Stress, Partner Violence, and Coagulopathy: Unmasking New Triggers for Venous Thromboembolism

Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, affects nearly 10 million individuals annually across all ethnicities, representing a substantial global health burden.[1] [2] This condition is marked by high recurrence rates, significant morbidity, and mortality. Complications such as major bleeding from anticoagulant therapy and long-term disability further emphasize its societal and clinical impact.[3]

The risk of VTE recurrence depends largely on the nature of the initial event.[4] Events associated with identifiable risk factors, such as surgery or immobilization, are classified as provoked and generally carry a lower recurrence risk once the triggering factor resolves. Conversely, persistent risk factors, such as active cancer[5] or chronic inflammatory diseases, are associated with a significantly elevated rate of recurrence. Unprovoked events, which occur without identifiable risk factors, carry the highest risk of long-term recurrence, even after standard anticoagulant therapy.[6] These distinctions are critical for developing individualized management strategies.

While the lifetime risk of VTE is similar for men and women, women face a higher incidence during their reproductive years,[7] mainly due to transient reproductive factors such as pregnancy, puerperium, and hormonal exposures.[8] [9] [10] Combined oral contraceptives (COCs), assisted reproductive technologies, and other hormone-based therapies further elevate the risk of thrombotic events during this period.[11] [12] In addition, large epidemiological studies have identified other cofactors, including age, family history of VTE, thrombophilia, smoking, endometriosis, cesarean delivery, multiparity, and multifetal pregnancies, as independent predictors of VTE recurrence.[13] [14]

Recently, psychosocial stressors such as perceived stress and intimate partner violence (IPV) have emerged as novel independent risk factors for VTE recurrence, likely mediated by mechanisms such as stress-induced coagulopathy.[15] Given that IPV and stress are significant global issues, they may act as unsuspected triggers of VTE, often misclassified as unprovoked events ([Fig. 1]).

Fig. 1 Classical and emerging risk factors for venous thromboembolism (VTE). Created with Canva.

In this issue, Bitsadze and colleagues[16] present findings from the VTE-WEAK study, one of the first multicenter, international studies to examine the relationship between VTE recurrence and psychosocial factors. This retrospective observational study included 7,754 women aged 18 to 55 with a history of VTE triggered by weak transient risk factors, such as COCs, pregnancy, puerperium, minor trauma, brief surgery, infection, or immobility. Among the cohort, 4,772 women reported a suspected recurrence, with 1,316 confirmed diagnoses. Stress and IPV were assessed using standardized questionnaires (PSS-10[17] and WAST[18]) at the time of recurrence evaluation.

The study reveals three key findings concerning VTE recurrence in this population: (1) Both moderate and high levels of perceived stress, and IPV, were identified as independent predictors of recurrence. High perceived stress showed a particularly strong association (Adjusted Odds Ratio (aOR): 10.03), while IPV also significantly increased recurrence risk (aOR: 1.95). These findings suggest a dose–response relationship and highlight the importance of addressing stress management in high-risk patients. (2) The study reported an annualized VTE recurrence rate of 3 per 100 patient-years, with a median follow-up of 5.28 years. Clinical factors such as a family history of VTE, varicose veins, and diabetes mellitus were also significantly associated with recurrence, underscoring the need for vigilant monitoring of high-risk individuals; and (3) the presence of new transient risk factors, particularly when thromboprophylaxis was not administered significantly influenced recurrence. This emphasizes the critical need for early risk identification and patient education on thromboprophylaxis to prevent recurrence.

The VTE-WEAK study is one of the first multicenter studies to investigate the relationship between VTE recurrence and psychosocial factors, such as stress levels and IPV. The findings align with previous studies suggesting that emotional stress and psychiatric conditions—often linked to depression, loneliness,[19] or anxiety[20] [21]—combined with hemostatic factors indicative of hypercoagulability, independently contribute to VTE risk. These associations remain significant even after adjusting for traditional risk factors, including age, sex, BMI, estrogen levels, smoking, education, and cancer.

On the other hand, IPV targeting women is often underreported and rarely recognized as a precipitating factor for thrombosis. Limited studies suggest that IPV may be an underestimated contributor to VTE risk, warranting further investigation. Indeed, Gris et al documented 20 cases of first VTE events in women of childbearing age with confirmed IPV, observing that additional clinical or laboratory risk factors were frequently present.[22] More recently, IPV, assessed using the self-administered WAST questionnaire, was identified as an independent risk factor for first VTE in women taking COCs, distinct from traditional risk factors.[23]

In summary, the VTE-WEAK study provides valuable insights into the complex interaction between psychosocial and clinical factors in VTE recurrence, broadening our understanding of this multifactorial condition. The findings highlight the critical need to incorporate IPV screening into VTE risk assessments, addressing an often-overlooked aspect of patient care. Moreover, the study reinforces the necessity of a holistic approach to VTE management, combining psychosocial evaluation with targeted interventions alongside traditional clinical strategies. Future research should prioritize prospective studies to further investigate the mechanisms underlying stress-induced coagulopathy, the identification of biomarkers, and the role of IPV in VTE recurrence. Such efforts could lead to the development of comprehensive prevention strategies that effectively address both the clinical and psychosocial dimensions of VTE recurrence.

