocrit (%) were compared. Plasma viscosity was significantly higher in patients with AMI with (P = .012) and without (P = .046) ST-segment elevation than in controls. Patients with AMI with and without ST-segment elevation had significantly lower albumin (P = .002 and P = .009) and globulin (P = .001 and P = .007) concentrations, red blood cell counts (P = .0001 and P = .004), and hematocrit (P = .014 and P = .040) and significantly higher fibrinogen concentrations (P = .0001 and P = .001) than controls. These findings suggest that AMI in males is associated with increased plasma viscosity and fibrinogen concentrations and with decreased albumin and globulin concentrations, erythrocyte count, and hematocrit, regardless of ST-segment elevation.
The aim of the study was to assess the factors associated with the anticoagulation treatment in patients with atrial fibrillation (AF). A total of 2242 consecutive patients who had been admitted with AF on their electrocardiogram were included in the study. After excluding valvular AF, 1745 patients with nonvalvular AF were analyzed. Mean CHA2DS2-VASc score [cardiac failure, hypertension, age ≥ 75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 -74 and sex category (female)], frequency of persistent/permanent AF, hypertension, diabetes mellitus (DM), stroke history, body mass index, and left atrial diameter were significantly higher in patients receiving anticoagulant therapy. Stroke history, persistent/permanent AF, hypertension, DM, age, heart failure, and left atrial diameter were independent predictors of warfarin prescription. Labile international normalized ratio was the only independent negative predictor of effective treatment with warfarin. In this study, we demonstrated that stroke history, persistent/permanent AF, hypertension, DM, and left atrial diameter were positive predictors, whereas advanced age and heart failure were negative predictors of oral anticoagulant use in patients with nonvalvular AF.
We assessed the prevalence of elevated quantitative latex agglutination assay for <sc>d</sc>-dimer in patients in the emergency department in whom pulmonary embolism (PE) was excluded. <sc>d</sc>-dimer was normal (<230 ng/mL) in 435 (83%) of the 522 patients. <sc>d</sc>-dimer was normal in 88% of the patients with musculoskeletal or related chest pain, 74% with pleurisy or pleuritic chest pain, and 85% with upper respiratory tract infection. <sc>d</sc>-dimer was 230 to 500 ng/mL in 65 (75%) of the 87 in whom <sc>d</sc>-dimer was elevated. Clinical probability was low in 31 (48%) of the 65 patients with <sc>d</sc>-dimer levels of 230 to 500 ng/mL. <sc>d</sc>-dimer was 230 to 500 ng/mL and clinical probability was low in 31 (36%) of the 87 patients who had computed tomographic (CT) angiograms because of elevated <sc>d</sc>-dimer. Negative likelihood ratio for PE is sufficiently low that PE can be excluded with reasonable certainty in such patients. Tailoring cutoff value to 500 ng/mL in patients with low clinical probability would have reduced CT angiograms by 36%.
The effect of anticoagulation by heparin on patients with non-ST elevation acute coronary syndrome (NSTE-ACS), receiving early dual antiplatelet therapy, has not been fully evaluated. We classified 355 patients with NSTE-ACS according to the adequacy of anticoagulation (percentage of low activated partial thromboplastin time [APTT] level). The 6-hour APTT level was optimal in only 23.1% of the patients treated with unfractionated heparin. The rate of poor preprocedural coronary blood flow (thrombolysis in myocardial infarction grade <3, 39.1%, 30.5%, 30.3%, and 33.9% in the 100% low-, 99%~50% low-, 49%~1% low-, and 0% low-APTT group, respectively, P = .632) and bleeding events did not differ between the groups. Instead, in multivariate analysis, the diagnosis of myocardial infarction was the only independent predictor of poor coronary flow. For bleeding events, the usage of glycoprotein IIb/IIIa inhibitor appeared to be a sole risk factor. In conclusion, inadequate preprocedural anticoagulation was not associated with adverse outcomes in patients with NSTE-ACS treated with dual antiplatelet agents.
Background: Platelet hyperaggregation is known to be associated with arterial and venous thromboembolic events. The prevalence of platelet hyperaggregation in patients with chronic kidney disease (CKD) has not been described to date. Methods: Platelet hyperaggregation in patients with renal disease was defined by comparison of platelet aggregation patterns to non-CKD patients without thromboembolic disorders and healthy controls. Results: Among the 30 hemodialysis patients and 34 renal transplant recipients, 20 (67%) and 28 (82%) showed significantly decreased median -epinephrine aggregation and increased 0.5 mol/L epinephrine response (65% and 54%) compared to healthy controls and non-CKD patients. In concordance to the laboratory finding of platelet hyperaggregability, renal transplant recipients showed a high rate of thromboembolic events (normal platelet aggregation: 0 events and platelet hyperaggregation: 30 events in 13 of 28 patients). Conclusions: Patients with CKD exhibit a hitherto unappreciated high prevalence of platelet hyperaggregability indicating sticky platelet syndrome. Laboratory testing of platelet hyperaggregability may supplement the assessment of thromboembolic complications in patients with CKD.
Aim: Although the relationship between red cell distribution width (RDW) and hypertension has been well documented, there is an absence of data on the association between RDW and preeclampsia. In the present study, we have aimed to investigate the correlation of RDW with preeclampsia and its severity. Methods: The study population consisted of 52 (35 mild and 17 severe) patients with preeclampsia and 50 control pregnancy patients. For the entire study population, baseline RDW was measured using an automatic blood counter. Results: Although there were no significant differences between the preeclampsia group and the control group in terms of hemoglobin and platelet counts, the RDW (14.1 ± 1.1 vs 16.9 ± 1.7, P < .001), systolic and diastolic blood pressure, proteinuria, white blood cell, and high-sensitivity C-reactive protein levels were significantly higher in the preeclampsia group. Moreover, subgroup analysis revealed that RDW levels were significantly increased in patients with severe preeclampsia when compared to the patients with mild preeclampsia (18 ± 1.5 vs 16.4 ± 1.5, P < .001). Conclusion: Our study results revealed that RDW levels were associated with both the presence and the severity of preeclampsia.
The aim of this study is to evaluate the effect of these new generation hemostatic agents on early-stage soft tissue healing of warfarin-treated rats by measuring the tissue factor (TF) activities. Rats in the warfarin group were treated intraperitonally with 0.1 mg/kg warfarin, and rats in the control group were treated with 1 mL/kg saline. All rats had 3 incisions on dorsal dermal tissue applied Celox, Ankaferd Blood Stopper (ABS), or no hemostatic agent. Six rats from each group were killed on day 4, and the other 6 were killed on day 8. Prothrombin time (PT) and TF activities were evaluated, respectively. Both the hemostatic agents positively affected the hemostasis. Warfarin treatment increased the PT levels as expected. Celox-treated dermal tissues had higher TF activity when compared to ABS-treated ones. The ABS affected the early-stage healing positively in clinical aspect, whereas Celox was more effective on hemostasis by means of increasing TF activities.
The underlying inflammatory or infectious condition in disseminated intravascular coagulation (DIC) may stimulate the formation of antiheparin/platelet factor 4 (PF4) antibody, and the resulting antibody may affect the clinical course of DIC. We investigated the prognosis of antiheparin/PF4 antibodies in patients with suspected DIC. We measured heparin/PF4 immunoglobulin G (IgG) and total antibody levels using an automated chemiluminescence system in 118 patients with DIC. Of the 118 patients, 13 (11.0%) patients were positive for total antiheparin/PF4, and 6 (5.1%) patients were positive for antiheparin/PF4 IgG. These 13 patients were negative for platelet-activating antibody and had low-heparin-induced thrombocytopenia probability scores. Patients with antiheparin/PF4 IgG were older and had lower antithrombin levels than patients without antiheparin/PF4 IgG. Patients with antiheparin/PF4 IgG had a higher risk of mortality than those without antiheparin/PF4 IgG. The presence of antiheparin/PF4 IgG in old age or low antithrombin level patients with DIC with old age or low antithrombin level suggests a poor prognosis.
The aim of this study was to evaluate the prevalence of aspirin resistance (AR) in patients undergoing hemodialysis (HD) and to assess the effect of HD on the results of the Multiplate test. A total of 54 patients undergoing HD were included in this study. Blood samples were taken just before and after the HD session. To determine AR, we used Multiplate test. Platelet aggregation values of the study population were 363.01 ± 225.69 aggregation unit (AU) x minutes before and 375.33 ± 254.05 AU x minutes after the HD (P = .597). There was strong correlation between the values before and after HD (R = .755, P < .0001). The AR status was changed in 9 (16.6%) patients after HD. Agreement of AR status before and after HD was substantial ( coefficient = .667, P < .0001). The prevalence of AR in patients undergoing HD seems higher than in most of the studied populations, and this study has shown that the AR statuses of a significant number of patients undergoing HD change after an HD session.
We studied the level of lipid peroxide, nitric oxide (NO), trace elements (TEs), and microparticles (MPs) in Gaucher disease (GD) before and after 1 year of enzyme replacement therapy (ERT). A total of 15 children with GD and 15 healthy controls were enrolled in this study. Serum level of lipid peroxide, NO, and TEs was determined. The MPs were detected by flow cytometry. The level of lipid peroxide was significantly higher in the patients than in the controls even after ERT. Although NO level was normalized in the patients after ERT, zinc and copper were still lower in the patients after ERT. The percentages of various MPs were significantly higher in the patients than in the controls both before and after ERT. There were positive correlations between chitotriosidase and both lipid peroxide and total MPs.
The GD is associated with alteration in oxidant and antioxidant status and high level of circulating MPs.
Background: Elevation of factor VIII is associated with higher risk of large vessel arterial occlusions including stroke. Methods: Factor VIII levels were examined in consecutive patients with acute ischemic stroke (AIS) presenting to a single center between July 2008 and May 2012. Factor VIII levels exceeding the laboratory reference range were considered elevated (>150%). Results: Factor VIII level was elevated in 72.4% (84 of 116) of the patients. Elevated factor VIII level was more frequent in blacks, diabetics, and patients who were anemic. Patients with elevated factor VIII had higher median baseline National Institute of Health Stroke Scale (NIHSS; 5 vs 2, P = .0295) and twice the frequency of neuroworsening (21.4% vs 9.4%), but discharge NIHSS and modified Rankin Scale were similar in the groups. Conclusions: High factor VIII level was found in the majority of tested patients with AIS. Several baseline differences were found between patients with normal and high factor VIII levels, but no differences were identified in outcome.
Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the autoantibody directed against factor VIII in patients without previous history of a bleeding disorder. We retrospectively analyzed the characteristics and outcomes of 49 patients with AHA diagnosed in our center from February 1994 to October 2012. Twenty-four patients with acute bleeding episodes were treated with prothrombin complex concentrate (PCC) at a relative low dose of 30 to -50 U/kg/d and achieved good outcomes without any adverse reaction. Corticosteroids alone or in combination with cyclophosphamide were used as the first-line therapy to eradicate the inhibitors. In 39 evaluable patients, 35 (89.7%) achieved complete remission (CR). This study demonstrates that when bypassing agents such as recombinant activated factor VII and activated PCCs are not affordable or available, low dose PCC is effective and safe to control acute bleeding in patients with AHA. First-line therapy achieved good outcomes with a CR rate of 89.7%.
It is implicated that diabetic patients are more resistant to aspirin therapy than patients with other diseases or healthy individuals. We evaluated the inhibitory effects of aspirin on aggregation and the cyclooxygenase activity of platelets of 10 patients with severe type-2 diabetes mellitis (DM) and compared the results with those of healthy individuals. Although platelet aggregation had a tendency to be more resistant to aspirin with the DM group, there was no significant difference in half maximal inhibitory concentration 50 values of aspirin on the cyclooxygenase activity between the patients with DM and healthy individuals. Thus, the residual platelet aggregability uninhibited by aspirin appears to be independent of the cyclooxygenase activity. Since adenosine diphosphate (ADP) receptor blocking almost completely inhibited the residual platelet aggregability, it is suggested that hyperreactivity to ADP is more prevalent in patients with DM.
Purpose: In this study, we aimed to investigate the relationship between saphenous vein graft disease (SVGD) and neutrophil-to-lympocyte ratio (NLR) with other possible confounding factors. Methods: A total of 120 patients were enrolled into the present study. Of all participants, 40 patients were with SVGD and 80 of them were with patent SVG. Results: The NLR, white blood cell (WBC) count, age of SVG, red cell distribution width (RDW), and mean platelet volume were significantly higher in the SVGD group. In regression analysis, NLR, WBC, RDW, and age of SVG remained as independent predictors of SVGD.Conclusion: To our knowledge, we showed for the first time that NLR is independently associated with SVGD. It can be easily used in this era, because it is easily available, widely used, and relatively cheap. Besides NLR, WBC count, SVG age, and RDW can also be used to predict SVGD.
Aspirin (ASA) is recommended for the prevention of cardiovascular disease; however, the compliance is low. Reported use may not reflect actual use. Serum thromboxane B2 (STxB2) measurement was evaluated to validate reported ASA use. Males aged 45 to 79 years and females aged 55 to 79 years completed a survey and STxB2 measurement (Thromboxane B2 EIA Kit; Cayman Chemical, Ann Arbor, Michigan). The 107 patients were grouped by use of ASA (56 ASA+ and 51 ASA-) and possible interfering medications (INT) such as nonsteroidal anti-inflammatory drugs. The STxB2 levels (ng/mL) were significantly lower in ASA users: ASA+ INT- 3.0 (0.7, 8.4), ASA+ INT+ 2.0 (0.8, 4.9), ASA- INT+ 176 (75, 390), and ASA- INT- 271 (199, 366). The INT use did not cause a significant difference in STxB2 levels. A STxB2 cut point of 25 ng/mL had high sensitivity (94.1%) and specificity (91.1%) for ASA use. The STxB2 was a reliable marker of ASA use and could be used to confirm ASA exposure in population-based health studies.
The aim of this study is to investigate the association between neutrophil to lymphocyte ratio (NLR) and severity of coronary atherosclerosis. A total of 172 patients undergoing coronary angiography were included in the study. Control group consisted of patients with normal coronary arteries. Patients with coronary stenosis were divided into 2 groups by use of Gensini scores. The NLR was higher in severe atherosclerosis group compared with mild atherosclerosis and control groups (P < .001). In correlation analysis, NLR showed significant correlation with Gensini score. A cutoff value of 2.5 for NLR predicted severe atherosclerosis with a sensitivity and specificity of 62% and 69%, respectively. After multivariate analysis, high levels of NLR were independent predictors of severe atherosclerosis together with glucose and high-density lipoprotein. Our study suggests that the NLR is a predictor of severe atherosclerosis that may be useful for cardiac risk stratification in patients with coronary artery disease.
