Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Epidemiology of venous thromboembolism

Key Points

  • Venous thromboembolism (VTE) occurs as often as stroke, and recurs frequently, with around 30% of patients with VTE experiencing recurrence within 10 years

  • Occurrence of VTE, especially pulmonary embolism (PE), is associated with reduction in survival, and PE is an independent predictor of reduced survival for up to 3 months

  • VTE is associated with high health-care costs and increased disability-adjusted life-years

  • Despite identification of VTE risk factors, development of new prophylaxis regimens, and improved uptake of VTE prophylaxis, the occurrence of VTE is increasing

Abstract

Thrombosis can affect any venous circulation. Venous thromboembolism (VTE) includes deep-vein thrombosis of the leg or pelvis, and its complication, pulmonary embolism. VTE is a fairly common disease, particularly in older age, and is associated with reduced survival, substantial health-care costs, and a high rate of recurrence. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and various risk factors. Major risk factors for incident VTE include hospitalization for surgery or acute illness, active cancer, neurological disease with leg paresis, nursing-home confinement, trauma or fracture, superficial vein thrombosis, and—in women—pregnancy and puerperium, oral contraception, and hormone therapy. Although independent risk factors for incident VTE and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be fairly constant, or even increasing.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Annual incidence of venous thromboembolism among residents of Olmsted County, MN, USA, from 1966 to 1990, by age and sex.
Figure 2: Annual incidence of venous thromboembolism among residents of Olmsted County, MN, USA, from 1966 to 1990, by age.
Figure 3: Trends over time in the incidence of venous thromboembolism, deep-vein thrombosis alone, and pulmonary embolism (with or without deep-vein thrombosis) among residents of Worcester, MA, USA.
Figure 4: Kaplan–Meier estimates of survival among residents of Olmsted County, MN, USA with incident venous thromboembolism diagnosed 1966–1990.111

Similar content being viewed by others

References

  1. Souto, J. C. 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. 67, 1452–1459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ariëns, R. A. et al. Activation markers of coagulation and fibrinolysis in twins: heritability of the prethrombotic state. Lancet 359, 667–671 (2002).

    Article  PubMed  Google Scholar 

  3. Larsen, T. B. et al. Major genetic susceptibility for venous thromboembolism in men: a study of Danish twins. Epidemiology 14, 328–332 (2003).

    PubMed  Google Scholar 

  4. Heit, J. A. et al. Familial segregation of venous thromboembolism. J. Thromb. Haemost. 2, 731–736 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Zöller, B., Ohlsson, H., Sundquist, J. & Sundquist, K. Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden. Thromb. Haemost. 109, 458–463 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Zöller, B., Li, X., Sundquist, J. & Sundquist, K. A nationwide family study of pulmonary embolism: identification of high risk families with increased risk of hospitalized and fatal pulmonary embolism. Thromb. Res. 130, 178–182 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Zöller, B., Li, X., Sundquist, J. & Sundquist, K. Shared familial aggregation of susceptibility to different manifestations of venous thromboembolism: a nationwide family study in Sweden. Br. J. Haematol. 157, 146–148 (2012).

    Article  PubMed  Google Scholar 

  8. Anderson, F. A. Jr et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch. Intern. Med. 151, 933–938 (1991).

    Article  PubMed  Google Scholar 

  9. Hansson, P. O., Welin, L., Tibblin, G. & Eriksson, H. Deep vein thrombosis and pulmonary embolism in the general population. 'The Study of Men Born in 1913'. Arch. Intern. Med. 157, 1665–1670 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Silverstein, M. D. et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch. Intern. Med. 158, 585–593 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Oger, E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb. Haemost. 83, 657–660 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Cushman, M. et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am. J. Med. 117, 19–25 (2004).