Publikationsverlauf

Eingereicht: 07. Januar 2025

Angenommen: 20. Januar 2025

Accepted Manuscript online:
27. Januar 2025

Artikel online veröffentlicht:
24. März 2025

• References

• 1 Liang B, Zha L, Peng B. et al. Association of cardiovascular health with the incidence of venous thromboembolism: a prospective study of 275,149 Participants from the UK Biobank. Thromb Haemost 2024; 124 (10) 948-957
• 2 Danilatou V, Dimopoulos D, Kostoulas T, Douketis J. Machine learning-based predictive models for patients with venous thromboembolism: a systematic review. Thromb Haemost 2024; 124 (11) 1040-1052
• 3 Gorog DA, Gue YX, Chao TF. et al. Assessment and mitigation of bleeding risk in atrial fibrillation and venous thromboembolism: executive summary of a european and Asia-Pacific Expert Consensus Paper. Thromb Haemost 2022; 122 (10) 1625-1652
• 4 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
• 5 Lanting VR, Takada T, Bosch FTM. et al. Risk of recurrent venous thromboembolism in patients with cancer: an individual patient data meta-analysis and development of a prediction model. Thromb Haemost 2024; (e-pub ahead of print).
• 6 Khan F, Tritschler T, Kahn SR, Rodger MA. Venous thromboembolism. Lancet 2021; 398 (10294): 64-77
• 7 Scheres LJJ, van Hylckama Vlieg A, Cannegieter SC. Sex-specific aspects of venous thromboembolism: What is new and what is next?. Res Pract Thromb Haemost 2022; 6 (04) e12722
• 8 Hwang HG, Lee JH, Bang SM. Incidence of pregnancy-associated venous thromboembolism: Second Nationwide Study. Thromb Haemost 2023; 123 (09) 904-910
• 9 Grandone E, Antonucci E, Colaizzo D. et al. Venous thromboembolism in women of childbearing age: insights from the START Registry. Thromb Haemost 2023; 123 (11) 1060-1068
• 10 Gris JC, Bourguignon C, Bouvier S. et al. Pregnancy after combined oral contraceptive-associated venous thromboembolism: an international retrospective study of outcomes. Thromb Haemost 2022; 122 (10) 1779-1793
• 11 Dix C, Moloney M, Tran HA, McFadyen JD. Venous thromboembolism and estrogen-containing gender-affirming hormone therapy. Thromb Haemost 2024; 124 (05) 387-398
• 12 Goualou M, Noumegni S, de Moreuil C. et al. Venous thromboembolism associated with assisted reproductive technology: a systematic review and meta-analysis. Thromb Haemost 2023; 123 (03) 283-294
• 13 Xu K, Chan NC. Risk factors for venous thromboembolism in women of childbearing age. Thromb Haemost 2023; 123 (11) 1069-1071
• 14 De Corte P, Milhoranca I, Mechsner S, Oberg AS, Kurth T, Heinemann K. Unravelling the causal relationship between endometriosis and the risk for developing venous thromboembolism: a pooled analysis. Thromb Haemost 2024; (e-pub ahead of print).
• 15 von Känel R. Stress-induced hypercoagulability: insights from epidemiological and mechanistic studies, and clinical integration. Semin Thromb Hemost 2024; (e-pub ahead of print).
• 16 Bitsadze V, Nikolaeva MG, Mousty È. et al. Venous thromboembolism at low risk of recurrence in young women: stress and violence associate with recurrence. An international case-control study. Thromb Haemost 2024; (e-pub ahead of print).
• 17 Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983; 24 (04) 385-396
• 18 Brown JB, Lent B, Brett PJ, Sas G, Pederson LL. Development of the Woman Abuse Screening Tool for use in family practice. Fam Med 1996; 28 (06) 422-428
• 19 Enga KF, Brækkan SK, Hansen-Krone IJ, Hansen JB. Emotional states and future risk of venous thromboembolism: the Tromsø Study. Thromb Haemost 2012; 107 (03) 485-493
• 20 Kowal C, Peyre H, Amad A. et al. Psychotic, mood, and anxiety disorders and venous thromboembolism: a systematic review and meta-analysis. Psychosom Med 2020; 82 (09) 838-849
• 21 von Känel R, Margani A, Stauber S. et al. Depressive symptoms as a novel risk factor for recurrent venous thromboembolism: a longitudinal observational study in patients referred for thrombophilia investigation. PLoS One 2015; 10 (05) e0125858
• 22 Gris JC, Nikolaeva MG, Khizroeva J. et al. Is intimate partner abuse underestimated as a precipitating factor for venous thromboembolism in women?. J Thromb Haemost 2023; 21 (11) 3203-3206
• 23 Chéa M, Bourguignon C, Bouvier S. et al. Intimate partner violence as a risk factor for venous thromboembolism in women on combined oral contraceptives: An international matched case-control study. Eur J Intern Med 2024; 122: 47-53