Semin Thromb Hemost 2016; 42(08): 808-820
DOI: 10.1055/s-0036-1592333
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Environmental and Genetic Risk Factors Associated with Venous Thromboembolism

Marta Crous-Bou*
1   Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
2   Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
,
Laura B. Harrington*
3   Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
,
Christopher Kabrhel
4   Department of Emergency Medicine, Center for Vascular Emergencies, Massachusetts General Hospital, Boston, Massachusetts
› Author Affiliations
Further Information

Publication History

Publication Date:
20 October 2016 (online)

Abstract

Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism, and a combination of environmental and genetic risk factors contributes to VTE risk. Within environmental risk factors, some are provoking (e.g., cancer, surgery, trauma or fracture, immobilization, pregnancy and the postpartum period, long-distance travel, hospitalization, catheterization, and acute infection) and others are nonprovoking (e.g., age, sex, race/ethnicity, body mass index and obesity, oral contraceptive or hormone therapy use, corticosteroid use, statin use, diet, physical activity, sedentary time, and air pollution). Additionally, VTE has a strong genetic basis, with approximately 50 to 60% of the variance in VTE incidence attributed to genetic effects. Some genetic susceptibility variants that contribute to risk have been identified in candidate genes, mostly related to the clotting system and responsible for inherited hypercoagulable states (e.g., factor V Leiden, prothrombin, fibrinogen gamma, or blood group non-O). Other susceptibility single-nucleotide polymorphisms have been identified from genome-wide association studies, such as the two new loci in TSPAN15 (rs78707713) and SCL44A2 (rs2288904) genes. Risk factors are not always associated with VTE in isolation; however, and an understanding of how environmental and genetic factors interact may provide insight into the pathophysiology of VTE, possibly identifying opportunities for targeted prevention and treatment.

* The authors Marta Crous-Bou and Laura B. Harrington contributed equally to the article.


 
  • References

  • 1 Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016; 41 (1) 3-14
  • 2 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (1) 93-102
  • 3 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158 (6) 585-593
  • 4 Bell EJ, Lutsey PL, Basu S , et al. Lifetime risk of venous thromboembolism in two cohort studies. Am J Med 2016; 129 (3) 339.e19-339.e26
  • 5 Luxembourg B, Schmitt J, Humpich M, Glowatzki M, Seifried E, Lindhoff-Last E. Intrinsic clotting factors in dependency of age, sex, body mass index, and oral contraceptives: definition and risk of elevated clotting factor levels. Blood Coagul Fibrinolysis 2009; 20 (7) 524-534
  • 6 Roach RE, 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 (1) 51-56
  • 7 Severinsen MT, Johnsen SP, Tjønneland A, Overvad K, Dethlefsen C, Kristensen SR. Body height and sex-related differences in incidence of venous thromboembolism: a Danish follow-up study. Eur J Intern Med 2010; 21 (4) 268-272
  • 8 Buckner TW, Key NS. Venous thrombosis in blacks. Circulation 2012; 125 (6) 837-839
  • 9 Goldhaber SZ. Race and venous thromboembolism: nature or nurture?. Circulation 2014; 129 (14) 1463-1465
  • 10 Zakai NA, McClure LA, Judd SE , et al. Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. Circulation 2014; 129 (14) 1502-1509
  • 11 Zakai NA, McClure LA. Racial differences in venous thromboembolism. J Thromb Haemost 2011; 9 (10) 1877-1882
