The Impact of Genetic and Acquired Risk Factors on Thromboembolic Events: A Retrospective Study

Abstract

This study, involving a cohort of 980 patients with arterial and/or venous events, evaluated the relative importance of genetic and traditional risk factors using a machine learning model approach. The analysis revealed that conventional risk factors—such as age, gender, tobacco use, obesity—and acquired thrombophilia (most prominently antiphospholipid syndrome [APS]) outperformed any genetic risk variants analyzed. Of note, the presence of heterozygous FVL mutations was associated with a reduced arterial risk, whereas carriers of heterozygous factor VII activation protease (FSAP) mutations had a lower risk of venous events.

Thus, by employing diverse statistical approaches, the study showed that acquired risk factors exert the most substantial impact on the development of thrombotic events, except for the well-known role of FVL mutations in venous events.

Keywords

thrombophilia - gene mutations - risk factors - antiphospholipid syndrome

Publikationsverlauf

Eingereicht: 14. Februar 2025

Angenommen: 16. Mai 2025

Artikel online veröffentlicht:
08. Juli 2025

• References

• 1 Nilius H, Mertins T, Boss R. et al. Long-term survival after venous thromboembolism: a prospective cohort study. Front Cardiovasc Med 2021; 8: 749342
• 2 Klemen ND, Feingold PL, Hashimoto B. et al. Mortality risk associated with venous thromboembolism: a systematic review and Bayesian meta-analysis. Lancet Haematol 2020; 7 (08) e583-e593
• 3 Wendelboe AM, Raskob GE. Global burden of thrombosis: epidemiologic aspects. Circ Res 2016; 118 (09) 1340-1347
• 4 Campello E, Spiezia L, Adamo A, Simioni P. Thrombophilia, risk factors and prevention. Expert Rev Hematol 2019; 12 (03) 147-158
• 5 Previtali E, Bucciarelli P, Passamonti SM, Martinelli I. Risk factors for venous and arterial thrombosis. Blood Transfus 2011; 9 (02) 120-138
• 6 Lowe GDO. Common risk factors for both arterial and venous thrombosis. Br J Haematol 2008; 140 (05) 488-495
• 7 Pastori D, Cormaci VM, Marucci S. et al. A comprehensive review of risk factors for venous thromboembolism: from epidemiology to pathophysiology. Int J Mol Sci 2023; 24 (04) 3169
• 8 Dahlbäck B. New molecular insights into the genetics of thrombophilia. Resistance to activated protein C caused by Arg506 to Gln mutation in factor V as a pathogenic risk factor for venous thrombosis. Thromb Haemost 1995; 74 (01) 139-148
• 9 Eppenberger D, Nilius H, Anagnostelis B, Huber CA, Nagler M. Current knowledge on factor V Leiden mutation as a risk factor for recurrent venous thromboembolism: a systematic review and meta-analysis. Front Cardiovasc Med 2022; 9: 883986
• 10 Wang Z, Wu H. The association of prothrombin gene G20210A mutation with recurrent venous thromboembolism: evidence from a meta-analysis. Ann Vasc Surg 2025; 110 (Pt B): 295-305
• 11 Simone B, De Stefano V, Leoncini E. et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, prothrombin 20210A and methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013; 28 (08) 621-647
• 12 Zhang Q, Jin Y, Li X. et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphisms and risk of venous thromboembolism—a meta-analysis and systematic review. Vasa 2020; 49 (02) 141-146
• 13 Zu J, Yang T. Exploring risk factors for lower extremity deep vein thrombosis patients with co-existing pulmonary embolism based on multiple logistic regression model. Clin Appl Thromb Hemost 2024 ;30:10760296241258230
• 14 Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: the Copenhagen City Heart Study and 2 meta-analyses. Blood 2002; 100 (01) 3-10
• 15 Kerlin BA, Yan SB, Isermann BH. et al. Survival advantage associated with heterozygous factor V Leiden mutation in patients with severe sepsis and in mouse endotoxemia. Blood 2003; 102 (09) 3085-3092
• 16 Aiolfi R, Fernandez JA, Deguchi H. et al. Survival advantage associated with heterozygous factor V Leiden mutation in SARS-Cov-2-infected K18-hACE2 mice. Blood 2023; 142 (Suppl. 01) 2563
• 17 Lindqvist PG. On the evolutionary advantage of coagulation factor V Leiden (FVL). Curr Med Chem 2015; 22 (32) 3676-3681
• 18 Chiasakul T, De Jesus E, Tong J. et al. Inherited thrombophilia and the risk of arterial ischemic stroke: a systematic review and meta-analysis. J Am Heart Assoc 2019; 8 (19) e012877
• 19 Mahmoodi BK, Tragante V, Kleber ME. et al. Association of factor V Leiden with subsequent atherothrombotic events: a GENIUS-CHD study of individual participant data. Circulation 2020; 142 (06) 546-555
• 20 Kanse SM, Parahuleva M, Muhl L, Kemkes-Matthes B, Sedding D, Preissner KT. Factor VII-activating protease (FSAP): vascular functions and role in atherosclerosis. Thromb Haemost 2008; 99 (02) 286-289
• 21 Hoppe B, Tolou F, Radtke H, Kiesewetter H, Dörner T, Salama A. Marburg I polymorphism of factor VII-activating protease is associated with idiopathic venous thromboembolism. Blood 2005; 105 (04) 1549-1551
• 22 Ahmad-Nejad P, Dempfle CE, Weiss C, Bugert P, Borggrefe M, Neumaier M. The G534E-polymorphism of the gene encoding the factor VII-activating protease is a risk factor for venous thrombosis and recurrent events. Thromb Res 2012; 130 (03) 441-444
• 23 van Minkelen R, de Visser MCH, Vos HL, Bertina RM, Rosendaal FR. The Marburg I polymorphism of factor VII-activating protease is not associated with venous thrombosis. Blood 2005; 105 (12) 4898 , author reply 4899
• 24 Gulesserian T, Hron G, Endler G, Eichinger S, Wagner O, Kyrle PA. Marburg I polymorphism of factor VII-activating protease and risk of recurrent venous thromboembolism. Thromb Haemost 2006; 95 (01) 65-67
• 25 Etscheid M, Muhl L, Pons D, Jukema JW, König H, Kanse SM. The Marburg I polymorphism of factor VII activating protease is associated with low proteolytic and low pro-coagulant activity. Thromb Res 2012; 130 (06) 935-941
• 26 Sidelmann JJ, Vitzthum F, Funding E, Münster AMB, Gram J, Jespersen J. Factor VII-activating protease in patients with acute deep venous thrombosis. Thromb Res 2008; 122 (06) 848-853
• 27 Roach REJ, Lijfering WM, Rosendaal FR, Cannegieter SC, le Cessie S. Sex difference in risk of second but not of first venous thrombosis: paradox explained. Circulation 2014; 129 (01) 51-56
• 28 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
• 29 Rothwell PM, Coull AJ, Silver LE. et al; Oxford Vascular Study. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 2005; 366 (9499) 1773-1783