Objective: To examine the efficacy and adverse events of recombinant human thrombopoietin (rhTPO) in the treatment of infection-associated thrombocytopenia in senile patients. Methods: The current study is a retrospective analysis of the patients receiving rhTPO for infection-associated thrombocytopenia in our hospital. Results: Forty-nine cases were included in the analysis as rhTPO group. The absolute platelet count after treatment, increase in platelet count, and the overall response rate were considerably higher in the rhTPO group than that in the control group. Improvement in bleeding score was higher in the rhTPO treatment group than that in the control group (2.1 ± 5.4 vs 0.4 ± 1.7). Bleeding event was stopped in 68.2% of the patients after rhTPO treatment and in 35% of the patients in the control group (P = .032). A stratified analysis indicated that the therapeutic efficacy is much better in patients without organ failure. Conclusion: Recombinant human TPO is effective in alleviating infection-associated thrombocytopenia and hemorrhage in senile patients, particularly if given prior to the emergence of organ failure.
Patients with prior stroke are susceptible to venous thromboembolism (VTE). We studied patients with stroke in the Worcester VTE study of 2488 consecutive patients hospitalized with VTE. In all, 288 (11.6%) had a clinical history of stroke and 2200 (88.4%) did not. Patients with stroke were more likely to die inhospital (9.2% vs 4%) and within 30 days of VTE diagnosis (16.7% vs 6.9%) compared with patients without stroke (all P < .001). Recent immobilization (adjusted odds ratio [OR] 2.15; 95% confidence interval [CI] 1.15-4.09) and inferior vena cava (IVC) filter insertion (adjusted OR 2.1; 95% CI 1.15-3.83) were associated with a doubling of inhospital death. Recent immobilization (adjusted OR 1.84; 95% CI 1.19-2.83) and IVC filter insertion (adjusted OR 1.94; 95% CI 1.2-3.14) were associated with an increased risk of death within 30 days of VTE. In conclusion, patients with VTE and prior stroke were more than twice as likely to die while hospitalized and within 30 days of VTE diagnosis.
The increased risk of cardiovascular and cerebrovascular events in patients with migraine remains unexplained. Prothrombotic states are thought to contribute to this increased risk. The present study aimed to compare the prevalence of prothrombotic states in patients with migraine and headache-free controls. We conducted a case–control study to screen for prothrombotic states protein C, protein S (PS), antithrombin III, factor V Leiden, lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein 1 antibodies in 101 consecutive patients with migraine and 148 controls. An underlying prothrombotic state was encountered in 11.8% of the patients with migraine, PS deficiency being the most common (4.0%). There was no significant difference in the prevalence of prothrombotic states in patients with migraine compared to controls. Traditional prothrombotic states do not seem to have a higher prevalence in patients with migraine compared to controls.
Objectives: We investigated the relationship between coagulation assessed by thromboelastography (TEG) and myocardial damage in ST-segment elevation myocardial infarction (STEMI). Methods: We measured platelet activity with TEG-maximum amplitude (TEG-MA) in 233 patients undergoing urgent percutaneous coronary intervention (PCI). Infarct size and myocardial salvage index were evaluated using cardiac magnetic resonance, and the relation of these parameters to posttreatment coagulation was examined retrospectively. Adverse events were adjudicated and related to the coagulation status during the index event. Results: Hypercoagulation was found in 82 (35.2%) patients and was neither correlated to infarct size nor correlated to myocardial salvage index (P = .28 and .65, respectively) or clinical adverse events. Patients who experienced an adverse event during follow-up had a slightly higher TEG-MA value than patients with an event-free follow-up, but this was not statistically significant (68.1 vs 67.3, P = .44). Conclusions: The TEG-MA does not appear to be a sensitive predictor of reperfusion success and prognosis in urgent PCI for STEMI.
Background: We frequently encounter high levels of activated partial thromboplastin time (aPTT) during heparin anticoagulation. The purpose of this study is, first, to investigate the rate of achieving and maintaining therapeutic aPTT in patients treated with heparin anticoagulation and second, to assess the adequacy the current nomogram. Methods: We included 197 patients who underwent anticoagulation with unfractionated heparin (UFH) according to the standard nomogram between September 2008 and May 2010. The primary endpoints were the rate of achieving a therapeutic range (TR) at the first sample, 24 hours, or 48 hours. We also compared heparin nomograms according to age (<70 years vs ≥70years).Results: Of the 197 patients, 131 had heparin loading. In the heparin loading group, there were 19.1% (n=25), 69.5% (n=91), and 90.1% (n=18) achieving TR at the first aPTT, 24 hours, and 48 hours, respectively. The therapeutic aPTT proportion was 39.2%, and the rate of peak level above 90 seconds was 93.1%. Peak levels of aPTT were higher in the older age group than in the younger age group (202.3 ± 124.2 versus 152.0 ± 78.9, p=0.007).Conclusion: Our results indicate a high rate of achieving therapeutic aPTT at 24hous and 48hours, but a low success rate for maintenance within the TR. Most patients had supratherapeutic aPTT of more than 90 seconds. Therefore, the TR of aPTT that matches heparin levels of 0.3 to 0.7 IU/mL measured by antifactor Xa assay should be determined. If not, we should consider adopting a new heparin dosing nomogram.
Right ventricular dysfunction (RVD) defined by echocardiography and/or by natriuretic peptides is a well-known predictor of prognosis in patients with pulmonary embolism (PE). This study investigated carbonic anhydrase IX (CA IX) levels for predicting echocardiographic RVD in patients with PE. A total of 150 normotensive patients with PE were included. The levels of CA IX, N-terminal pro-brain-type natriuretic peptide (NT-proBNP), and high-sensitive cardiac troponin T were significantly elevated in patients with PE with RVD on echocardiography. A receiver–operating characteristic curve analysis showed a value of 0.751 for CA IX, 0.714 for NT-proBNP, and 0.650 for high-sensitive troponin-T to predict RVD on echocardiography. The cutoff value to predict RVD was 32.45 pg/mL for CA IX (sensitivity: 89.3% and specificity: 51.1%). There was a significant positive correlation between the CA IX level and the systolic pulmonary arterial pressure on echocardiography ( = .21; P = .035). The CA IX is a significant serologic predictor of RVD in acute PE and correlates with systolic pulmonary arterial pressure.
Obesity is associated with an increased risk of vascular thrombotic events. We sought to investigate how obesity and weight loss affect plasma fibrin clot properties. A total of 29 obese patients were studied before and after 3-month low-fat diet. Plasma fibrin clot parameters, including fibrin clot permeation coefficient (Ks), the lag phase of the turbidity curve, clot lysis time (t50%), maximum rate of increase in D-dimer levels, and maximum D-dimer concentrations, were determined. Low-fat diet resulted in the reduction of body weight (P < .0001), body mass index (P < .0001), fat mass (P < .0001), total cholesterol (P < .0001), low-density lipoprotein cholesterol (P = .0005), triglycerides (P = .008), and plasminogen activator inhibitor 1 (P = .02), but not in fibrinogen or C-reactive protein. The only change in fibrin clot variables was shorter t50% (P = .02). Baseline t50%, but not posttreatment, correlated with waist circumference (r = .44, p = .02). This study demonstrates that weight loss in obese people can increase the efficiency of fibrin clot lysis.
Myocardial injury following carotid endarterectomy (CEA) is a common cause of morbidity and mortality, and its risk varies depending on the severity and extent of disease. However, when patients with sympotomatic severe carotid stenosis undergo CEA, the frequency and potential predictors of myocardial injury remain unknown. A total of 40 patients (32 men and 8 women) who underwent successful standard CEA were observed. Cardiac troponin I (cTnI) concentrations were assessed before surgery and on postoperative days 1, 2, and 3 in all patients. Myocardial injury was defined as the peak cTnI concentration > 0.04 ng/mL. In all, 42.5% patients had postoperative myocardial injury. Previous ischemic stroke and abnormal ST-segment changes were the preoperative predictors of myocardial injury after CEA, with odds ratios of 4.1 (95% confidence interval, 1.1-16.1; P = .04) and 5.9 (95% confidence interval, 1.3-27.7; P = .04), respectively. Sympotomatic patients with those conditions should receive more attention to myocardial injury, when presented for CEA.
Left ventricular (LV) systolic dysfunction and chronic systolic heart failure (HF) predispose to intraventricular thrombus formation and embolization resulting in stroke. Current guideline recommends the use of oral anticoagulants in patients with atrial fibrillation and history of previous thromboembolism. However, anticoagulant treatment in patients with LV systolic dysfunction with sinus rhythm and without history of previous thromboembolism is still on debate. Recent epidemiologic date has reported increased stroke rate in patients with systolic HF shortly after diagnosis. This review focuses on the possible causes of increased stroke rate shortly after the diagnosis of HF and subsequently suggests a rationale for the use of oral anticoagulant in these patient groups.
Background: The slow coronary flow (SCF) is characterized by angiographically normal or near-normal coronary arteries with delayed progression of the contrast agent into distal vasculature. We aimed to investigate neutrophil-to-lymphocyte (N/L) ratio and the carotid intima-media thickness (CIMT) value in patients with SCF compared to patients with newly diagnosed coronary artery disease (CAD) and normal patients. Materials and Methods: We enrolled 60 consecutive patients with SCF, 68 patients with CAD, and 72 normal patients. The association between thrombolysis in myocardial infarction frame count, CIMT, and N/L ratio and other clinical and laboratory parameters were evaluated. Results: The N/L ratio was significantly higher not only in patients with SCF but also in patients with CAD, compared to those of controls. The N/L ratio was positively and moderately correlated with CIMT in the whole study population. Conclusions: The NL ratio is significantly associated with reduced coronary blood flow, and elevated N/L ratio might be an independent predictor for the presence of SCF.
We describe thrombosis, deep venous thrombosis (DVT) pulmonary embolism (PE; n = 9) and hip-knee osteonecrosis (n = 5) that developed after testosterone therapy (median 11 months) in 14 previously healthy patients (13 men and 1 woman; 13 Caucasian and 1 African American), with no antecedent thrombosis and previously undiagnosed thrombophilia–hypofibrinolysis. Of the 14 patients, 3 were found to be factor V Leiden heterozygotes, 3 had high factor VIII, 3 had plasminogen activator inhibitor 1 4G4G homozygosity, 2 had high factor XI, 2 had high homocysteine, 1 had low antithrombin III, 1 had the lupus anticoagulant, 1 had high anticardiolipin antibody Immunoglobulin G, and 1 had no clotting abnormalities. In 4 men with thrombophilia, DVT-PE recurred when testosterone was continued despite therapeutic international normalized ratio on warfarin. In 60 men on testosterone, 20 (33%) had high estradiol (E2 >42.6 pg/mL). When exogenous testosterone is aromatized to E2, and E2-induced thrombophilia is superimposed on thrombophilia–hypofibrinolysis, thrombosis occurs. The DVT-PE and osteonecrosis after starting testosterone are associated with previously undiagnosed thrombophilia–hypofibrinolysis. Thrombophilia should be ruled out before administration of exogenous testosterone.
The aim of this study was to establish a method to predict the antiplatelet effects of aspirin in vivo based on in vitro results. Aspirin in 5 different concentrations was added to the platelet-rich plasma samples, and the rates of platelet aggregation induced by collagen were determined in vitro. In addition, platelet aggregation and plasma drug concentration values were determined in vivo before and after the administration of aspirin (162 mg). The 50% effective concentration (EC50) values obtained from the in vivo and in vitro experiments were shown to have relevance, because the EC50 ratio for each subject was the same (0.23 ± 0.03). The actual and predicted values for the rate of inhibition of platelet aggregation were well correlated (P < .0001, r = .95) when the predicted rate was determined using the present method. Our results suggest that the antiplatelet effects of aspirin can be predicted using blood samples obtained before its administration.
Aim: The aim of the present study was to investigate the predictive value of preoperative neutrophil–lymphocyte ratio (NLR) in postoperative saphenous vein graft patency in patients undergoing coronary artery bypass grafting (CABG) surgery. Method: We retrospectively analyzed 444 patients who had undergone CABG and a further control coronary angiography due to recurrence of symptoms. The patients were divided into tertile groups according to the NLR. The primary end point was 50% saphenous vein graft stenosis or more or complete occlusion. Result: The saphenous vein graft failure in the 3 groups based on NLR was 33%, 66.2%, and 79.1%, in the low-, middle- and high-risk groups, respectively. In multivariate regression modeling, current smoker, diabetes mellitus, target artery diameter <1.5 mm, and NLR independently predicted saphenous vein graft patency in patients after CABG. Conclusion: Preoperative NLR is clearly an independent predictor of saphenous vein graft patency in patients after CABG.
Although animals housed for research purposes are strictly monitored for lighting, temperature, and humidity, the acoustic environment receives less attention. In a retrospective study, we investigated the effect of construction-induced noise on coagulation using thromboelastography in a group of healthy control rats. Animals were unintentionally exposed to noise due to construction in the vicinity of the animal care facility where these rats were housed. We compared the results to those of age-, gender-matched nonexposed rats. There was a significant shortening of the reaction (R) time (P = .009) and a trend toward an increase in coagulation index (CI; P = .09), indicating hypercoagulability. The short R time and increase in CI were correlated with an elevated plasma cortisol and corticosterone, indicating that the hypercoagulability seen in these rats is stress induced. Noise is a stress factor for which animals need to be monitored, particularly if those animals are selected as controls for hemostasis studies.
Background: We assessed the effects of protamine overdosing on thrombelastometry, bleeding, and transfusions in patients after cardiopulmonary bypass (CPB). Methods: In group 1 (n = 15), representing the clinical standard, the protamine dose was based on the initial heparin dose, and group 2 (n = 15) received protamine based on the heparin concentration measured after CPB. Primary end points were thromboelastometric parameters. Secondary end points were perioperative blood loss and utilization of blood products. Results: During CPB, heparin concentrations decreased by 40%, resulting in overdosing of protamine in group 1. Thromboelastometry revealed longer clotting time (CT) in group 1 (P values < .05). Four patients in group 1 but none in group 2 had excessive prolonged CT values (>360 seconds) and concomitant microvascular bleeding, requiring substantial replacement of coagulation factors. Conclusions: Heparin dose-based protamine management leads to protamine overdosing with inhibition of the coagulation process. Protamine management guided by heparin concentration avoids these complications.
Background: Atrial fibrillation (AF) is the most common cardiac rhythm disorder. Atrial fibrillation causes a 5-fold increased risk for thromboembolic stroke. It is known that eosinophils play an important role in thrombosis. We aimed to compare the number of eosinophil counts of the patients with and without thrombi in the left atrium (LA) or in the left atrial appendage (LAA) and to ascertain the association of eosinophil counts with the presence of thrombi.
Method: The study included 89 patients diagnosed with persistent AF who underwent transesophageal echocardiography and designated to undergo cardioversion. The patients were divided into 2 groups: group 1 consisted of 40 patients (18 male; average age 63.27 ± 1.4) who had thrombus formation in the LA or LAA, and group 2 consisted of 49 patients (23 male; average age 66.53 ± 1.56) who did not have any thrombus in the LA or LAA. These patients underwent concurrent routine biochemical tests and eosinophil count on whole blood count was also performed.
Results: Baseline characteristics of the study groups were comparable. Group 1 patients had higher eosinophil and mean platelet volume values than group 2 (233.0 ± 30.7 vs 118.9 ± 11.8 and 9.77 ± 0.20 vs 8.27 ± 0.12 fL, P < .001, respectively). In group 1, the patients’ LA diameter is higher than that in group II. Conclusion: As a result, our study revealed a relationship between eosinophil count and LA thrombus in patients with nonvalvular AF.