  • 12 Lijfering WM, Flinterman LE, Vandenbroucke JP, Rosendaal FR, Cannegieter SC. Relationship between venous and arterial thrombosis: a review of the literature from a causal perspective. Semin Thromb Hemost 2011; 37 (8) 885-896
  • 13 Vessey M, Mant D, Smith A, Yeates D. Oral contraceptives and venous thromboembolism: findings in a large prospective study. Br Med J (Clin Res Ed) 1986; 292 (6519) 526
  • 14 Manzoli L, De Vito C, Marzuillo C, Boccia A, Villari P. Oral contraceptives and venous thromboembolism: a systematic review and meta-analysis. Drug Saf 2012; 35 (3) 191-205
  • 15 Cushman M, Kuller LH, Prentice R , et al; Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292 (13) 1573-1580
  • 16 Anderson GL, Limacher M, Assaf AR , et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291 (14) 1701-1712
  • 17 Bensyl DM, Iuliano DA, Carter M, Santelli J, Gilbert BC. Contraceptive use—United States and territories, Behavioral Risk Factor Surveillance System, 2002. MMWR Surveill Summ 2005; 54 (6) 1-72
  • 18 National Institutes of Health. National Institutes of Health State-of-the-Science Conference statement: management of menopause-related symptoms. Ann Intern Med 2005; 142 (12 Pt 1) 1003-1013
  • 19 de Bastos M, Stegeman BH, Rosendaal FR , et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014; (3) CD010813
  • 20 Lidegaard O, Nielsen LH, Skovlund CW, Løkkegaard E. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10. BMJ 2012; 344: e2990
  • 21 Smith NL, Blondon M, Wiggins KL , et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med 2014; 174 (1) 25-31
  • 22 Mohammed K, Abu Dabrh AM, Benkhadra K , et al. Oral vs transdermal estrogen therapy and vascular events: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100 (11) 4012-4020
  • 23 Johannesdottir SA, Horváth-Puhó E, Dekkers OM , et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013; 173 (9) 743-752
  • 24 Huerta C, Johansson S, Wallander MA, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007; 167 (9) 935-943
  • 25 Majoor CJ, Sneeboer MM, de Kievit A , et al. The influence of corticosteroids on hemostasis in healthy subjects. J Thromb Haemost 2016; 14 (4) 716-723
  • 26 Glynn RJ, Danielson E, Fonseca FA , et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009; 360 (18) 1851-1861
  • 27 Desai CS, Martin SS, Blumenthal RS. Non-cardiovascular effects associated with statins. BMJ 2014; 349: g3743
  • 28 Steffen LM, Folsom AR, Cushman M, Jacobs Jr DR, Rosamond WD. Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. Circulation 2007; 115 (2) 188-195
  • 29 Hansen-Krone IJ, Enga KF, Südduth-Klinger JM , et al. High fish plus fish oil intake is associated with slightly reduced risk of venous thromboembolism: the Tromsø Study. J Nutr 2014; 144 (6) 861-867
  • 30 Lutsey PL, Steffen LM, Virnig BA, Folsom AR. Diet and incident venous thromboembolism: the Iowa Women's Health Study. Am Heart J 2009; 157 (6) 1081-1087
  • 31 Varraso R, Kabrhel C, Goldhaber SZ, Rimm EB, Camargo Jr CA. Prospective study of diet and venous thromboembolism in US women and men. Am J Epidemiol 2012; 175 (2) 114-126
  • 32 Hoevenaar-Blom MP, Nooyens AC, Kromhout D , et al. Mediterranean style diet and 12-year incidence of cardiovascular diseases: the EPIC-NL cohort study. PLoS ONE 2012; 7 (9) e45458
  • 33 Fitzgerald KC, Chiuve SE, Buring JE, Ridker PM, Glynn RJ. Comparison of associations of adherence to a Dietary Approaches to Stop Hypertension (DASH)-style diet with risks of cardiovascular disease and venous thromboembolism. J Thromb Haemost 2012; 10 (2) 189-198