    Article  PubMed  Google Scholar 

  13. Heit, J. A. Venous thromboembolism: disease burden, outcomes and risk factors. J. Thromb. Haemost. 3, 1611–1617 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Spencer, F. A. et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J. Gen. Intern. Med. 21, 722–727 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Naess, I. A. et al. Incidence and mortality of venous thrombosis: a population-based study. J. Thromb. Haemost. 5, 692–699 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Spencer, F. A. et al. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J. Thromb. Thrombolysis 28, 401–409 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Tagalakis, V., Patenaude, V., Kahn, S. R. & Suissa, S. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am. J. Med. 126, 832.e13–832.e21 (2013).

    Article  Google Scholar 

  18. Huang, W., Goldberg, R. J., Anderson, F. A., Kiefe, C. I. & Spencer, F. A. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985–2009). Am. J. Med. 127, 829–839.e5 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rothwell, P. M. et al. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet 363, 1925–1933 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Koton, S. et al. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA 312, 259–268 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. White, R. H., Zhou, H. & Romano, P. S. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann. Intern. Med. 128, 737–740 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Schneider, D., Lilienfeld, D. E. & Im, W. The epidemiology of pulmonary embolism: racial contrasts in incidence and in-hospital case fatality. J. Natl Med. Assoc. 98, 1967–1972 (2006).

    PubMed  PubMed Central  Google Scholar 

  23. Zakai, N. A. et al. Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. Circulation 129, 1502–1509 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cheuk, B. L., Cheung, G. C. & Cheng, S. W. Epidemiology of venous thromboembolism in a Chinese population. Br. J. Surg. 91, 424–428 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Klatsky, A. L., Armstrong, M. A. & Poggi, J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian-Americans. Am. J. Cardiol. 85, 1334–1337 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. White, R. H., Zhou, H., Murin, S. & Harvey, D. Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb. Haemost. 93, 298–305 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Hooper, W. C., Holman, R. C., Heit, J. A. & Cobb, N. Venous thromboembolism hospitalizations among American Indians and Alaska Natives. Thromb. Res. 108, 273–278 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Heit, J. A. et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch. Intern. Med. 162, 1245–1248 (2002).

    Article  PubMed  Google Scholar 

  29. Heit, J. A., Sobell, J. L., Li, H. & Sommer, S. S. The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J. Thromb. Haemost. 3, 305–311 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Prandoni, P. et al. The long-term clinical course of acute deep venous thrombosis. Ann. Intern. Med. 125, 1–7 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Heit, J. A. et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch. Intern. Med. 160, 761–768 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Hansson, P. O., Sörbo, J. & Eriksson, H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch. Intern. Med. 160, 769–774 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. van Dongen, C. J., Vink, R., Hutten, B. A., Büller, H. R. & Prins, M. H. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis. Arch. Intern. Med. 163, 1285–1293 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Schulman, S. et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J. Thromb. Haemost. 4, 734–742 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Prandoni, P. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 92, 199–205 (2007).

    Article  PubMed  Google Scholar 

  36. Spencer, F. A. et al. Patient outcomes after deep vein thrombosis and pulmonary embolism: the Worcester Venous Thromboembolism Study. Arch. Intern. Med. 168, 425–430 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Nieto, J. A. et al. Clinical outcome of patients with major bleeding after venous thromboembolism. Findings from the RIETE Registry. Thromb. Haemost. 100, 789–796 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. White, R. H., Chan, W. S., Zhou, H. & Ginsberg, J. S. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb. Haemost. 100, 246–252 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Kyrle, P. A., Rosendaal, F. R. & Eichinger, S. Risk assessment for recurrent venous thrombosis. Lancet 376, 2032–2039 (2010).

    Article  PubMed  Google Scholar 

  40. Verso, M. et al. Long-term death and recurrence in patients with acute venous thromboembolism: the MASTER registry. Thromb. Res. 130, 369–373 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Schulman, S. et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N. Engl. J. Med. 336, 393–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Kearon, C. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N. Engl. J. Med. 340, 901–907 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Agnelli, G. et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N. Engl. J. Med. 345, 165–169 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Schulman, S. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N. Engl. J. Med. 332, 1661–1665 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Agnelli, G. et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann. Intern. Med. 139, 19–25 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Prandoni, P. et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann. Intern. Med. 137, 955–960 (2002).