Aims:We aimed to investigate the determinants of angiographic thrombus burden in patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (pPCI).
Methods:The study population consisted of 662 patients with nonanemic STEMI who underwent pPCI. Clinical, laboratory, and demographic properties of the patients were recorded. Baseline hematologic indices were measured at the time of admission. Angiographic coronary thrombus burden was scored based on thrombolysis in myocardial infarction (TIMI) thrombus grades. After wiring and/or small balloon dilation, patients with thrombus burden grades 4 and 5 were defined as high thrombus burden, and patients with thrombus burden <grade 4 was defined as low thrombus burden.
Result:Patients with high thrombus burden had more family history of coronary artery disease, longer pain to balloon time, higher Killip class (≥II), higher neutrophil to lymphocyte ratio, red cell distribution width (RDW), baseline creatine kinase-MB fraction (CK-MB) and baseline troponin, higher peak CK-MB, and peak troponinbut lower triglycerides. Angiographically, patients with high thrombus burden had longer lesion in the infarct-related artery, less frequent direct stenting, lower epicardial and myocardial perfusion, more frequent distal embolization, and more frequent electrocardiographic and angiographic no reflow. In multivariate logistic regression analysis, only RDW (odds ratio: 1.29, 95% confidence interval 1.19-1.39, P < .001) was determined as independent predictor. The area under the receiver–operating characteristic curve of the RDW was 0.733 (0.690-0.776, P < .001) to predict high TIMI thrombus burden.
Conclusion:Present study results demonstrated that high thrombus burden in patients with STEMI was associated with impaired postprocedural epicardial and myocardial perfusion and higher no reflow and distal embolization; and increased RDW values were independent predictors of coronary thrombus burden.
Patients with iliac deep vein thrombosis (DVT) have a poor prognosis and high incidence of postthrombotic syndrome (PTS). We evaluated the effect of low-molecular-weight heparin (LMWH; tinzaparin) versus usual care (tinzaparin plus warfarin for ≥12 weeks at home) in the development of PTS according to DVT location (iliac/noniliac) by retrospective analysis of the Home-LITE cohort (480 patients with proximal DVT). Patients with iliac DVT had an overall odds ratio of 0.53 (95% confidence interval [CI] 0.33, 0.83; P = .0079) for PTS (including ulcer data) in favor of tinzaparin. Patients with noniliac DVT had a similar odds ratio (0.79 [95% CI 0.67, 0.93], P = .0046) to that reported in the overall Home-LITE population (0.76 [95% CI 0.66, 0.89], P = .0004; including ulcer data), both in favor of tinzaparin. Long-term LMWH may be a suitable alternative for the prevention of PTS in patients with iliac DVT who are unlikely to undergo invasive thrombolysis.
Introduction: AVE5026 represents a new generation of ultra-low-molecular-weight heparin (LMWH) with high anti-Xa and low anti-IIa activities (anti Xa–IIa ratio >30). In addition, AVE5026 exhibits a relatively higher proportion of AT components. Materials and Methods: The anticoagulant, antiplatelet, antithrombotic, and bleeding effects of AVE5026 in comparison to other heparins were investigated in this study. Results: AVE5026 demonstrated weak effects in the global clotting assays; however, in the amidolytic anti-Xa assay, AVE5026 produced strong inhibitory effects. AVE5026 showed no cross-reactivity with the heparin-induced thrombocytopenia antibodies in the platelet aggregation system. AVE5026 produced a dose-dependent antithrombotic response after intravenous (IV) and subcutaneous (SC) administration in thrombosis models. The relative bleeding effects of AVE5026 in a rat tail bleeding and rabbit blood loss model were negligible after both IV and SC administration. Conclusions: This superior safety efficacy index in animal models in comparison with other LMWH may translate into improved antithrombotic efficacy with decreased bleeding risk.
We assessed the effect of the topical application of epsilon-aminocaproic antifibrinolytic acid (EACA) on the pericardium of patients submitted to coronary artery bypass graft (CABG) without the use of cardiopulmonary bypass (CPB). This is a prospective, randomized, and double-blind study. We evaluated 26 patients with chronic coronary heart disease indicated for CABG without CPB (EACA and placebo groups). The analysis of the postoperative hematological results showed no difference between groups in hemoglobin and hematocrit. There was no difference between the groups regarding the postoperative bleeding through the drains in the first 24 hours, 48 hours, and accumulated loss until removal of drains. The use of EACA in patients undergoing CABG without CPB presented no difference in the reduction of the amount of bleeding and the need for blood transfusions.
Background: Platelets play an important role in the pathogenesis of coronary artery disease (CAD). The importance of dual antiplatelet therapy to prevent recurrent ischemic events in patients who have acute coronary syndrome and who will undergo percutaneous coronary intervention (PCI) is well known and widely accepted as a gold standard. However, despite this apparently effective therapy, incidence of adverse ischemic events could not be decreased enough. Resistance to aspirin/clopidogrel is an important risk factor for adverse ischemic clinical events. Up-to-date studies revealed many risk factors for antiplatelet resistance, one of which is hypertension (HT). Currently, there is no sufficient number of studies evaluating the association between HT and antiplatelet resistance, which is the aim of this study. Methods: We enrolled 145 consecutive patients (19 female [13.1%], 126 male [86.9%], mean age 55 ± 10) with stable CAD receiving regular antiplatelet therapy composed of 100 mg/d aspirin and 75 mg/d clopidogrel. All patients had been implanted nondrug-eluting coronary stent and/or stents at least 1 month ago. The HT was diagnosed by 24-hour blood pressure (BP) monitoring. Clopidogrel and aspirin resistance was measured by impedance aggregometry method. Results: We included 49 patients with HT and 96 nonhypertensive patients with stable CAD. Aspirin resistance was detected in 22 (16.4%) of 134 patients who received aspirin. Clopidogrel resistance was detected in 55 (37.9%) of 145 patients who received clopidogrel. Prevalance of aspirin and clopidogrel resistance was significantly higher in the hypertensive group than in the nonhypertensive group (P = .030 and P = .007, respectively). Correlation analysis revealed weak but significantly positive correlation between clopidogrel resistance and serum uric acid levels, mean platelet volume, platelet count, and 24-hour mean systolic BP (r = -.180, P = .030; r = .189, P = .016; r = .226, P = .006; and r = .200, P = .016, respectively). Conclusion: We demonstrated higher incidence of antiplatelet resistance in patients with HT. Upon this finding, which is emerged from an actual group of patients with HT, cardioprotective effect of antiplatelet therapy in patients with HT should be argued.
Venous thromboembolism (VTE) is a common complication of cancer and chemotherapy. We evaluated the baseline clinical characteristics, thromboprophylaxis patterns, frequency and timing of VTE, and clinical outcomes in 1000 adult hospitalized patients with active cancer. Overall, symptomatic VTE occurred in 5.4% of hospitalized patients with cancer. The VTE occurred in 2.3% of patients with cancer during hospitalization and in 3.4% between hospital discharge and day 90. Few (13.9%) hospitalized patients with cancer received extended duration pharmacological prophylaxis after hospital discharge. Cancer was the most frequent known cause of death in both the groups. In conclusion, VTE was common in hospitalized patients with cancer, especially after discharge. Inhospital death and death between discharge and day 90 were frequent in hospitalized patients with cancer who developed VTE.
Platelets play an important role in various thrombotic diseases, including myocardial infarction. Because red wine consumption is inversely associated with death due to ischemic heart diseases, the effects of grape components on platelet function have been extensively investigated. Grape seed extracts (GSEs) reportedly inhibit platelet aggregation; however, the underlying mechanism has not been elucidated. We discovered that GSEs inhibit platelet aggregation induced by collagen and thrombin-receptor agonist peptide and increase basal levels of tyrosine phosphorylation, which was also observed in the presence of a protein tyrosine phosphatase (PTP) inhibitor. An in vitro phosphatase assay indicated that GSE dose dependently inhibited PTP-1B and Src homology 2 domain-containing phosphatase-1 activity, which positively regulates platelet aggregation. We propose that GSEs inhibit platelet aggregation by inhibiting tyrosine phosphatase activity. Moreover, we showed that GSE ingestion inhibited platelet aggregation in mice without enhancing tail bleeding, implying that GSE supplementation might be beneficial to prevention of thrombotic diseases.
Controversies exist over the currently recommended guidelines for the use of low-molecular-weight heparin (LMWH) in neonates. We retrospectively studied 30 neonates treated with LMWH and found a poor therapeutic response to recommended doses as measured by anti-Xa levels. Sixty percent of the study participants required their doses to be increased because of subtherapeutic anti-Xa levels during the initial course of their treatment. The mean starting enoxaparin dose was 1.53 ± 0.38 mg/kg. The mean enoxaparin dose, once therapeutic anti-Xa levels had been achieved, was 1.86 ± 0.50 mg/kg. Preterm and term infants required doses of 2.06 ± 0.61 mg/kg and 1.67 ± 0.26 mg/kg, respectively, to achieve therapeutic anti-Xa levels. In summary, our results suggest that higher initial doses are required to achieve therapeutic anticoagulation in neonates.
Currently, several newer oral anticoagulants namely dabigatran (anti-IIa), rivaroxaban (anti-Xa), and apixaban are available for various clinical implications. Another oral anti-Xa edoxaban is under development. A parenteral anti-Xa drug namely otamixaban is also under development for cardiovascular interventions. Bleeding complications have been reported in the new oral anticoagulants and have been managed by conventional approaches with limited success. Prothrombin complex concentrates (PCCs) are reported to neutralize the anticoagulant activity of these agents. The PCCs are also able to generate endogenous factor Xa and IIa along with other proteases that are capable of neutralizing the circulating anti-Xa or anti-IIa activities of the newer anticoagulants. The generation of Xa and IIa is also dependent on the type of tissue factor available for their activation. These reported studies suggest that different tissue factors differentially activate a PCC namely Profilnine SD. Furthermore, dabigatran differs from rivaroxaban and other factor Xa inhibitors in its inhibitory profile.
The cirrhosis population represents a unique subset of patients who are at risk for both bleeding and developing venous thromboembolic events (VTEs). It has been commonly misunderstood that these patients are naturally protected from thrombosis by deficiencies in coagulation factors. As a result, the cirrhosis population is often falsely perceived to be "autoanticoagulated." However, the concept of "autoanticoagulation" conferring protection from thrombosis is a misnomer. While patients with cirrhosis may have a bleeding predisposition, not uncommonly they also experience thrombotic events. The concern for this increased bleeding risk often makes anticoagulation a difficult choice. Prophylactic and therapeutic management of VTE in patients with cirrhosis is a difficult clinical problem with the lack of clear established guidelines. The elucidation of laboratory and/or clinical predictors of VTE will be useful in this setting. This review serves to examine VTE and the use of anticoagulation in the cirrhosis population.
An increasing number of mutations and polymorphisms have been identified in the von Willebrand factor (VWF) gene of patients with von Willebrand disease (VWD). Most of the sequence alterations are within exon 28, duplicated in the VWF pseudogene on chromosome 22. Genetic recombination causing the gene conversion between the VWF gene and its pseudogene is associated with multiple substitutions in the VWF gene and with VWD. In the present study, VWF gene exon 28 was analyzed in 33 patients with VWD by DNA sequencing. A total of 73% of the patients were heterozygous for p.D1472H, p.V1485L, p.1500A, p.1501F, p.L1503P, and p.S1506L single-nucleotide polymorphisms. Family analysis revealed that the gene conversion occurred between the VWF gene and its pseudogene in 3 patients. Case-control association analysis by Haploview 4.2 did not show an association between the haplotype and VWD. In conclusion, a common exon 28 haplotype in the Turkish population, which might have arisen from the gene conversion events in the founder population, was identified.
The effects of graduated compression stockings (GCSs) on venous blood velocity were measured in 26 hospitalized medical patients while supine at rest. Peak blood velocity in the right femoral vein was 21.6 cm/s without GCS and 23.0 cm/s with GCS [not significant (NS)]. Peak blood velocity in the right popliteal vein was 12.5 cm/s without GCS and 15.0 cm/s with GCS (NS). Mean blood velocity in the right femoral vein did not increase significantly with GCS, but mean blood velocity in the right popliteal vein increased marginally from 5.0 cm/s to 5.8 cm/s (P = .05). Among 11 patients with venous insufficiency (refilling time ≤19 s), neither peak nor mean blood velocity in the femoral or popliteal veins increased significantly with GCS. In conclusion, thigh-length GCS in hospitalized patients had little or no effect on popliteal or femoral vein blood velocity while supine at rest, irrespective of whether the patients had venous insufficiency.
Objectives: The aim of this study is to investigate the relationship between left ventricular thrombus (LVT) developments and the SYNTAX score (SS) in patients undergoing primary percutaneous coronary intervention (PPCI) for first anterior wall ST-segment elevation myocardial infarction (STEMI). Methods: We enrolled 160 patients. All participants were evaluated by serial transthoracic echocardiography. Baseline clinical, echocardiographic, and procedural features of PPCI were analyzed to find predictors of LVT development. Results: The LVT was detected in 32 (20%) patients. Left ventricular ejection fraction (LVEF) and SS-I were found to be independent predictors of LVT development. Receiver–operating characteristic curve analysis revealed a cutoff value >19.5 for SS-I (area under the curve: 0.697, 95% confidence interval 0.620-0.767, P < .001) with a specificity of 45.3% and a sensitivity of 84.3%. Conclusion: High SS which was obtained through diagnostic angiogram of PPCI may be associated with LVT development in patients with first anterior wall STEMI.
Background: Red cell distribution width (RDW) has been shown to be helpful in predicting adverse long-term events in patients with cardiovascular diseases. However, to date, no study has been conducted on the relationship between RDW and thromboembolism risk in atrial fibrillation (AF). Therefore, we aimed to investigate the relationship between RDW and CHA2DS2-VASc score used for the evaluation of thromboembolism risk in patients with AF. Methods: The study population consisted of 320 patients with AF. We calculated CHA2DS2-VASc risk score for each patient and baseline hemoglobin, white blood cell, RDW, mean platelet volume, platelet counts, estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF), and left atrial volume index (LAVi) were measured. Results: High CHA2DS2-VASc score group had higher RDW, lower LVEF, higher LAVi, and lower eGFR values when compared to the low CHA2DS2-VASc score group. The multivariate logistic regression analysis performed to predict high CHA2DS2-VASc scores revealed that RDW eGFR, LVEF, and LAVi were independent predictors. The area under the receiver–operating characteristic curve of RDW was 0.65 (0.59-0.71, P < .001) to predict high CHA2DS2-VASc score. Conclusion: Our study results indicate that RDW values are significantly correlated with CHA2DS2-VASc score in nonanemic patients with AF, while also being independent predictor of high CHA2DS2-VASc score.