  • 34 Hansen-Krone IJ, Enga KF, Njølstad I, Hansen JB, Braekkan SK. Heart healthy diet and risk of myocardial infarction and venous thromboembolism. The Tromsø Study. Thromb Haemost 2012; 108 (3) 554-560
  • 35 Kabrhel C, Varraso R, Goldhaber SZ, Rimm E, Camargo Jr CA. Physical inactivity and idiopathic pulmonary embolism in women: prospective study. BMJ 2011; 343: d3867
  • 36 van Stralen KJ, Le Cessie S, Rosendaal FR, Doggen CJ. Regular sports activities decrease the risk of venous thrombosis. J Thromb Haemost 2007; 5 (11) 2186-2192
  • 37 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162 (10) 1182-1189
  • 38 Borch KH, Hansen-Krone I, Braekkan SK , et al. Physical activity and risk of venous thromboembolism. The Tromso study. Haematologica 2010; 95 (12) 2088-2094
  • 39 van Stralen KJ, Doggen CJ, Lumley T , et al. The relationship between exercise and risk of venous thrombosis in elderly people. J Am Geriatr Soc 2008; 56 (3) 517-522
  • 40 Brook RD, Franklin B, Cascio W , et al; Expert Panel on Population and Prevention Science of the American Heart Association. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 2004; 109 (21) 2655-2671
  • 41 Baccarelli A, Martinelli I, Zanobetti A , et al. Exposure to particulate air pollution and risk of deep vein thrombosis. Arch Intern Med 2008; 168 (9) 920-927
  • 42 Baccarelli A, Martinelli I, Pegoraro V , et al. Living near major traffic roads and risk of deep vein thrombosis. Circulation 2009; 119 (24) 3118-3124
  • 43 Dales RE, Cakmak S, Vidal CB. Air pollution and hospitalization for venous thromboembolic disease in Chile. J Thromb Haemost 2010; 8 (4) 669-674
  • 44 Pun VC, Hart JE, Kabrhel C, Camargo Jr CA, Baccarelli AA, Laden F. Prospective study of ambient particulate matter exposure and risk of pulmonary embolism in the Nurses' Health Study cohort. Environ Health Perspect 2015; 123 (12) 1265-1270
  • 45 Kan H, Folsom AR, Cushman M , et al. Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study. J Thromb Haemost 2011; 9 (4) 672-678
  • 46 Shih RA, Griffin BA, Salkowski N , et al. Ambient particulate matter air pollution and venous thromboembolism in the Women's Health Initiative Hormone Therapy trials. Environ Health Perspect 2011; 119 (3) 326-331
  • 47 Franchini M, Mengoli C, Cruciani M, Bonfanti C, Mannucci PM. Association between particulate air pollution and venous thromboembolism: a systematic literature review. Eur J Intern Med 2016; 27: 10-13
  • 48 Heit JA, Phelps MA, Ward SA, Slusser JP, Petterson TM, De Andrade M. Familial segregation of venous thromboembolism. J Thromb Haemost 2004; 2 (5) 731-736
  • 49 Vossen CY, Conard J, Fontcuberta J , et al. Familial thrombophilia and lifetime risk of venous thrombosis. J Thromb Haemost 2004; 2 (9) 1526-1532
  • 50 Vossen CY, Conard J, Fontcuberta J , et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3 (3) 459-464
  • 51 Souto JC, Almasy L, Borrell M , et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67 (6) 1452-1459
  • 52 Souto JC, Almasy L, Borrell M , et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101 (13) 1546-1551
  • 53 Couturaud F, Kearon C, Leroyer C , et al; Groupe d'Etude de la Thrombose de Bretagne Occidentale (G.E.T.B.O). Incidence of venous thromboembolism in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. Thromb Haemost 2006; 96 (6) 744-749
  • 54 Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost 2009; 7 (Suppl. 01) 301-304
  • 55 Larsen TB, Sørensen HT, Skytthe A, Johnsen SP, Vaupel JW, Christensen K. Major genetic susceptibility for venous thromboembolism in men: a study of Danish twins. Epidemiology 2003; 14 (3) 328-332
