["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend This study provides the first in vivo evidence that acute psychological stress triggers systemic free radical formation and prothrombotic remodelling of blood clot microstructure. By inducing stress in healthy participants, we observed a significant increase in oxidative stress (A•−), a shortening of the intrinsic pathway of coagulation (activated partial thromboplastin time (aPTT)) and the formation of denser, more fibrin‐rich clot networks (Df). These findings identify oxidative stress as a critical mechanistic link between psychological stress and cardiovascular disease, highlighting it as a potential target for preventative therapies. Created in https://BioRender.com.\n\n\n\n\n\n\n\n\n\nAbstract\nPsychological stress is a recognised, yet mechanistically unresolved, risk factor for cardiovascular disease (CVD) partly through its association with a hypercoagulable state. Free radical–mediated oxidative stress has been proposed as a key upstream driver of this haemostatic imbalance. In this randomised cross‐over study we investigated whether acute psychological stress promotes systemic radical formation and prothrombotic alterations in clot microstructure in eight healthy males. The Trier Social Stress Test was used to induce psychological stress. Antecubital venous blood was collected to measure the ascorbate free radical (A•−, electron paramagnetic resonance spectroscopy) and clot microstructure (Df, Fourier transform rheology), alongside standard coagulometry. Compared with the control condition (quiet sitting), psychological stress increased A•− (P = 0.042) and Df (P = 0.008), the latter reflecting larger, denser and more fibrin‐rich networks. We also observed selective shortening of activated partial thromboplastin time (aPTT) (P = 0.018), indicating activation of the intrinsic coagulation pathway. This study provides the first in vivo evidence that acute psychological stress triggers systemic free radical formation and drives prothrombotic remodelling of clot architecture. These findings identify oxidative stress as a mechanistic link between psychological stress and CVD risk and highlight it as a compelling target for prevention and therapy.\n\n\n\n\n\n\n\n\n\nKey points\n\nAlthough psychological stress is a recognised risk factor for cardiovascular disease (CVD), its mechanistic association with a hypercoagulable state remains unresolved.\nAcute psychological stress, induced by the Trier Social Stress Test (TSST), significantly increased systemic free radical formation, as measured by elevated levels of ascorbate free radical (A•−) via electron paramagnetic resonance (EPR) spectroscopy, and was associated with the formation of larger, denser, more fibrin‐rich clots confirmed by increased fractal dimension (Df).\nThe concurrent increase in A•− and Df suggests that free radical–mediated oxidative stress is an upstream driver of psychological stress‐induced activation of haemostasis, specifically altering clot quality.\nThe TSST selectively shortened activated partial thromboplastin time (aPTT), indicating activation of the intrinsic/contact coagulation pathway. There were no changes in prothrombin time (PT) or D‐dimer, suggesting haemostatic activation occurred without engaging fibrinolysis.\nThe findings demonstrate that even a brief episode of emotional stress can increase thrombotic potential in healthy individuals and identify oxidative stress as a key mechanistic link and a potential therapeutic target for treating stress‐related CVD.\n\n\n"]