Acute coronary syndrome (ACS) encompasses a spectrum of diseases, ranging from ST-elevation myocardial infarction to non-ST-elevation myocardial infarction and unstable angina. A key initiating event in the pathology of ACS is atheromatous plaque disruption, in which the exposure of thrombogenic material triggers simultaneous activation of primary and secondary hemostatic pathways. Targeting platelet-mediated thrombus formation with dual antiplatelet therapy comprising acetylsalicylic acid and a P2Y12 antagonist is the current mainstay for management of ACS. However, a significant proportion of patients remain at risk of cardiovascular events. Fibrin is an important contributor to thrombogenesis and may account for the residual event rates. This review examines evidence for the role of the coagulation cascade in thrombus formation in ACS, which provides a rationale for the use of anticoagulation therapy. The current status of research with novel oral anticoagulants in combination with dual antiplatelet therapy for the secondary prevention of ACS is also discussed.
Deep venous thrombosis (DVT) in children is more often associated with underlying pathological conditions than with hereditary thrombophilia. The present study is a retrospective analysis of thrombophilia in 285 pediatric patients with venous thrombosis at different sites. Four common thrombophilia markers, that is protein C, protein S, antithrombin III, and factor V Leiden (FVL) mutation, were analyzed. Thrombosis in hepatic and portal veins was more common in pediatric patients (73%) when compared to other sites (27%). Overall, hereditary thrombophilia accounted for 15.5% of the patients with venous thrombosis. The FVL mutation, which was the major causative factor in Budd–Chiari syndrome and portal vein thrombosis cases in the adult group, was not a major contributing factor in pediatric group, that is, 1.8% of the patients. In conclusion, the risk factors for venous thrombosis vary in different age groups.
Background: We aimed to investigate the association between electrocardiographic (ECG) grade III ischemia and angiographic thrombus burden in patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (pPCI). Methods: The study population consisted of 307 patients with STEMI. Baseline ECGs of the patients were analyzed for grade III ischemia; angiographic thrombus burden was assessed by thrombolysis in myocardial infarction thrombus classification. Results: A total of 108 (35%) patients had low thrombus burden whereas 199 (65%) patients had high thrombus burden. Grade III ischemia was more prevalent in patients with high thrombus burden (25.1% vs 11.1%, P = .004). Only grade III ischemia (odds ratio: 2.59, 95% confidence interval 1.24-5.39, P = .011) and history of coronary artery disease (CAD) were found to be the independent predictors of high thrombus burden. Conclusion: Grade III ischemia on ECG and previous history of CAD were independent predictors of coronary thrombus burden in patients with STEMI who underwent pPCI.
Background: The objective of this study was to evaluate whether admission neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) might reflect amputation in patients with critical limb ischemia (CLI) who could not get surgical or radiological (percutaneous transluminal angioplasty) revascularization. Methods: A total of 104 patients with nonreconstructable CLI over a 5-year period were collected prospectively. Results: Admission NLR levels of ≥3.2 and a PLR of ≥160 were found to represent the optimal cutoff values to risk stratification of patients. If both levels were elevated, patients had a median overall limb survival of 22 months. For cases where both levels were less than the cutoff values, the median overall limb survival time was not reached but was greater than 60 months. Conclusions: Admission NLR and PLR both merit further evaluation as prognostic indices in patients with CLI.
Based on the premise that the capacity of plasma to generate thrombin in vitro is a comprehensive and precise functional test of the clotting system, we designed a cross-sectional, single-center study involving 83 patients with rare bleeding disorders (RBDs) to compare the usefulness of the thrombin generation (TG) assay versus conventional tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT) in predicting bleeding risk in patients with RBD in southern Iran. The TG parameters consisted of endogenous thrombin potential, lag time, peak, time to peak (ttPeak), and start tail. The area under the receiver–operating characteristic (ROC) curve showed statistically significant associations between bleeding risk and lag time, ttPeak, and start tail. We determined cutoff values for these 3 TG parameters and obtained a negative predictive value of 86% to 90% in patients with RBD who had a bleeding score (BS) ≤13. The ROC curves for the association of PT and aPTT with BS did not indicate any significant association. Correlation analysis supported the results of ROC curve analysis, only lag time, ttPeak, and start tail showed significant positive correlations with BS (P < .05). Disease severity based on plasma factor activity was significantly associated with prolonged lag time and ttPeak and with prolonged PT (P <.05). We suggest that TG assay is a potentially more useful tool for predicting the bleeding risk in patients with RBD. However, the small sample size in different RBD subgroups precluded subgroup analysis. Prospective multicenter studies with larger numbers of patients are therefore advisable.
We aimed to scrutinize the risk factors for thrombosis in children with acute lymphoblastic leukemia treated with the Berlin-Frankfurt-Münster 95 protocol. The study population was 82 children younger than 16 years of age. The children were followed up for 10 years until January 2007. Thrombosis occurred in 10 (12%) of 82 patients during the treatment course, mainly after the M protocol. The most common risk factor was factor V Leiden (FVL; 15.6%). This was followed by methyleneterahydrofolate reductase (MTHFR; 9.3%), elevated lipoprotein (1.5%), and prothrombin (PT) 20210A (1.5%) in descending order. The risk of thrombosis was found to be significantly high in patients with FVL mutation (odds ratio = 7.1, 95% confidence interval = 1.6-30.5). The risk of thrombosis was not significant in patients with MTHFR and PT20210A mutation (P = .2). Age, catheter usage, FVL mutation, and prednisolone treatment are significant risk factors for thromboemboli occurrence.
A debate concerns the utility of large screening for acquired or inherited thrombophilia. The study concerns relationship between inherited thrombophilic status and lower limb deep vein thrombosis (LDVT) and highlights the possible use of extensive thrombophilia screening to determine an emerging risk of LDVT. From January 2010 to January 2012, 103 consecutive patients with LDVT were considered. In all, 57 (55.3%) patients with LDVT showed inherited thrombophilia. The most frequent trombophilic alterations were deficiency of protein S (33 patients, 32.0%), methylentethrafolate reductase (MTHFR) gene C677T variant (22 patients, 21.4%), protrombin gene G20210A alteration (50, 14.6%), and deficiency of protein C (12, 11.6%). Age and MTHFR variant were found related to LDVT and thrombophilia was related to distal LDVT. A high frequency of thrombophylic factor was found in patients with LDVT, but we believe that a generic genetic screening should not be suggested for these patients.
With advances in modern imaging techniques, portal vein thrombosis (PVT) is being increasingly diagnosed. It has a wide ranging clinical spectrum from being an asymptomatic state to a potentially life-threatening situation. It is not unusual to find it as an incidental finding in the abdominal imagings done for other reasons. It is commonly associated with cirrhosis and abdominal malignancies and also has a strong association with prothrombotic disorders. It is often difficult for the clinicians to decide whether PVT is acute or chronic. This poses great challenges to its management strategies that include anticoagulants, thrombolysis, and surgical options. Timely diagnosis and appropriate management have great bearings on its outcomes of morbidity and mortality. In this clinician-oriented review, we have provided a concise review of clinical aspects of PVT and discussed various management strategies while addressing the common questions that come to a physician’s mind dealing with such a patient.
The aim of the study was to analyze the relation between platelet reactivity and intramyocardial hemorrhage (IMH) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Platelet reactivity was measured in 49 patients with means of impedance aggregometry (Multiplate) before reperfusion and repeated in the subacute phase of STEMI. Cardiovascular magnetic resonance was used to detect IMH, which was found in 16 (33%) patients. There were no differences in platelet reactivity between patients with and without IMH before reperfusion. Reassessment in the subacute phase of STEMI demonstrated that patients with IMH had lower thrombin receptor activating peptide (TRAP)-induced platelet aggregation (P = .004) and trends toward lower values of ristocetin and collagen-induced platelet aggregation (P = .09 and P = .07). The TRAP-induced platelet aggregation and initial perfusion grade were the factors independently associated with IMH. Intramyocardial hemorrhage is related to more potent inhibition of platelet aggregation in the subacute phase of STEMI.
Objectives: We examined the association between neutrophil to lymphocyte ratio (NLR) and the complexity of coronary artery disease assessed by SYNTAX score (SS). Methods: The study population included patients with chest pain who had undergone coronary angiography for stable angina pectoris. Patients were classified depending on whether the SS was 0 or SS > 0. Results: Left ventricular ejection fraction, estimated glomerular filtration rate, and NLR were found to be the independent predictors of high SS in multivariate analysis. The area under the receiver–operating curve of NLR was 0.72 (0.65-0.80, P < .001) for predicting high SS. The optimal cutoff value of NLR to predict high SS was 2.7 (sensitivity of 72% and a specificity of 61%). There was a significant correlation between NLR ratio and continuous SS (r = .552, P < .001). Conclusion: The NLR is a readily measurable systemic inflammatory marker and is associated with both the presence and the complexity of coronary artery disease.
Background: Hospitalized medically ill patients receiving antithrombotic medications experience increased risk of bleeding. We examined antithrombotic use, bleeding rates, and associated risk factors at 30 days post discharge. Methods: This retrospective database analysis included nonsurgical patients aged ≥40 years hospitalized for ≥2 days during 2005 to 2009. Previously cited, validated International Classification of Diseases, Ninth Revision, Clinical Modification codes for major bleeding were used to define clinically relevant bleeding. Results: Of the 327,578 patients, 9.1% received antithrombotic medications, of which 3.7% were anticoagulants. Rates of major and minor bleeding were 1.8% and 7.1%, respectively. Preindex gastroduodenal ulcer, thromboembolic stroke, blood dyscrasias, liver disease, and rehospitalization were the strongest predictors of major bleeding. Other risk factors included increasing age, male gender, and hospital stay of ≥3 days. Conclusions: Careful consideration of these demonstrated bleed-associated comorbidities before initiating anticoagulation or combining antithrombotic medications in medically ill patients may improve strategies for prevention of postdischarge thromboembolism.
The study was conducted to evaluate the effect of anticoagulant therapy in women with thrombophilia and to detect the possible differences among carriers of mutations (factor V [FV] Leiden and FIIG20210) and those with natural anticoagulant deficiency. The 4-year prospective investigation included 85 pregnant women, with a history of recurrent fetal loss (RFL). They were treated with prophylactic doses of low-molecular-weight heparin (nadroparin) starting from 6 to 8 weeks of gestation. Pregnancy outcomes were evaluated based on the thrombophilia type. Carriers of thrombophilic mutations had a live birth rate of 93%, compared to 41.6% for women with natural anticoagulant deficiencies. Significant differences between the groups were also observed for intrauterine fetal death, intrauterine growth restriction, and postpartum thrombosis. The optimal therapy for women with natural anticoagulant deficiency and RFL remains unclear and future prospective study with a large number of patients is required to determine the best treatment for these severe thrombophilic conditions.
Objectives: We aimed to investigate the relationship between red cell distribution width (RDW) value and coronary collateral circulation (CCC) in patients with non-ST elevation myocardial infarction (NSTEMI). Methods: The study population consisted of 322 consecutive patients with NSTEMI. The patients were classified into impaired CCC (group 1, Rentrop grades 0-1) or good CCC (group 2, Rentrop grades 2-3). Baseline RDW was measured as part of the automated complete blood count. Results: The RDW values were significantly higher in patients with impaired CCC than in those with good CCC (17.2 ± 2.3 vs 14.5 ± 2.5, P < .001). In multivariate logistic regression analysis, RDW (odds ratio: 1.52, 95% confidence interval: 1.30-1.78, P < .001), baseline creatine kinase MB (CK-MB), and absence of preinfarction angina were found to be the independent predictors of impaired CCC. In receiver–operating characteristic curve analysis, the RDW value >15.5 yielded an area under curve value of 0.783, with 77% sensitivity and 73% specificity. Conclusions: Our study results demonstrated that, high RDW, high CK-MB, and absence of preinfarction angina were found to be independent predictors of impaired CCC.
Objectives: The neutrophil to lymphocyte ratio (NLR) has been investigated as a new predictor for cardiovascular risk. Admission NLR would be predictive of adverse outcomes after primary angioplasty for ST-segment elevation myocardial infarction (STEMI). Methods: A total of 2410 patients with STEMI undergoing primary angioplasty were retrospectively enrolled. The study population was divided into tertiles based on the NLR values. A high NLR (n = 803) was defined as a value in the third tertile (>6.97), and a low NLR (n = 1607) was defined as a value in the lower 2 tertiles (≤6.97). Results: High NLR group had higher incidence of inhospital and long-term cardiovascular mortality (5% vs 1.4%, P < .001; 7% vs 4.8%, P = .02, respectively). High NLR (>6.97) was found as an independent predictor of inhospital cardiovascular mortality (odds ratio: 2.8, 95% confidence interval: 1.37-5.74, P = .005). Conclusions: High NLR level is associated with increased inhospital and long-term cardiovascular mortality in patients with STEMI undergoing primary angioplasty.
This study aimed to investigate the oxidative stress, hypoxia biomarkers, and circulating microparticles (MPs) in β thalassemia major. The study included 56 children with thalassemia and 46 healthy controls. Hypoxia biomarkers, oxidative stress biomarkers, and total plasma fragmented DNA (fDNA) were detected by the standard methods. The MPs were assessed by flow cytometry. Hypoxia and oxidative stress biomarkers, fDNA, and MPs were higher and total antioxidant capacity (TAC) was lower in patients with thalassemia than the controls. In splenectomized patients and those who had complications, vascular endothelial growth factor (VEGF), malondialdehyde, fDNA, endothelial, platelet, and activated platelet MP levels were higher while, TAC was lower than the nonsplenectomized patients. In conclusion, the increased tissue hypoxia, oxidative stress in β thalassemia, and its relationship with DNA damage and MPs release could explain many complications of thalassemia and may have therapeutic implications. The VEGF could serve as an important indicator for adequacy of blood transfusion in thalassemia.
Background: Endovascular treatment of cerebral venous sinus thrombosis (CVST) includes pharmacological and mechanical thrombolysis. Methods: The authors searched the English literature on CVST from 1990 to 2012 for all case reports or case series of mechanical thrombectomy. Results: A total of 64 patients were treated in all published studies. The techniques for mechanical thrombectomy included rheolytic thrombectomy with an AngioJet device (46.9%), clot retraction with the Penumbra system (4.7%), clot retraction with a Fogarty catheter (1.6%), clot retraction with a microsnare (3.1%), balloon venoplasty without stenting (18.7%), balloon venoplasty with stenting (4.7%), and an amalgam of techniques (18.7%). Nine (16.1%) patients died. At the most recent follow-up, 40 (62.5%) patients had no disability or minor disability and 7 (10.9%) patients had major disability. Conclusion: Randomized multiinstitutional clinical trials with larger number of participants are needed to sufficiently compare the effect of intrasinus thrombolysis and mechanical thrombectomy to standard-of-care anticoagulation therapy.