  • 56 Reitsma PH. How to identify new genetic risk factors for VTE?. Thromb Res 2009; 123 (Suppl. 04) S22-S24
  • 57 Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost 2009; 102 (2) 360-370
  • 58 Wolpin BM, Kabrhel C, Varraso R , et al. Prospective study of ABO blood type and the risk of pulmonary embolism in two large cohort studies. Thromb Haemost 2010; 104 (5) 962-971
  • 59 Canonico M, Olié V, Carcaillon L, Tubert-Bitter P, Scarabin PY ; EStrogen and THromboEmbolism Risk (ESTHER) Study Group. Synergism between non-O blood group and oral estrogen in the risk of venous thromboembolism among postmenopausal women: the ESTHER study. Thromb Haemost 2008; 99 (1) 246-248
  • 60 Streiff MB, Segal J, Grossman SA, Kickler TS, Weir EG. ABO blood group is a potent risk factor for venous thromboembolism in patients with malignant gliomas. Cancer 2004; 100 (8) 1717-1723
  • 61 Larsen TB, Johnsen SP, Gislum M, Møller CA, Larsen H, Sørensen HT. ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population-based, nested case-control study. J Thromb Haemost 2005; 3 (2) 300-304
  • 62 Teixeira Mello TB, Machado TF, Montavão SA, Ozello MC, Annichino-Bizzacchi JM. Assessing the coagulation factor levels, inherited thrombophilia, and ABO blood group on the risk for venous thrombosis among Brazilians. Clin Appl Thromb Hemost 2009; 15 (4) 408-414
  • 63 Ohira T, Cushman M, Tsai MY , et al. ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). J Thromb Haemost 2007; 5 (7) 1455-1461
  • 64 Morelli VM, de Visser MC, van Tilburg NH , et al. ABO blood group genotypes, plasma von Willebrand factor levels and loading of von Willebrand factor with A and B antigens. Thromb Haemost 2007; 97 (4) 534-541
  • 65 Morelli VM, De Visser MC, Vos HL, Bertina RM, Rosendaal FR. ABO blood group genotypes and the risk of venous thrombosis: effect of factor V Leiden. J Thromb Haemost 2005; 3 (1) 183-185
  • 66 Tirado I, Mateo J, Soria JM , et al. The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism. Thromb Haemost 2005; 93 (3) 468-474
  • 67 Miñano A, Ordóñez A, España F , et al. AB0 blood group and risk of venous or arterial thrombosis in carriers of factor V Leiden or prothrombin G20210A polymorphisms. Haematologica 2008; 93 (5) 729-734
  • 68 Jick H, Slone D, Westerholm B , et al. Venous thromboembolic disease and ABO blood type. A cooperative study. Lancet 1969; 1 (7594) 539-542
  • 69 Nefzger MD, Hrubec Z, Chalmers TC. Venous thromboembolism and blood-group. Lancet 1969; 1 (7600) 887
  • 70 Hill H, Loudon NB, Pitcher CS, Pocock VM. Venous thromboembolic disease and ABO blood type. Lancet 1969; 1 (7595) 623
  • 71 Talbot S, Wakley EJ, Ryrie D, Langman MJ. ABO blood-groups and venous thromboembolic disease. Lancet 1970; 1 (7659) 1257-1259
  • 72 Allan TM. Venous thromboembolism and blood-group. Lancet 1970; 1 (7641) 303
  • 73 Allan TM. ABO blood-groups and venous thromboembolism. Lancet 1971; 2 (7735) 1209-1210
  • 74 Allan TM. ABO blood groups and age groups in surgical venous thromboembolism. Atherosclerosis 1976; 23 (1) 141-142
  • 75 Bates M. Venous thromboembolic disease and ABO blood type. Lancet 1971; 1 (7692) 239
  • 76 Westerholm B, Wiechel B, Eklund G. Oral contraceptives, venous thromboembolic disease, and ABO blood type. Lancet 1971; 2 (7725) 664
  • 77 Talbot S, Wakley EJ, Langman MJ. A19 A29 B, and O blood-groups, Lewis blood-groups, and serum triglyceride and cholesterol concentrations in patients with venous thromboembolic disease. Lancet 1972; 1 (7761) 1152-1154