    Article  PubMed  Google Scholar 

  47. Kyrle, P. A. & Eichinger, S. The risk of recurrent venous thromboembolism: the Austrian Study on Recurrent Venous Thromboembolism. Wien. Klin. Wochenschr. 115, 471–474 (2003).

    Article  PubMed  Google Scholar 

  48. Douketis, J. D., Foster, G. A., Crowther, M. A., Prins, M. H. & Ginsberg, J. S. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch. Intern. Med. 160, 3431–3436 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Murin, S., Romano, P. S. & White, R. H. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb. Haemost. 88, 407–414 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Kyrle, P. A. et al. The risk of recurrent venous thromboembolism in men and women. N. Engl. J. Med. 350, 2558–2563 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Laczkovics, C. et al. Risk of recurrence after a first venous thromboembolic event in young women. Haematologica 92, 1201–1207 (2007).

    Article  PubMed  Google Scholar 

  52. Kim, T. M. et al. Clinical predictors of recurrent venous thromboembolism: a single institute experience in Korea. Thromb. Res. 123, 436–443 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Eichinger, S. et al. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch. Intern. Med. 168, 1678–1683 (2008).

    Article  PubMed  Google Scholar 

  54. Romualdi, E., Squizzato, A. & Ageno, W. Abdominal obesity and the risk of recurrent deep vein thrombosis. Thromb. Res. 119, 687–690 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Garcia-Fuster, M. J. et al. Long-term prospective study of recurrent venous thromboembolism in patients younger than 50 years. Pathophysiol. Haemost. Thromb. 34, 6–12 (2005).

    Article  PubMed  Google Scholar 

  56. Heit, J. A. et al. Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism. J. Thromb. Haemost. 9, 1133–1142 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Agnelli, G., Becattini, C. & Prandoni, P. Recurrent venous thromboembolism in men and women. N. Engl. J. Med. 351, 2015–2018 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Baglin, T., Luddington, R., Brown, K. & Baglin, C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 362, 523–526 (2003).

    Article  PubMed  Google Scholar 

  59. Baglin, T., Luddington, R., Brown, K. & Baglin, C. High risk of recurrent venous thromboembolism in men. J. Thromb. Haemost. 2, 2152–2155 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. McRae, S., Tran, H., Schulman, S., Ginsberg, J. & Kearon, C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 368, 371–378 (2006).

    Article  PubMed  Google Scholar 

  61. Lijfering, W. M. et al. A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 114, 2031–2036 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Le Gal, G. et al. Risk of recurrent venous thromboembolism after a first oestrogen-associated episode. Data from the REVERSE cohort study. Thromb. Haemost. 104, 498–503 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Christiansen, S. C., Lijfering, W. M., Helmerhorst, F. M., Rosendaal, F. R. & Cannegieter, S. C. Sex difference in risk of recurrent venous thrombosis and the risk profile for a second event. J. Thromb. Haemost. 8, 2159–2168 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Douketis, J. et al. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. BMJ 342, d813 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Hutten, B. A. et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J. Clin. Oncol. 18, 3078–3083 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Pinede, L. et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 103, 2453–2460 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Prandoni, P. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100, 3484–3488 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Louzada, M. L., Majeed, H., Dao, V. & Wells, P. S. Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies. Blood Coagul. Fibrinolysis 22, 86–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Louzada, M. L. et al. Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism. Circulation 126, 448–454 (2012).

    Article  PubMed  Google Scholar 

  70. Chee, C. E. et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 123, 3972–3978 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Iorio, A. et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch. Intern. Med. 170, 1710–1716 (2010).

    PubMed  Google Scholar 

  72. Baglin, T. et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. J. Thromb. Haemost. 8, 2436–2442 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Kovacs, M. J. et al. Patients with a first symptomatic unprovoked deep vein thrombosis are at higher risk of recurrent venous thromboembolism than patients with a first unprovoked pulmonary embolism. J. Thromb. Haemost. 8, 1926–1932 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Schulman, S., Svenungsson, E. & Granqvist, S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am. J. Med. 104, 332–338 (1998).