Purpose: The purpose of this study is to investigate the hispathological, biochemical, and clinical efficiency of Ankaferd Blood Stopper (ABS) in preventing postoperative intraabdominal adhesions. Method: A total of 40 Wistar albino species female rats were randomly separated into 4 groups. For the control group, 1 mL normal saline was administered; and for the second, third, and fourth groups 0.5, 1, and 2 mL, respectively, ABS was administered. Statistical analyses were evaluated with Tukey and analysis of variance test. Findings: Significant increase was observed in fibroblast and vascularization microscopically with increasing amount of ABS used. Degree of adhesion in the group administered with normal saline was lower compared to the other groups. Adhesion thickness and prevalence macroscopically increased with the increasing amount of ABS used in groups. Conclusion: It was determined in our study that ABS is not efficient in preventing intraabdominal adhesions; on the contrary, adhesions were increased with the increased amount of ABS used.
Background. Telangiectasia is the dilation of dermal capillaries mainly due to hypertension and vein insufficiency. Treatments of choice for this condition are sclerotherapy with foam liquid or intradermal fiber optic laser energy delivery. Aim. The aim of this study was to assess the efficacy of a new therapeutic approach consisting in the use of polymerized hyaluronic acid mesotherapic injections following sclerotherapy in the areas of the skin affected by telangiectasia in patients without major vein insufficiency. Materials and Methods. A total of 20 women, aged between 19 and 64 years, affected by recurrent lower leg telangiectasia, were included in this study. Patients were preliminarily submitted to echo color Doppler sonography to rule out severe saphenofemoral valve and lower limb major vein insufficiency. All patients underwent 3 sessions a month of polidocanol 1% capillary injections for 2 months. This was followed by 0.1 ml cross-linked hyaluronic acid introduction in the polidocanol 1% needle track. A total of 50 mesotherapic injections (0.05 ml each) were performed on the skin surface where an ice pack was previously applied for 4 to 5 minutes. A follow-up visit was performed at 3 months. The results, based on photographic examination, were rated as follows: poor improvement (0%-50%), good improvement (51%-75%), and very good improvement (76%-100%). The side effects of the clinical procedure, in terms of pain, itching, paresthesia, ecchymosis, and relapse of telangiectasia over the treated skin surface, as well as a persisting pigmentation in the injection spots and induced benefits related to leg heaviness and comfort, were recorded. Results. In total, 6 patients displayed a slight venous insufficiency, 3 patients displayed patent venous insufficiency, and 11 patients did not show any venous insufficiency. Before treatment, itching was present in 18 out of 20 patients, paresthesia in 15 out of 20 patients, ecchymosis in 16 out of 20 patients, and leg heaviness in 15 out of 20 patients. At the 3-month follow-up, an improvement of 0% to 50% was observed in 4 patients who had a relapse in telangiectasia. A 51% to 75% improvement was observed in 3 patients and a 76% to 100% improvement occurred in 13 patients. At the 3-month follow-up, itching persisted only in 4 patients; paresthesia was absent in 12 patients, while 3 patients still presented this symptom; ecchymosis was absent in 16 patients; 15 patients reported a feeling of lightweight legs. Among the patients with relapsing telangiectasia, 2 patients reported pigmentation due to hemosiderin deposit in the skin at the 3-month follow-up. The slight venous insufficiency, observed at the beginning of the study, improved in 5 out of 6 patients. The patients’ compliance with the procedure was high and 16 out of 20 patients declared their willingness to repeat the whole clinical procedure, if necessary. Conclusions. This pilot clinical study supports the use of hyaluronic acid mesotherapic injections following sclerotherapy for treatment of lower leg telangiectasia without major venous insufficiency. We propose that the prolonged persistence of cross-linked hyaluronic acid, across the microvascular venous areas, is able to induce a stronger stromal tissue, thus preventing relapse. Further clinical studies, comparing this new approach with existing clinical procedures, are needed in a larger number of patients.
This study aimed to investigate the significance of the prethrombotic state (PTS) and 4 plasma markers in predicting perisurgical adverse cardiac events in patients with coronary heart disease (CHD) undergoing abdominal surgery. Perioperative adverse effects were recorded in 128 consecutive patients with CHD undergoing elective abdominal surgery. Plasma <sc>d</sc>-dimer, P-selectin, von Willebrand factor (VWF), and thrombus precursor protein were measured before and after the surgery. Patients with abnormal values in one or more of the 4 PTS markers were identified as having PTS, and data were analyzed by univariate and multivariate logistic regression. Abnormal presurgery levels of the 4 markers were found more frequently in those with adverse perioperative cardiac events than in those without. Multivariate analysis showed the odds ratios for adverse cardiac events to be 64.3 (PTS, P < .001), 25.7 (VWF, P = .003), and 23.5 (P-selectin, P = .04). Preoperative PTS is an independent risk factor for perioperative events in patients with CHD undergoing noncardiac surgery.
Background: The purpose of this study is to investigate the acute and chronic effects of cigarette smoking on cyclooxygenase- 1(COX-1)-mediated platelet reactivity among cigarette smokers. Methods: The levels of collagen-induced platelet aggregation, platelet COX-1 activity, and expressions were compared between smokers and age-matched nonsmokers. In smokers, the acute effects of cigarette smoking were assessed by repeating these measurements an hour after smoking. Results: Twenty-five smokers and age-matched nonsmokers (all men; mean age, 29 years) were studied. Collagen-induced platelet aggregation and plasma/urinary thromboxane B2 (TXB2) and 11-dehydroxythromboxane B2 levels were higher in cigarette smokers compared to nonsmokers. Greater expression of platelet COX-1 was observed in smokers than in nonsmokers. Among smokers, collagen-induced platelet aggregation correlated positively with platelet volume and circulating nicotine and cotinine concentrations. The levels of plasma/urinary TXB2 were significantly increased an hour after cigarette smoking. Conclusion: Cigarette smoking aggravates COX-1-mediated platelet reactivity in young, otherwise healthy, smoking men.
Background: Previous studies have demonstrated that platelet activation occurs in patients with aortic stenosis (AS). This study sought to evaluate the changes in hematologic and clinical parameters noted with the improvement in AS following transcatheter aortic valve implantation (TAVI) in patients with severe AS at high risk of surgery. Patients and Methods: The study included 33 patients who underwent TAVI. In addition to biochemical, clinical, and echocardiographic examinations, hematologic blood parameters were recorded before TAVI, at discharge, and at 1 and 4 months. Results: Mean platelet volume (MPV) showed a progressive decrease after TAVI. On echocardiography at 1 month, aortic valve area significantly increased, with significant decreases in peak and mean gradients. Progressive decreases were also noted in N-terminal proB-type natriuretic peptide levels. Conclusion: Our findings show that TAVI improves hemodynamic parameters of the valve with marked clinical and echocardiographic improvement, resulting in decreased platelet activation and MPV in patients with severe AS.
We aimed to assess the effective factors on high mean platelet volume (MPV) in patients with stable coronary artery disease (CAD). A total of 411 patients (247 males and 164 females; mean age: 61.7 ± 9.9 years) with angiographically proven CAD were included. The patients were divided into 2 groups according to the median MPV value (MPVlow group <9.5 fL and MPVhigh group ≥9.5 fL). The SYNTAX score, high sensitive C-reactive protein (hsCRP) levels, and frequencies of diabetes and hypertension were higher in MPVhigh group compared to MPVlow group. Aortic distensibility (AD) and platelet count of patients in MPVhigh group were lower than patients in MPVlow group (P < .05, for all). Multivariate linear regression analysis showed that MPV was independently related with diabetes (β = 0.135, P = .007), hsCRP (β = 0.259, P < .001), platelet count (β = -0.144, P < .001), and AD (β = -0.425, P < .001). High MPV value is independently related to AD, as well as diabetes, hsCRP, and platelet count in patients with stable CAD.
Introduction: Despite various guidelines for venous thromboembolism (VTE) prevention, malpractice in prescribing thromboprophylaxis is common. In this study, factors associated with prescribing or not prescribing appropriate chemical thromboprophylaxis were assessed. Materials and methods: We enrolled high-risk patients for VTE (based on Caprini score) in the general surgery ward. They were divided into 2 groups based on receiving appropriate prophylaxis or not. Factors associated with prescribing thromboprophylaxis were analyzed. Results: A total of 613 patients were enrolled in this study. Head and neck operations (P < .0001), minor surgeries (P = .001), mastectomy (P = .012), and medical treatment (P = 0.034) were the factors associated with not prescribing thromboprophylaxis. In contrast, age (P < .0001), laparoscopic surgeries (P = .011), surgery duration (< .0001), oral contraceptive pill consumption (P = .005), and complete bed rest (P = .002) were protective factors. Conclusion: Minor surgeries, head and neck operations, mastectomy, and medical treatment are associated with overlooking anticoagulant administration. It is recommended to consider aforementioned pitfalls in routine practice and education.
Objective: To examine the effects of the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) gene polymorphisms and their interactions with environmental factors on serum lipid levels. Methods: We investigated totally 340 patients with essential hypertension, from Dongzhi community, Anhui, China. High-throughput TaqMan allelic discrimination assay was used for the genotyping of MTHFR C677T (Ala222Val), MTHFR A1298C (Glu429Ala), MTRR A66G (Ile22Met), and MTRR His595Tyr. Results: Compared with the MTRR 66AA genotype carriers, the GG genotype carriers had lower serum total cholesterol (TC) levels (adjusted β ± standard error [SE]: -0.5 ± 0.2 mmol/L; P = .003) and low-density lipoprotein cholesterol (LDL-C) levels (adjusted β ± SE: -0.4 ± 0.2 mmol/L; P = .005). Their false discovery rate (FDR)-adjusted P values were 0.056 and 0.056, respectively. We further found that there was a statistically significant interaction between 677TT genotype and sex in their associations with LDL levels (P interaction = .020), and significant interaction between 677TT genotype and smoking on LDL levels (P interaction = .036). A similar pattern of interaction was found between 66GG and drinking on levels of TC (P interaction = .034) and LDL (P interaction = .020). However, there were no significant interactions observed after FDR adjustment. Conclusion: Both MTHFR and MTRR gene polymorphisms could be important genetic determinants of serum lipid levels in Chinese patients with hypertension. These findings need to be replicated in a larger sample.
Neutrophils and lymphocytes (N/L) ratio and carotid intima–media thickness (C-IMT) value have been studied as new predictors of cardiovascular risk. We aimed to investigate N/L ratio and C-IMT value in patients with cardiac syndrome X (CSX) and compare patients with coronary artery disease (CAD) and normal participants. A total of 288 participants were enrolled in the study. The N/L ratio and C-IMT value were compared among the 3 groups. There were no statistically significant differences in N/L levels between CSX and CAD groups. The N/L ratio was found significantly increased in patients with CSX and CAD, compared to the control group. Patients with CAD and CSX had significantly higher C-IMT value compared to control participants. Significant positive correlation was found between C-IMT value and plasma level of N/L ratio. The relationship among CSX and higher N/L ratio level and C-IMT suggests that endothelial dysfunction may contribute to the etiopathogenesis of the CSX.
There is limited data on the role of hyperhomocysteinemia as a risk factor for cerebral veno-sinus thrombosis (CVT) in Indians. We examined the association between plasma homocysteine (Hcy), methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, and CVT in 185 patients with aseptic CVT (puerperal 80 and nonpuerperal 105) and 248 healthy controls (puerperal 67 and nonpuerperal 181). Fasting Hcy was higher in patients compared to controls (20.25 ± 5.97 vs 9.81 ± 5.19 μmol/L, P < .001) and associated with 4.54-fold (95% confidence interval [CI]: 2.74-7.53) increase in risk of CVT. Risk was higher in puerperal (odds ratio [OR]: 8.7, 95% CI: 2.73-26.91) compared to nonpuerperal CVT (OR: 3.82, 95% CI: 2.09-6.96). Plasma Hcy was higher in MTHFR 677TT compared to 677CT and 677CC genotypes (34.44 ± 32.8 vs 25.81 ± 33.3 vs 18.50 ± 23.7 μmol/L, respectively, P < .001), but the risk associated with MTHFR 677TT was insignificant (OR: 1.91, 95% CI: 0.53-7.06). We conclude that hyperhomocysteinemia is a risk marker for Indian patients with aseptic CVT. MTHFR 677TT genotype is not linked with CVT but is a determinant of plasma Hcy.
We sought to determine the prognostic value of neutrophil to lymphocyte ratio (NLR) in non-ST elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP). A total of 308 (mean age 59.22 ± 11.93) patients with NSTEMI and UAP were prospectively evaluated. The study population was divided into tertiles based on admission NLR values. The patients were followed for clinical outcomes for up to 3 years after discharge. In the Kaplan-Meier survival analysis, 3-year mortality was 21.6% in patients with high NLR versus 3% in the low-NLR group (P < .001). In a receiver–operating characteristic curve analysis, an NLR value of 3.04 was identified as an effective cut point in NSTEMI and UAP of a 3-year cardiovascular mortality (area under curve [AUC] = 0.86, 95% confidence interval [CI] 0.8-0.92). An NLR value >3.04 yielded a sensitivity of 79% and specificity of 71%. Admission NLR is the strong and independent predictor of a 3-year cardiovascular mortality in patients with NSTEMI and UAP.
Data from the Nationwide Inpatient Sample, 1999 to 2008, were used to assess the effects of advancing age on in-hospital case fatality rate of patients with acute pulmonary embolism (PE) stratified according to stability. Among adults, all-cause case fatality was affected more by advancing age (1.8 deaths/10 years of age) than death attributable to PE (0.7 deaths/10 years of age). All-cause case fatality rate was affected more by advancing age in unstable adults than in stable adults (5.3 deaths/10 years of age vs 1.7 deaths/10 years of age). Case fatality rate attributable to PE was also affected more by advancing age in unstable adults than in stable adults (4.1 deaths/10 years of age vs 0.6 deaths/10 years of age). Limited data suggest that the case fatality rate of children was comparable to that of the elderly individuals. These results may influence the prognostic value of risk assessment tools for patients with PE.
Elevated red blood cell distribution width (RDW) has been associated with adverse outcomes of heart failure and pulmonary hypertension. A total of 702 consecutive patients with acute pulmonary embolism (PE) were evaluated. There was a graded increase in mortality rate with RDW quartiles of 5.8% in quartile I (≤13.6), 9.7% in quartile II (13.7%-14.5%), 13.1% in quartile III (14.6%-16.3%), and 20% in quartile IV (>16.3%; P < .001). Patients who died had higher baseline RDW values (16.1% [11.7-28.3] vs 14.5% [10.7-32.5]; P < .001). The optimal cutoff value of RDW for predicting in-hospital mortality was ≥15%. The area under the curve of mortality for RDW was 0.649 (confidence interval [CI]: 0.584-0.715); the negative predictive value was 93%. In multivariable regression analysis, RDW remained associated with an increased odds of death (odds ratio: 1.2, 95% CI: 1.1-1.4). High RDW level was an independent predictor of short-term mortality in PE. The RDW levels may provide a potential marker to predict outcome in patients with PE.