  • 78 Jick H, Porter J. Thrombophlebitis of the lower extremities and ABO blood type. Arch Intern Med 1978; 138 (10) 1566-1567
  • 79 Parr JC, White LE. ABO blood-groups and the visual outcome of a retinal venous occlusion. Trans Ophthalmol Soc N Z 1978; 30: 19-22
  • 80 Robinson WM, Roisenberg I. Venous thromboembolism and ABO blood groups in a Brazilian population. Hum Genet 1980; 55 (1) 129-131
  • 81 Wautrecht JC, Vincent G, Dereume JP. Venous thromboembolic disease and Klinefelter's syndrome [in French]. J Mal Vasc 1986; 11 (2) 125-127
  • 82 Mercier B, Oger E, Le Gal G, Mottier D, Ferec C. Phenotypic but not allelic ABO blood group association with risk of venous thrombosis. Thromb Haemost 2005; 93 (2) 388-389
  • 83 Morange PE, Trégouët DA. Current knowledge on the genetics of incident venous thrombosis. J Thromb Haemost 2013; 11 (Suppl. 01) 111-121
  • 84 Folsom AR, Cushman M, Tsai MY , et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 2002; 99 (8) 2720-2725
  • 85 Dowling NF, Austin H, Dilley A, Whitsett C, Evatt BL, Hooper WC. The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study. J Thromb Haemost 2003; 1 (1) 80-87
  • 86 Heit JA, Sobell JL, Li H, Sommer SS. The incidence of venous thromboembolism among factor V Leiden carriers: a community-based cohort study. J Thromb Haemost 2005; 3 (2) 305-311
  • 87 Herrington DM, Vittinghoff E, Howard TD , et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol 2002; 22 (6) 1012-1017
  • 88 Major DA, Sane DC, Herrington DM. Cardiovascular implications of the factor V Leiden mutation. Am Heart J 2000; 140 (2) 189-195
  • 89 Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92 (8) 1107-1114
  • 90 Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995; 92 (10) 2800-2802
  • 91 Germain M, Chasman DI, de Haan H , et al; Cardiogenics Consortium. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet 2015; 96 (4) 532-542
  • 92 Arellano AR, Bezemer ID, Tong CH , et al. Gene variants associated with venous thrombosis: confirmation in the MEGA study. J Thromb Haemost 2010; 8 (5) 1132-1134
  • 93 De Stefano V, Chiusolo P, Paciaroni K , et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91 (10) 3562-3565
  • 94 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost 1997; 78 (3) 990-992
  • 95 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88 (10) 3698-3703
  • 96 Rosendaal FR, Vos HL, Poort SL, Bertina RM. Prothrombin 20210A variant and age at thrombosis. Thromb Haemost 1998; 79 (2) 444
  • 97 Matsui T, Titani K, Mizuochi T. Structures of the asparagine-linked oligosaccharide chains of human von Willebrand factor. Occurrence of blood group A, B, and H(O) structures. J Biol Chem 1992; 267 (13) 8723-8731
  • 98 Kamphuisen PW, Eikenboom JC, Rosendaal FR , et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol 2001; 115 (1) 156-158
  • 99 Tsai AW, Cushman M, Rosamond WD , et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113 (8) 636-642
  • 100 Smith NL, Chen MH, Dehghan A , et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121 (12) 1382-1392
  • 101 Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6 (1) 62-69
  • 102 Heit JA, Armasu SM, Asmann YW , et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J Thromb Haemost 2012; 10 (8) 1521-1531
  • 103 Heit JA, Cunningham JM, Petterson TM, Armasu SM, Rider DN, DE Andrade M. Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism. J Thromb Haemost 2011; 9 (6) 1133-1142
  • 104 Lane DA, Mannucci PM, Bauer KA , et al. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76 (5) 651-662
  • 105 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317 (16) 991-996
  • 106 Gandrille S, Borgel D, Sala N , et al; Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Protein S deficiency: a database of mutations—summary of the first update. Thromb Haemost 2000; 84 (5) 918
  • 107 Cushman M. Inherited risk factors for venous thrombosis. Hematology (Am Soc Hematol Educ Program) 2005; 452-457
  • 108 Trégouët DA, Heath S, Saut N , et al. Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach. Blood 2009; 113 (21) 5298-5303
  • 109 Germain M, Saut N, Greliche N , et al. Genetics of venous thrombosis: insights from a new genome wide association study. PLoS ONE 2011; 6 (9) e25581
  • 110 Tang W, Teichert M, Chasman DI , et al. A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Genet Epidemiol 2013; 37 (5) 512-521
  • 111 Soria JM, Morange PE, Vila J , et al. Multilocus genetic risk scores for venous thromboembolism risk assessment. J Am Heart Assoc 2014; 3 (5) e001060
  • 112 de Haan HG, Bezemer ID, Doggen CJ , et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 2012; 120 (3) 656-663
  • 113 Folsom AR, Tang W, Weng LC , et al. Replication of a genetic risk score for venous thromboembolism in whites but not in African Americans. J Thromb Haemost 2016; 14 (1) 83-88
  • 114 Crous-Bou M, De Vivo I, Camargo Jr CA , et al. Interactions of established risk factors and a GWAS-based genetic risk score on the risk of venous thromboembolism. Thromb Haemost 2016; 116 (3) 116
  • 115 Bounameaux H. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 2000; 356 (9225) 182-183
  • 116 Girard P. Factor V Leiden paradox. Lancet 2000; 356 (9234) 1028-1029
  • 117 van Stralen KJ, Doggen CJ, Bezemer ID, Pomp ER, Lisman T, Rosendaal FR. Mechanisms of the factor V Leiden paradox. Arterioscler Thromb Vasc Biol 2008; 28 (10) 1872-1877
  • 118 van Langevelde K, Flinterman LE, van Hylckama Vlieg A, Rosendaal FR, Cannegieter SC. Broadening the factor V Leiden paradox: pulmonary embolism and deep-vein thrombosis as 2 sides of the spectrum. Blood 2012; 120 (5) 933-946
  • 119 Leroyer C, Mercier B, Escoffre M, Férec C, Mottier D. Factor V Leiden prevalence in venous thromboembolism patients. Chest 1997; 111 (6) 1603-1606
  • 120 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346 (8983) 1133-1134
  • 121 Mazoyer E, Ripoll L, Gueguen R , et al; FITENAT Study Group. Prevalence of factor V Leiden and prothrombin G20210A mutation in a large French population selected for nonthrombotic history: geographical and age distribution. Blood Coagul Fibrinolysis 2009; 20 (7) 503-510
  • 122 Rosendaal FR. Venous thrombosis: the role of genes, environment, and behavior. Hematology (Am Soc Hematol Educ Program) 2005; 2005: 1-12
  • 123 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353 (9159) 1167-1173
  • 124 Rosendaal FR. Venous thrombosis: prevalence and interaction of risk factors. Haemostasis 1999; 29 (Suppl S1): 1-9
  • 125 Kraft P, Hunter D. Integrating epidemiology and genetic association: the challenge of gene-environment interaction. Philos Trans R Soc Lond B Biol Sci 2005; 360 (1460) 1609-1616
  • 126 Kraft P, Yen YC, Stram DO, Morrison J, Gauderman WJ. Exploiting gene-environment interaction to detect genetic associations. Hum Hered 2007; 63 (2) 111-119
  • 127 van Boven HH, Vandenbroucke JP, Briët E, Rosendaal FR. Gene-gene and gene-environment interactions determine risk of thrombosis in families with inherited antithrombin deficiency. Blood 1999; 94 (8) 2590-2594
  • 128 Delluc A, Le Moigne E, Tromeur C , et al. Site of venous thromboembolism and prothrombotic mutations according to body mass index. Results from the EDITH study. Br J Haematol 2011; 154 (4) 486-491