Several medicines are currently used to inhibit the platelet activity. We aim to monitor the residual platelet activity (RPA) despite antiplatelet therapy and assess its relationship with major adverse events. The impedance platelet aggregation was employed to determine RPA. Totally, 202 patients with acute coronary syndrome (ACS) were followed up for 10 months for major clinical events of myocardial infarction, cerebrovascular accident (CVA), and all cause mortality, and RPA after clopidogrel loading was assessed in 30 patients. The RPA at 2 hours after 300 mg clopidogrel loading was 1 (± 2.3 ) induced by adenosine diphosphate. Residual platelet activity of patients who experienced death, MI, or CVA was significantly higher than those who did not experience (P < .05). Cutoff values of RPA showed optimal negative predictive values (96%-97%) and poor positive predictive values (16%-29%). Therefore, RPA monitored by whole blood impedance platelet aggregation may have high exclusionary predictive value for the occurrence of major clinical events in patients with ACS.
This study was sought to evaluate the interobserver agreement for interpreting the chest radiograph of patients with suspected acute pulmonary embolism (PE). The chest radiographs of 300 patients with clinically suspected acute PE were reviewed by 4 radiologists. Observers assessed the chest radiographic abnormalities and classified the chest radiograph as normal or abnormal. We found that the overall interobserver agreement was good for the exclusion of any pleural or parenchymal abnormality (k = 0.6; 95% CI: 0.56-0.64) but fair (k = 0.28; 95% CI: 0.17-0.40) between junior radiologists when evaluating supine chest radiographs. The level of interobserver agreement for the interpretation of the chest radiograph as consistent or not with PE was fair (k = 0.24; 95% CI: 0.19-0.29), regardless of the observer experience. In conclusion, chest radiography may be reliably used for targeting patients with suspected acute PE for different subsequent diagnostic investigations.
Factor V (FV) plays a crucial role in both procoagulant and anticoagulant pathways. It was indicated that -426G/A change in the promoter of the FV gene may have an effect on the occurrence of thrombosis. We aimed to investigate the effect of -426G/A gene variation on thrombus formation in the thrombosis patients of age 0 and 18 years and 70 years and older. The study included 179 patients with the diagnosis of thromboembolism and also 221 healthy individuals as controls. The Polymerase chain reaction–restriction fragment length polymorphism method was used to detect -426G/A. It was observed that carrying AA genotype does not have a significant risk of thrombosis between the patients and controls (for 0-18 age group P = .96, odds ratio [OR]: 1.13 [0.38-3.30], for ≥70 age P = .94, OR: 0.69 [0.11-4.28]). The same results were obtained when FV Leiden mutation carriers were excluded (for 0-18 age group P = .95, OR: 1.15 [0.35-3.78], for ≥70 age P = .89, OR: 0.73 [0.11-4.56]). In this study, an effect on thrombosis of -426G/A polymorphism was not determined.
Background: Endothelial dysfunction marker, von Willebrand factor (vWF), is physically connected with osteoprotegerin (OPG) in the Weibel-Palade bodies. We aimed to compare the effect of unfractionated (UFH) and low-molecular-weight (LMWH enoxaparin) heparin used as anticoagulants during hemodialysis (HD) on plasma levels and relationships of OPG, soluble receptor activator of nuclear factor B Ligand (sRANKL), and vWF. Methods: Totally 21 clinically stable chronic HD patients were randomly assigned to either enoxaparin (n = 10) or UFH (n = 11) anticoagulation and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. The OPG, RANKL, and vWF levels were measured at T0, T10, and T180 of HD session after each period of evaluation. Results: The baseline sRANKL level was higher under UFH treatment. Its over-HD level does not behave significantly different under enoxaparin and UFH treatment. Plasma OPG levels expressly changed during both enoxaparin (2 analysis of variance [ANOVA] = 31.13, P < .016) and UFH (2 ANOVA = 8.26, P = .016) anticoagulation, and its increment at T10 and T180 was significantly different between both the heparins. The main negative predictor of OPG concentration was the total cholesterol level (β = -.51, P = .025). von Willebrand factor concentration remained stable during UFH anticoagulation, whereas constant, no significant increments were noticed, under enoxaparin treatment. After 10 minutes of HD, especially under enoxaparin use, a positive correlation between OPG and vWF increase was noticed (P = .03, R = .45). Conclusions: Impact of heparin on endothelial cells and simultaneously on OPG/RANK/RANKL axis reinforces the presumption of the pathophysiological linkage between bone mineralization and endothelial dysfunction in end-stage renal disease.
This study was undertaken to evaluate the impact of progestins as part of low-estrogen (ethinyl estradiol [EE2] ≤35 μg) combined oral contraceptives (COCs) on hemostatic variables. One hundred ninety-five healthy women took oral contraceptives with following formulations: 35 EE2/norgestimate (NGM), 35 EE2/cyproterone acetate, 35 EE2/norethisterone, 30 EE2/levonorgestrel, 30 EE2/drospirenone (DRSP), 20 EE2/gestodene, and 20 EE2/DRSP, for 6 months. Hemostatic assays (prothrombin time, activated partial thromboplastin time, fibrinogen, resistance to activated protein C ratio, protein C, protein S, factor VIII [FVIII], antithrombin, plasminogen, α2-antiplasmin, inhibitor of plasminogen activator type 1 [PAI-1] and <sc>d</sc>-dimers) were performed in 3 time points: at baseline, after 3, and 6 cycles. For each formulation, results were compared according to baseline values, intergroup analysis, and the amount of estrogen or progestin component. Most of the variables were changed except FVIII. Significant difference between oral contraceptives was found in antithrombin, protein C, protein S activities, and PAI-1 values, but changes were mostly within reference range.
Some now recommend a lung scan if the plain chest radiograph is normal instead of computed tomographic (CT) angiography to minimize the risks of radiation in younger patients with suspected pulmonary embolism. The purpose of this investigation is to determine practice standards according to age and gender in regard to noninvasive imaging. Data are from the Nationwide Inpatient Patient, 1998 to 2009. In 2006 to 2009, the proportion of females with pulmonary embolism imaged with CT angiography was 275 (90%) of 305 among teenagers and girls, 3990 (87%) of 4570 among women 20 to 40 years, and 25 650 (85%) of 30 160 among women >40 years. Among males the proportion imaged with CT angiography was 175 (92%) of 190 among teenagers and boys, 3000 (89%) of 3370 among men 20 to 40 years, and 21 280 (86%) of 24 800 among men >40 years. In conclusion, contrary to the recommendations of some, CT angiography is usually obtained in young patients.
Increased levels of factor VIII (FVIII) are a prevalent and independent risk factor for deep venous thrombosis (DVT). After a median of 10 years of the first DVT, we evaluated FVIII coagulation levels in 55 patients with DVT of the lower limbs and previous high levels of FVIII and in 74 controls. Subsequently, we analyzed the presence of post-thrombotic syndrome (PTS) in patients and its relationship with FVIII levels. After a median of 10 years of the first DVT, the FVIII levels were still significantly higher in patients when compared to controls (P < .001). Patients with severe PTS showed increased levels of FVIII when compared to patients with moderate or absent PTS (P < .001). We demonstrated a persistent increase in FVIII levels in a subset of patients with DVT, but in a lower magnitude after 10 years of the first DVT episode. Moreover, we observed a significant association between increased FVIII levels and severe PTS.
We aimed to determine whether red cell distribution width (RDW) and mean platelet volume (MPV) values differ between patients with reactive amyloid A (AA) amyloidosis due to chronic inflammatory disease and in healthy participants. In this study, 33 patients with AA amyloidosis and 40 age- and sex-matched healthy controls were enrolled. Erythrocyte sedimentation rate (ESR), RDW, platelet count (PLT), and MPV levels were retrospectively obtained from our computerized patient database. We found RDW, ESR, and PLT levels to be significantly higher in patients with AA amyloidosis compared with the controls (P < .0001). Mean platelet volume was significantly lower in patients with amyloidosis (P < .0001). Inflammatory diseases such as AA amyloidosis may demonstrate low MPV and high RDW levels.
During the process of thrombopoiesis, invaginations of the plasma membrane occur in megakaryocytes. Since acetylsalicylic acid (aspirin), the most commonly used anti-inflammatory and antiplatelet drug, interacts with the lipid bilayers of the plasma membranes, this drug would affect the process of thrombopoiesis. In the present study, employing a standard patch-clamp whole-cell recording technique, we examined the effects of aspirin on delayed rectifier K+-channel (Kv1.3) currents and the membrane capacitance in megakaryocytes. Using confocal imaging of di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate (di-8-ANEPPS) staining, we also monitored the membrane invaginations in megakaryocytes. Aspirin suppressed both the peak and the pulse-end currents with a significant increase in the membrane capacitance. Massive di-8-ANEPPS staining after treatment with aspirin demonstrated the impaired membrane micro-architecture of megakaryocytes. This study demonstrated for the first time that aspirin induces microscopic surface changes in megakaryocytes. Such surface changes were thought to stimulate thrombopoiesis in megakaryocytes as detected by the increase in the membrane invaginations.
Thromboembolic events can be seen in patients with mitral valve prolapse (MVP). It is unclear whether platelet activation may contribute to these events in patients with MVP. Thus, we aimed to evaluate mean platelet volume (MPV) in patients with MVP and its association with the severity of MVP. This study included 312 patients with MVP and 240 control participants. Mean platelet volume was significantly higher in patients with MVP than in controls (8.9 ± 0.7 vs 7.9 ± 0.6 fL, P = .001). In linear regression analysis, MPV was independently associated with the degree of mitral regurgitation (β = .23, 95% confidence interval (CI): 0.14-0.32, P = .001), maximal leaflet displacement (β = .24, 95%CI: 0.17-0.31, P = .001), and mean thickness of the anterior (β = .47, 95%CI: 0.27-0.61, P = .001) and posterior leaflets (β = .22, 95%CI: 0.03-0.41, P = .02). Our findings show that MPV can be elevated in patients with MVP and may be independently associated with severity of mitral regurgitation, leaflet displacement, and thickness of the leaflets.
Exact age determination of deep venous thrombosis (DVT) is important for an appropriate treatment. The purpose of this present study is to assess the age of acute DVT with the area of venous thrombi in elasticity imaging during the thrombosis procession. The thrombus area is obtained from a specially designed program. It was applied to clot specimens induced in human great saphenous (n = 15) at selected time points following the initiation of thrombosis. The relative mean proportion of blood clots was 50.01% ± 12.44% at day 1; 69.94% ± 8.19% at day 3; 81.93% ± 6.15% at day 6; and 92.37% ± 4.06% at day 9. The results indicated that the thrombus area increased significantly over time, while the normalized strain values inside the thrombus changed only a little. The pathological analyses also showed the same results. Therefore, we conclude that the area of venous thrombi in elasticity imaging may be a novel function for acute DVT staging.
The aim was to evaluate the right ventricular function in patients with inherited thrombophilia and deep vein thrombosis (DVT) without pulmonary embolism. A total of 38 patients with DVT without symptomatic pulmonary embolism and 30 patients with varicose veins were enrolled. Clinical data, echocardiography, and 2 thrombophilic mutations were analyzed. Factor V Leiden (FVL) polymorphism was significantly frequent in the study group (P = .007). The difference in prothrombin G20210A polymorphism between the study and control groups was at a near-significant level (P = .058). There was statistically significant decrease in tricuspid annular plane systolic excursion values in patients with FVL and prothrombin G20210A polymorphism. Combined FVL and prothrombin G20210A polymorphisms were more closely related to the decrease in this value (P = .006). Deep vein thrombosis had no additional adverse effects on right ventricle. Impaired right ventricular systolic function occurs in FVL and prothrombin G20210A polymorphisms.
Purpose: The aim of this study is to investigate the relationship between the criteria comprising metabolic syndrome (MS) and neutrophil–lymphocyte ratio (NLR), a simple and reliable indicator of inflammation. Method: Seventy patients with MS and 71 age- and sex-matched control participants were included. Patients were classified into 3 groups based on the number of MS criteria: group 1 (with 3 criteria), group 2 (with 4 criteria), and group 3 (with 5 criteria). The NLR was calculated from complete blood count. Results: Patients with MS had significantly higher NLR compared to the control group. Moreover, the group 3 patients had higher NLR than those in groups 2 and 1 (P = .008 and P = .078, respectively), whereas there was no difference between the patients meeting 3 and 4 MS criteria (P = .320). Besides, NLR increased as the severity of MS increased (r = .586, P < .001). The cutoff level for NLR with optimal sensitivity and specificity was calculated as 1.84. Serum glucose and high-sensitive C-reactive protein level were found to be independent predictors of an NLR value greater than 1.84. Conclusion: The present study indicated a significant correlation between the criteria of MS and inflammation on the basis of NLR. Furthermore, there an increase in NLR as the severity of MS increases.
Three factor VII (FVII) promoter haplotypes are associated with stratified plasma FVII levels. To our knowledge, this is the first study examining the distribution of FVII gene polymorphism and levels in Turkish population. The study population was classified into 3 groups according to the absence of coronary arterial disease and presence or absence of a history of myocardial infarction. It was found that the levels of FVII coagulant activity (FVIIc) were higher in the event group than that of the other groups. Participants with high FVIIc levels were found to have 2-fold increased risk for myocardial infarction. The alleles at the FVII loci in all cases are similar. In conclusion, our results indicate that FVIIc levels have an important predictive role in cardiovascular events. The distribution of FVII gene polymorphisms in the Turkish population shows significant differences when compared with European populations.
The anti-inflammatory, antioxidative, and antiarteriosclerosis activities of simvastatin along with its protective effects on the endothelium suggest that it may also have antiaging effects. The aim of this study was to investigate the antiaging effects of simvastatin as well as its effects on sirtuin 1 (SIRT1) expression in endothelial cells. Aged rats and human umbilical vein endothelial cells were treated with simvastatin in the presence and absence of oxidized low-density lipoprotein (OX-LDL). Aortic β-galactosidase staining was undertaken to determine senescence, and SIRT1 protein expression was evaluated using Western blot analysis. After simvastatin therapy, arterial endothelial cell aging was significantly reduced, and SIRT1 expression was significantly increased. The OX-LDL significantly accelerated the senescence of umbilical vein endothelial cells and decreased SIRT1 expression. The OX-LDL-induced downregulation of SIRT1 was blocked by simvastatin. Simvastatin treatment also reduced umbilical vein endothelial cell aging and increased SIRT1 expression.
Considering the high frequency of bleeding complications following fibrinolytic treatment in neonates, peripheral nerve blockade (PNB) has been proposed alone or in association with lower doses of tissue plasminogen activator, as a possible new therapeutic approach in the management of neonatal limb ischemia (LI) secondary to vasospasm and/or thrombosis. The present article provides a review of the current knowledge about the topic, in order to evaluate the efficacy and safety of this therapeutic approach. According to the few case reports documented in literature and to our experience, PNB could be considered as valid procedure for the treatment of LI, especially during neonatal period, when the risk of serious bleeding associated with fibrinolytic or anticoagulant therapy is higher. Peripheral nerve blockade resulted in a safe and effective procedure for the treatment of neonatal vascular spasm and thrombosis.