  • 129 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci PM. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol 1999; 19 (3) 700-703
  • 130 Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 1990; 10 (6) 1067-1073
  • 131 Juhan-Vague I, Vague P, Alessi MC , et al. Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabete Metab 1987; 13 (3 Pt 2) 331-336
  • 132 Juhan-Vague I, Alessi MC, Joly P , et al. Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response. Arteriosclerosis 1989; 9 (3) 362-367
  • 133 Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313 (25) 1557-1563
  • 134 Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998; 97 (11) 1037-1041
  • 135 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91 (4) 700-711
  • 136 Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997; 95 (7) 1777-1782
  • 137 Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Hennekens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation. Ann Intern Med 1997; 126 (7) 528-531
  • 138 van Boven HH, Reitsma PH, Rosendaal FR , et al. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75 (3) 417-421
  • 139 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344 (8935) 1453-1457
  • 140 Andreassi MG, Botto N, Maffei S. Factor V Leiden, prothrombin G20210A substitution and hormone therapy: indications for molecular screening. Clin Chem Lab Med 2006; 44 (5) 514-521
  • 141 Gary JL, Barber RC, Reinert CM, Starr AJ. A prospective study of thrombophilia in trauma patients with pulmonary embolism. J Trauma Acute Care Surg 2012; 72 (1) 247-250
  • 142 Westrich GH, Weksler BB, Glueck CJ, Blumenthal BF, Salvati EA. Correlation of thrombophilia and hypofibrinolysis with pulmonary embolism following total hip arthroplasty: an analysis of genetic factors. J Bone Joint Surg Am 2002; 84-A (12) 2161-2167
  • 143 Wåhlander K, Larson G, Lindahl TL , et al. Factor V Leiden (G1691A) and prothrombin gene G20210A mutations as potential risk factors for venous thromboembolism after total hip or total knee replacement surgery. Thromb Haemost 2002; 87 (4) 580-585
  • 144 Bowler DJ, Bale E, O'Byrne J. Factor V Leiden: prevalence and thromboembolic complications after total hip replacement in Ireland. Ir J Med Sci 2007; 176 (4) 273-277
  • 145 Baba-Ahmed M, Le Gal G, Couturaud F, Lacut K, Oger E, Leroyer C. High frequency of factor V Leiden in surgical patients with symptomatic venous thromboembolism despite prophylaxis. Thromb Haemost 2007; 97 (2) 171-175
  • 146 Atluri P, Raper SE. Factor V Leiden and postoperative deep vein thrombosis in patients undergoing open Roux-en-Y gastric bypass surgery. Obes Surg 2005; 15 (4) 561-564
  • 147 van Stralen KJ, Rosendaal FR, Doggen CJ. Minor injuries as a risk factor for venous thrombosis. Arch Intern Med 2008; 168 (1) 21-26
  • 148 Ringwald J, Berger A, Adler W, Kraus C, Pitto RP. Genetic polymorphisms in venous thrombosis and pulmonary embolism after total hip arthroplasty: a pilot study. Clin Orthop Relat Res 2009; 467 (6) 1507-1515
  • 149 Bedair H, Berli M, Gezer S, Jacobs JJ, Della Valle CJ. Hematologic genetic testing in high-risk patients before knee arthroplasty: a pilot study. Clin Orthop Relat Res 2011; 469 (1) 131-137
  • 150 Bare LA, Arellano AR, Tong CH , et al. Genetic variants of F11, statin use and venous thrombosis. J Thromb Haemost 2011; 9 (6) 1249-1251
  • 151 Harrington LB, Wiggins KL, Sitlani CM , et al. The association of F11 genetic variants with the risk of incident venous thrombosis among women, by statin use. Thromb Haemost 2016; 115 (3) 682-684