Objective: To evaluate the efficacy and safety of darexaban (YM150) in Asian patients undergoing total hip or total knee arthroplasty. Methods: In 2 phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies, patients were randomized to oral darexaban 15 mg twice daily (bid), darexaban 30 mg bid, oral placebo bid, or subcutaneous enoxaparin 20 mg bid. Primary efficacy outcome for both studies was total venous thromboembolism (VTE) incidence. Results: Both darexaban doses were statistically significantly superior to placebo for total VTE incidence (hip study: darexaban 15 mg bid [2.9%] vs placebo [17.1%], P < .001; darexaban 30 mg bid [5.2%] vs placebo [17.1%], P = .003; and knee study: darexaban 15 mg bid [27.2%] vs placebo [52.8%], P = .002; darexaban 30 mg bid [15.5%] vs placebo [52.8%], P < .001). In both studies, the incidence of bleeding events was low across all treatment groups. Conclusion: Darexaban is effective and well tolerated as VTE prophylaxis in Asian patients undergoing elective major orthopedic surgery.
This study was conducted to evaluate current unfractionated heparin (UFH) dosing regimen and establish an institutional therapeutic range for UFH in a public hospital in Jordan. In the first part, medical records of 241 patients who received UFH were reviewed retrospectively. In the second part, blood samples were withdrawn from 60 patients on UFH, and activated partial thromboplastin time and anti-Xa assay were measured. Most activated partial thromboplastin time readings were not therapeutic (91.4%) and recurrence of thrombosis was reported in 35.3% of patients. In the second part, therapeutic activated partial thromboplastin time range corresponding to the UFH concentration of 0.3 to 0.7 anti-factor Xa unit/mL was 56 to 95 seconds, which corresponds to an activated partial thromboplastin time range of 1.5 of 2.8 times the mean control value. The traditional activated partial thromboplastin time range ratio of 1.5 to 2.5 times the control value can result in subtherapeutic UFH levels.
Atrial fibrillation (AF) not only is an independent risk factor for death but also confers significant risk of morbidity from stroke associated with left atrial thrombus. The association of interleukin 6 (IL-6) polymorphism with thrombus in AF has not been investigated before. We carried out a case–control study in Han Chinese. The IL-6 -634C/G genotypes of 31 patients with thrombus and 45 patients without thrombus were detected by polymerase chain reaction and restriction fragment length polymorphism. The frequencies of the IL-6 genotypes (CC, CG, and GG) were 29.03%, 54.54%, and 16.13% for the patients with thrombus, and 55.56%, 40.00%, and 4.44% for the patients without thrombus, respectively (P = .0391). Compared with the CC genotype, the G allele carriers (CG + GG) had a 2.79-fold increased risk of thrombus or severe spontaneous echocontrast (SEC). These results suggest that IL-6 -634C/G polymorphism is associated with thrombus and severe SEC, and the G allele is an independent risk for thrombus and severe SEC in Han Chinese patients with AF.
Objective: To investigate the impact of bivalirudin alternative treatment on antiheparin/platelet factor 4 antibody levels perioperatively in rats undergoing cardiopulmonary bypass (CPB). Methods: Two groups of rats received heparin pretreatment and two groups of rats not, and during CPB all the four groups received either bivalirudin or heparin. Pre-CPB and post-CPB day 7 venous blood samples were used to determine the levels of antiheparin/PF4 antibody immunoglobulin (Ig) G with enzyme-linked immunosorbent assay. Results: Preoperative heparin pretreatment increased the antiheparin/PF4 antibody IgG levels (P < .01), while the administration of heparin further increased this levels (P < .01). The use of bivalirudin prevented further increase in antiheparin/PF4 antibody IgG levels. Conclusion: Bivalirudin, as a direct thrombin inhibitor, could circumvent the increased antiheparin/PF4 antibody level in circulation due to the heparin administration.
Introduction: Mean platelet volume (MPV) is an independent cardiovascular disease predictor, and characteristics of MPV in patients with diabetic nephropathy (DN) are not well known. Aim: To determine the MPV levels in patients at different stages of DN. Patients and Methods: The MPV levels were investigated in healthy participants (group 1, n = 157), patients with type 2 diabetes mellitus without complication (group 2, n = 160), diabetic patients with clinical proteinuria (group 3, n = 144), and in patients with chronic kidney disease due to DN (group 4, n = 160). Findings: The MPV level was higher in all diabetic patients than that in normal participants (P < .05). The MPV values had a positive correlation with the serum creatinine and proteinuria, and a negative correlation with the glomerular filtration rate ([GFR] P < .001 for all, r values; .72, and .82, and -.92, respectively). Conclusion: The MPV values were higher in diabetic groups than that in normal participants. Both GFR and proteinuria were the most powerful determinants of MPV.
Intracerebral hemorrhage (ICH) is associated with a higher mortality rate among stroke subtypes. The amount of hematoma at baseline and subsequent expansion are considered strong independent markers for determining poor clinical outcome. Even though reduction in blood pressure to prevent and control the amount of bleeding in ICH has received considerable amount of attention, the impact of coagulopathy and platelet dysfunction, on the bleeding diathesis has not been extensively investigated. With the increasing use of antiplatelets and/or anticoagulants, given the aging population, a deeper understanding of the interactions between ICH and hemostatic mechanisms is essential to help minimize the risk of a catastrophic coagulopathy-related ICH. In this review article, etiology and risk factors associated with coagulopathy-related ICH are discussed. An overview of coagulation abnormalities, hemostatic agents, and blood biomarkers pertaining to ICH is included.
Guidelines for the diagnosis and management of heparin-induced thrombocytopenia (HIT) vary between hospitals. Recent guidelines recommend initiating alternative anticoagulant therapy in patients with suspected HIT while awaiting laboratory test results confirming the presence of heparin–PF-4 antibodies (PF-4). This retrospective chart review was designed to assess the current state of management of patients with thrombocytopenia suspected to be due to HIT at 26 US hospitals. Most hospitals (25 of 26; 96.2%) had guidelines in place for the management of suspected HIT, with 7 (26.9%) having a "halt heparin, test, and await results" (ie, "test and wait") policy. One-third of hospitals had a wait time for obtaining PF-4 antibodies of 3 days or more. Hospital guidelines for the management of HIT may actually discourage the use of optimal HIT management strategies.
We aimed to examine the levels of lymphocyte subsets and regulatory T cells in patients with newly diagnosed immune thrombocytopenia (ITP) and their correlation with the course of ITP. The study included 40 pediatric patients with acute ITP and 30 controls. Lymphocytes and regulatory T cells were analyzed by flow cytometry. The percentages of CD19+ and CD8+ cells were significantly increased while that of CD4+ cells and CD4+/CD8+ ratio were significantly decreased. The percentages of CD4+CD25+High and CD4+CD25+High forkhead box protein 3 (Foxp3+) cells and the expression of Foxp3+ in CD4+CD25+High cells were significantly decreased in patients. Age, platelet count, and mean platelet volume (MPV) in patients with brief duration of thrombocytopenia were significantly decreased than in those with prolonged duration. The percentages of CD8+, CD4+CD25+High, and CD4+CD25+High Foxp3+ were significantly increased in patients with brief duration. Age, platelet count and MPV, and CD8+ cells had prognostic significance. CD4+CD25+High Foxp+ T cells may be a helpful prognostic marker in children with acute ITP.
Disseminated intravascular coagulopathy (DIC) is a serious disease with fatal consequences. We prospectively analyzed Innovance <sc>d</sc>-dimer immunoturbidimetric assay in 68 patients diagnosed with DIC on the background of malignancy (22), severe infection (20), or multitrauma (26) at a single institution between January 2010 and January 2011. Median age was 61 years (range 20-89). All patients were assessed according to the International Society of Thrombosis and Haemostasis (ISTH) DIC score. Applying a threshold of Innovance <sc>d</sc>-dimer of 10 mg/L fibrinogen equivalent unit (normal <0.5) was correlated with the highest sensitivity in malignancy (86%) and trauma/surgery (80%) compared to 54% in infection. The specificity remained high at 97% in infection, 81% in trauma and 77% in malignancy with a negative predictive value of 97% in trauma and malignancy, and 88% in infection. Our data suggest that Innovance <sc>d</sc>-dimer is a useful and simple tool that enhances the ISTH DIC diagnostic criteria. Further studies to confirm these findings are warranted.
Background: Vitamin D deficiency is associated with cardiovascular disease such as coronary artery disease, heart failure, and hypertension. Vitamin D deficiency activates the renin–angiotensin–aldosterone system, which affects the cardiovascular system. For this reason, it could be suggested that there is a relationship between vitamin D deficiency and atrial fibrillation (AF). In our study, we compared 25-hydroxyvitamin D (25-OHD) levels between nonvalvular AF, valvular AF, and control groups in sinus rhythm. Method: A total of 102 patients with nonvalvular chronic AF without any other cardiovascular disease (mean age 62.51 ± 5.88; group I) and 96 patients with AF, which is associated with mitral valve disease (mean age 61.51 ± 5; group II) were included in our study. Of all, 100 age-matched healthy people with sinus rhythm were accepted as control groups (mean age 61.35 ± 5.44). Routine biochemical parameters, 25-OHD and parathormone levels were performed. Results: Baseline characteristics of the study groups were comparable. Group I patients had a lower vitamin D level than group II and the control group (6.51 ± 4.89, 9.24 ± 7.39, and 11.18 ± 6.98 ng/mL, P < .001, respectively). In groups I and II, the patients’ left atrium diameter and systolic pulmonary artery pressure are higher than the control group. Conclusion: As a result, our study revealed a relationship between vitamin D deficiency and nonvalvular AF.
The primary objective was to evaluate the response rate of rituximab therapy for children with chronic immune thrombocytopenic purpura (ITP) and Evans syndrome (ES) and immune reconstitution of these children after rituximab therapy. Eleven patients with chronic ITP and 2 with ES between 6 and 18 years of age and platelet count less than 20 x 109/L received rituximab. Overall response (OR) was defined as an increase in platelet count above 50 x 109/L. The mean age of 13 children (9 girls, 4 boys) was 11.2 ± 3.8 years (6-18). One of the patients with ES had been splenectomized; others were not. The patients mean follow-up time was 10.3 ± 9.3 months after rituximab therapy. Two patients achieved complete response, 4 patients achieved partial response, and OR rate was 46% (6 of 13) after therapy. Seven patients have no response. In conclusion, rituximab may be considered prior to splenectomy in children with chronic ITP and ES with an acceptable toxicity profile.
Immunological thrombocytopenias, as other forms of thrombocytopenia, are associated with bleeding. Occasionally, these patients manifest thrombotic events. A total of at least 29 patients were reported to have had either arterial (20 cases) or venous (9 cases) thrombosis while platelet count was less than 50 x 103/μL. The most frequent clinical manifestation was a myocardial infarction. Thrombosis occurred in the large majority of patients during prednisone therapy. Patients receiving cortisone or patients with Cushing syndrome show a hypercoagulable state characterized by elevated factor VIII levels, decreased fibrinolysis, and abnormal von Willebrand factor multimers composition. The same is probably true for prednisone-treated patients with thrombocytopenia. However, the 2 conditions are not identical since prednisone is a mainly glycoactive compound, whereas cortisol produced in excess in Cushing syndrome is mainly mineraloactive. The presence of large, young, hyperactive platelets may also play a role. Prednisone-treated patients with thrombocytopenia have to be considered as potentially thrombophilic.
Background: The relationships between the endothelial progenitor cells (EPCs)-CD34+ and CD14+ and coronary artery disease (CAD) were reported and the association of CD34+ cells with renal function was studied previously. Another kind EPC-CD14+ cell and its association with renal function in patients with CAD have not been reported yet. Our aim was to assess CD14+ cell counts versus renal function in CAD. Methods and Results: We studied 242 patients with severe angiographic CAD and 30 healthy control participants. The CD14+ cells were enumerated by flow cytometry. With lowering glomerular filtration rate (GFR), CD14+ cell numbers (percentage of lymphocytes, median and interquartile range) decreased: 0.04 (0.03-0.06), 0.03 (0.02-0.05), 0.02 (0.01-0.03) for estimated glomerular filtration rate (eGFR) ≥90, 60 to 89, and 30 to 89 mL/min per 1.73 m2, respectively (P < .001 for trend). The CD14+ cell counts correlated with eGFR (r = .27, P = .03). By multivariate liner regression analysis, the difference remains significant (P = .02). Conclusions: The CD14+ cell depletion is associated with renal dysfunction in CAD.
We hypothesized that leukocytes have 2 opposing effects on patients with ischemic stroke treated with recombinant tissue plasminogen activator (rtPA). Patients with ischemic stroke treated with rtPA were divided into 2 groups using the peripheral leukocyte count: high leukocyte group (HLG) and low leukocyte group (LLG) and were evaluated with the National Institutes of Health stroke scale (NIHSS) during the first 24 hours. We defined significant improvement (SI) as NIHSS improving by more than 50% from the baseline, and deterioration following improvement (DFI) as the achievement of SI within 24 hours but its subsequent loss at 24 hours. Fifty-three patients were enrolled, and the rate of SI within 24 hours was higher in HLG than in LLG (85.2% vs 42.3%, P = .0011). However, the rate of DFI was significantly higher in HLG than in LLG (29.6% vs 7.7%, P = .0413). We found that leukocytes might have not only deleterious but also beneficial effects in intravenous rtPA treatment.
Platelet gel (PG) includes concentrated dose of growth factors which plays role in physiological processes of healing. The goal of this study is to evaluate repairing effects of intra-articular injection of PG use in a rat model of knee osteoarthritis (OA). A total of 20 rats were randomly distributed into a PG group and a control group. Both the groups were induced OA in knee joints with intra-articular formaline injection. The rats in the PG group and the control group were injected in the knee joint with PG and 0.9% NaCl solution, respectively. Two weeks after last injections, all rats were sacrificed by ether asphyxiation. Tissue samples were obtained from the knee joints and were examined histopathologically. No statistically significant differences were found between the groups regarding cartilage healing (P > .05). We were unable to determine any beneficial or harmful effects of PG on joint cartilage healing in OA.
Induction chemotherapy is associated with increased thrombosis risk in children with acute lymphoblastic leukemia (ALL). In this prospective study, we explored the effects of ALL and induction chemotherapy on the procoagulant, anticoagulant, and fibrinolytic systems in 20 children with ALL. The levels of <sc>d</sc>-dimer, factor VIII, von Willebrand factor, protein C, antithrombin III, and thrombin-activated fibrinolysis inhibitor (TAFI) were elevated at diagnosis. These changes were not related with peripheral blast count. The levels of fibrinogen, <sc>d</sc>-dimer, coagulation inhibitors, and plasminogen decreased, whereas the levels of tissue factor pathway inhibitor and plasminogen activator inhibitor 1 increased progressively following prednisolone monotherapy, administration of vincristine plus daunorubicin, and <sc>l</sc>-asparaginase. The levels of factor VIII, <sc>d</sc>-dimer, and TAFI remained elevated during the study period. In conclusion, coagulation activation and impaired fibrinolysis already exist at diagnosis, whereas induction chemotherapy leads to reactivation of coagulation and progressive impairment in fibrinolytic and anticoagulant capacities in childhood ALL.
Introduction: The sticky platelet syndrome (SPS) seems to be a common cause of thrombosis, although no molecular substrate to explain platelet hyperaggregability has been found. Objective: To analyze an association between the SPS phenotype and the platelet glycoprotein (GP) IIIa PLA1/A2 (human platelet antigen [HPA]-1a/b) gene polymorphism. Methods: Along an 18-month period, Mexican mestizo thrombophilic patients were prospectively accrued. The SPS phenotype was assessed by aggregometry, whereas a tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction analysis was used to detect the PLA1 and PLA2 alleles. Results: A total of 95 individuals with SPS and 127 healthy donors were studied; in 11 of the donors and 16 of the patients with SPS the A2 allele of the GP IIb/IIIA was found, yielding a weak and nonsignificant association (odds ratio 2.14, 95% CI 0.94-4.85). Conclusion: In Mexican mestizo patients, the platelet GP IIIa PLA1/A2 gene polymorphism does not lead to the SPS phenotype.
This is the first study from north India that investigated the association of thrombomodulin (TM) polymorphisms with acute myocardial infarction (AMI) in 350 patients (≤ 40 years, n = 184 and ≥ 60 years, n = 166) and 350 matched-controls. The TM polymorphisms were determined by polymerase chain reaction–single-stranded conformational polymorphism and DNA sequencing. The TM 1418TT genotype (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.3-6.4; P = .012) was independent risk predictor of young AMI as were hypertension (OR 3.3; 95% CI 1.8-5.9; P < .001), diabetes mellitus (OR 14.3; 95% CI 2.9-44.6; P = .001), smoking (OR 13.8; 95% CI 7.7-24.7; P < .001), family history (OR 1.8; 95% CI 1.1-3.3; P = .045), high body mass index (OR 2.2; 95% CI 1.3-3.6; P = .002), and high waist–hip ratio (OR 4.1; 95% CI 2.4-7.1; P < .001). Mean plasma TM also showed association with young AMI (P < .001). Smoking carriers of TM 1418CT + TT genotype had significantly higher risk of AMI (OR 12.8; 95% CI 6.0-27.3; P < .001) when compared with nonsmoking noncarriers. In conclusion, TM 1418C/T polymorphism is independent predictor of AMI and synergies with smoking.
Intra-abdominal thrombosis is a complication of paroxysmal nocturnal hemoglobinuria (PNH). There is scarcity of data on cases presenting with thrombosis in whom PNH is the predisposing factor. We assessed the role of PNH defect in 81 patients with intra-abdominal thrombosis, 44 patients of Budd Chiari syndrome and 37 patients of extra hepatic venous obstruction. Flowcytometry with glycosylphosphatidyl inositol-anchored proteins (GPI-AP)-CD55, -CD59, and -CD16 was performed on all patients and controls to assess the prevalence of deficiencies and PNH-type phenotype clone size. Deficiencies of individual GPI-AP were seen in 17.3% cases versus 3.4% controls. This was due to CD55 deficiency on red blood cells and CD16 deficiency on the granulocytes. Deficiency of multiple GPI-APs was less frequent (3.7% cases). Data of this study indicate that the PNH defect as detected with CD55, CD59, and CD16 is not an important cause of intra-abdominal thrombosis in northwestern India.
We examined the hypothesis that the factor V Leiden (FVL) and G20101A prothrombin gene mutations are commonly associated with hip osteonecrosis. We prospectively evaluated 244 consecutively referred adults with osteonecrosis (ON), 161 idiopathic and 83 secondary. Cases (n = 244) did not differ from 104 normal controls by race. Of the 244 patients, 23 (9.4%) were FVL heterozygotes versus 2 of 104 controls (1.9%), P = .013, risk ratio (RR) = 4.90, 95% confidence interval (CI) 1.18 to 20.4. Of the 161 patients with idiopathic ON, 15 (9.3%) were FVL heterozygotes versus 2 of 104 normal controls (1.9%), P = .017, RR = 4.84, 95% CI 1.13 to 20.8. Of the 83 patients with secondary ON, 8 (9.6%) FVL heterozygotes versus 2 of 104 normal controls (1.9%), P = .024, RR = 5.01, 95% CI 1.09 to 23.0. Prothrombin gene heterozygosity in normal controls (2.9%) did not differ from ON cases (3.4%), P = 1.0. The thrombophilic FVL mutation is commonly associated with and may be pathoetiologic for hip osteonecrosis.
Background: Cyclooxygenase 1 (COX-1), COX-2, and HO-1 are involved in the process of aspirin’s effect. The genetic susceptibility of these enzymes to aspirin resistance (AR) is unclear. Methods: A total of 431 patients took aspirin. Using arachidonic acid-induced light transmittance aggregation combined with adenosine diphosphate-induced light transmittance aggregation, 36 participants served for AR, 164 participants for semi-AR, and 231 participants for aspirin sensitivity (AS). The AR with 9 single-nucleotide polymorphism in COX-1, COX-2, and HO-1 genes was investigated. Results: COX-1 rs1330344 (-1676A>G) is associated with AR. G-Allele carriers significantly increased the risk of AR. For patients with AS as control, P is .02 (odds ratio [OR] = 1.77, confidence interval [CI]: 1.07-2.92). For patients with semi-AR as control, P is .05. HO-1 rs2071746 (-413A>T) is associated with AR. T-Allele carriers significantly increased the risk of AR. For patients with AS as control, P is .04 (OR = 1.70, CI: 1.02-2.79). For patients with semi-AR as control, P is .05 (OR = 1.68, CI: 1.00-2.80). Conclusion: rs2071746 in HO-1 gene, rs1330344 in COX-1 gene contribute to AR.
FVA4070G (R2 polymorphism) influences plasma factor V (FV) concentration and was associated with mild activated protein C resistance. This polymorphism was reported to have a trans inheritance with FV Leiden (FVL) mutation. The aim of this study is to investigate the inheritance of R2 polymorphism in the homozygous FVL carriers. In this study, 99 patients with thrombosis and 7 individuals without a history of thrombosis all of which homozygous for FVL were included. Of 99 patients, 1 was heterozygous for FV A4070G. Additionally, 6 polymorphisms in the FV gene were analyzed for the heterozygous R2 patient and her family. When the allelic distribution was classified, 8 different haplotypes were obtained. In contrast to the literature, it was shown that R2 polymorphism could be inherited in cis position with FVL and also the family members could have co-inheritance of the FVL and R2 on the same chromosome as proband.
One of the major concerns remaining in the treatment with stenting is the occurrence of stent thrombosis (ST). We reviewed 1960 consecutive patients (mean age 56 ± 11.6 years, 84.6% males) treated with primary coronary stenting for ST elevation myocardial infarction between 2003 and 2008. All clinical, angiographic, and follow-up data were retrospectively collected. The data when the patient had angina pectoris was obtained from medical record. Early ST was observed in 89 (4.5%) patients. We identified 86 patients with early ST and known date and time of symptom onset. In these patients (mean age 59.2 ± 13.9, 83.7% males), symptoms occurred mostly at night time (00.00-6.00 <scp>am</scp>) and during winter months but the day of the week effect was not presence. In conclusion, occurrences of early ST throughout the week were equally distributed, but early ST was more likely to occur in the winter months and night hours.
The previously reported activated intravascular coagulation system in the acute phase of respiratory distress syndrome (RDS) has not been evaluated in the long term. We assessed the activities of coagulation system of a cohort of premature infants with RDS in comparison with healthy premature infants (HPIs), healthy mature infants (HMIs), and pediatric laboratory controls over a 6-month period. Cord and venous blood samples were taken at birth, at the first month and sixth month. Protein C (PC), free protein S (f-PS), and antithrombin (AT) activities, thrombin–antithrombin (TAT) complex, prothrombin fragment 1 + 2 (PF1 + 2), and fibrinogen levels were measured. Mean PC, f-PS, <scp>d</scp>-dimer, and fibrinogen values were similar at all periods for HPI and RDS groups. Low neonatal anticoagulant proteins increased within 6 months in HMI and HPI groups. However, in RDS group, the AT activity remained significantly lower together with significantly higher TAT and PF1 + 2 levels both at the first month and at sixth month, suggesting a long-term consumption coagulopathy.
This retrospective, descriptive study aimed to assess hematologic testing practices in 100 patients with preeclampsia undergoing neuraxial blockade (NB). Prior to NB, platelet (PLT) count was performed in 61 (98%) of 62 women in labor and in 37 (97%) of 38 women undergoing cesarean delivery (CD). No patients had a pre-NB PLT count <70 x 109/L. Pre-NB tests for prothrombin time (PT) and activated partial thromboplastin time (APTT) were less common and varied among laboring patients (15 [24%] of 62) and patients prior to CD (18 [47%] of 38). Prior to NB, PT and APTT values were within normal limits in all patients. The time intervals between laboratory testing and NB ranged from <2 to >12 hours. The lack of consistency in pre-NB coagulation testing and the variable time intervals between laboratory tests and NB may be due to a lack of consensus among anesthesiologists for determining "safe" hemostatic conditions for NB placement in patients with preeclampsia.
The aim of the present research was to assess the differences in blood platelet and plasma proteome profiles of patients with uremia in comparison with healthy participants. It was found that 23 peptides in the platelet proteome profiles of hemodialyzed patients and only 6 peptides in nondialyzed patients were upregulated. On the other hand, 18 peptides with reduced expression in nondialyzed patients and only 1 peptide in hemodialyzed patients were found. For serum, only 6 upregulated peptides in patients undergoing hemodialysis and 15 peptides in nondialyzed patients were found, most of these were about 10 kDa. A decrease in serum peptide expression was not observed. In conclusion, it should be noted that the process of hemodialysis modifies the platelet proteome to a greater extent than uremia alone, however the sera of nondialyzed patients have much larger amounts of low-molecular-weight peptides than those of hemodialyzed patients.
Objective: To investigate the efficacy of recombinant human soluble thrombomodulin (rTM) in disseminated intravascular coagulation (DIC) associated with severe postpartum hemorrhage (PPH). Patients and Methods: We conducted a retrospective review of 36 patients with severe PPH complicated by DIC admitted to a single tertiary center. The first 26 patients were treated without rTM (control group), and the next 10 consecutive patients were treated with rTM. Clinical parameters including bleeding symptoms and coagulation indices were evaluated. Results: Baseline characteristics, total blood loss, and transfusion requirements were similar between the 2 groups. On day 2, there was a significant difference between the 2 groups in the decrease in <scp>d</scp>-dimer level from baseline. The incidence of bleeding symptoms was decreased in the rTM group compared with the control group. No adverse events were observed in the rTM group. Conclusion: Recombinant human thrombomodulin may be an effective adjunctive therapy in the management of DIC related to PPH.
The information about the thromboembolic events, the optimal treatment choice, the dose, and duration of antithrombotic therapy in children are limited. More clinical data are required. Recombinant tissue plasminogen activator (r-tPA) is increasingly used in pediatric thrombosis. We retrospectively analyzed the clinical course of 7 children (9.3 ± 2.1 years; 34 days to 16 years) with arterial thrombosis (n = 1) and intracardiac thrombosis (n = 6). The children were treated with r-tPA. The dose ranged between 0.2 and 0.4 mg/kg per h infused for 3 to 4 hours. This dose was repeated between 2 to 7 times till the thrombolysis was achieved. Treatment side effects were closely monitored. Complete clot lysis was achieved in all cases. None of them had severe bleeding except mild recurrent epistaxis occurring in 2 cases. In conclusion, r-tPA is an effective and safe therapy under close hemostatic control in children.
Conventional prothrombin time (PT) assays have limited sensitivity and dynamic range in monitoring the anticoagulant activity of direct factor Xa inhibitors. Hence, new assays are needed. We modified a PT assay by adding calcium chloride (CaCl2) to the thromboplastin reagent to increase assay dynamic range and improve sensitivity. Effects of calcium and sodium ion concentrations, and sample handling, were evaluated to optimize assay performance. Increasing concentrations of calcium ions produced progressive increases in PT across the factor Xa inhibitor concentrations of 0 to 2500 nmol/L for razaxaban and apixaban. The greatest effect was seen when the thromboplastin reagent was diluted 1:2.25 with 100 mmol/L CaCl2 (thus selected for routine use). The optimized assay showed an interassay precision of 1.5 to 9.3 percentage coefficient of variation (%CV) for razaxaban and 3.1 to 4.6 %CV for apixaban. We conclude that the modified PT assay is likely to be suitable as a pharmacodynamic marker for activity at therapeutic concentrations of factor Xa inhibitors.
Anticoagulants used during percutaneous coronary intervention (PCI) should not only prevent coronary events, but also minimize the risk of periprocedural complications. Current anticoagulation therapies for PCI include unfractionated heparin (UFH), enoxaparin, fondaparinux, and bivalirudin. UFH and enoxaparin have good efficacy and safety profiles in PCI; furthermore, associated periprocedural complications such as catheter thrombosis are rare. Although newer anticoagulants seem safe and effective in patients with acute coronary syndromes, clinical trial data suggest that some pure factor Xa (FXa) inhibitors are associated with increased rates of catheter thrombosis, compared with heparin-based agents. Experimental systems show that polytherapeutic agents, including UFH and enoxaparin, are more effective anticoagulants than certain single-target agents. More studies are needed to assess whether catheter thrombosis is a class-, drug-, or dose-related effect, and how best to prevent it. Future trials should report the rates of periprocedural complications when assessing the safety of novel anticoagulation therapies in PCI.
Microparticles are small membrane vesicles released from activated cells and are associated with thrombosis and inflammation. Microparticles contain a unique subset of surface proteins derived from the parent cell and may be responsible for their diverse biological functions. To identify these proteins, juvenile baboons (Papio anubis, n = 4) underwent iliac vein thrombosis with 6-hour balloon occlusion. Plasma samples were taken at baseline and at 2 days postthrombosis for microparticle analysis. Microparticles were extracted from platelet-poor plasma, digested separately with trypsin and tagged using isobaric tagging for relative and absolute quantitation reagents. The digests were subjected to 2-dimensional liquid chromatographic separation followed by matrix-assisted laser desorption/ ionization tandem mass spectrometry. Peak lists were generated and searched against all primate sequences. For protein identity, a minimum of 2 peptides at 95% confidence interval was required. Later, isobaric tagging for relative and absolute quantitation ratios were generated comparing relative protein level of day 2 to baseline. The proteomic analysis was performed twice for each blood sample, totaling 8 experiments. Proteins were considered elevated or depressed if the isobaric tagging for relative and absolute quantitation ratio deviated by 20% change from normal and a P value less than .05. Significantly, 7 proteins were differentially expressed on day 2 compared to baseline, and appeared in at least 3 animals and regulated in at least 4 experiments. Among these 7 proteins, upregulated proteins include various forms of fibrinogen and α-1-antichymotrypsin and downregulated proteins include immunoglobulins. These proteins influence thrombosis and inflammation through hemostatic plug formation (fibrinogen), inhibiting neutrophil adhesion (α-1-antichymoptrypsin), and immunoregulation (immunoglobulins). Further studies are needed to confirm the mechanistic role of these proteins in the pathogenesis of venous thrombosis.