    Article  CAS  PubMed  Google Scholar 

  75. Garcia, D., Akl, E. A., Carr, R. & Kearon, C. Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood 122, 817–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Jayakody Arachchillage, D. & Greaves, M. The chequered history of the antiphospholipid syndrome. Br. J. Haematol. 165, 609–617 (2014).

    Article  PubMed  Google Scholar 

  77. van den Belt, A. G. et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch. Intern. Med. 157, 2227–2232 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Vossen, C. Y. 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. 3, 459–464 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Brouwer, J. L. et al. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb. Haemost. 101, 93–99 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. den Heijer, M. et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood 109, 139–144 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Verhovsek, M. et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann. Intern. Med. 149, 481–490 (2008).

    Article  PubMed  Google Scholar 

  82. Douketis, J. et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann. Intern. Med. 153, 523–531 (2010).

    Article  PubMed  Google Scholar 

  83. Cosmi, B. et al. Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood 115, 481–488 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Palareti, G. et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 124, 196–203 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Tan, M., Mos, I. C., Klok, F. A. & Huisman, M. V. Residual venous thrombosis as predictive factor for recurrent venous thromboembolim in patients with proximal deep vein thrombosis: a sytematic review. Br. J. Haematol. 153, 168–178 (2011).

    Article  PubMed  Google Scholar 

  86. Le Gal, G. et al. Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study. J. Thromb. Haemost. 9, 1126–1132 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Ho, W. K., Hankey, G. J., Quinlan, D. J. & Eikelboom, J. W. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch. Intern. Med. 166, 729–736 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Gándara, E. et al. Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study. Thromb. Haemost. 110, 1172–1179 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Zhu, T., Martinez, I. & Emmerich, J. Venous thromboembolism: risk factors for recurrence. Arterioscler. Thromb. Vasc. Biol. 29, 298–310 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Cushman, M. et al. Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial. J. Thromb. Haemost. 4, 2199–2203 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Biere-Rafi, S. et al. Statin treatment and the risk of recurrent pulmonary embolism. Eur. Heart J. 34, 1800–1806 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. White, R. H., Murin, S., Wun, T. & Danielsen, B. Recurrent venous thromboembolism after surgery-provoked versus unprovoked thromboembolism. J. Thromb. Haemost. 8, 987–997 (2010).

    CAS  PubMed  Google Scholar 

  93. Douketis, J. D., Crowther, M. A., Foster, G. A. & Ginsberg, J. S. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am. J. Med. 110, 515–519 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Eichinger, S. et al. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism. Arch. Intern. Med. 164, 92–96 (2004).

    Article  PubMed  Google Scholar 

  95. Jiménez, D. et al. The risk of recurrent venous thromboembolism in patients with unprovoked symptomatic deep vein thrombosis and asymptomatic pulmonary embolism. Thromb. Haemost. 95, 562–566 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Boutitie, F. et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 342, d3036 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Galanaud, J. P. et al. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J. Thromb. Haemost. 12, 436–443 (2014).

    Article  PubMed  Google Scholar 

  98. den Exter, P. L. et al. Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. Blood 122, 1144–1149 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Rodger, M. A. et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 179, 417–426 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Eichinger, S., Heinze, G., Jandeck, L. M. & Kyrle, P. A. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 121, 1630–1636 (2010).

    Article  PubMed  Google Scholar 

  101. Tosetto, A. et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J. Thromb. Haemost. 10, 1019–1025 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Kyrle, P. A. & Eichinger, S. Clinical scores to predict recurrence risk of venous thromboembolism. Thromb. Haemost. 108, 1061–1064 (2012).

    Article  PubMed  Google Scholar 

  103. Poli, D. & Palareti, G. Assessing recurrence risk following acute venous thromboembolism: use of algorithms. Curr. Opin. Pulm. Med. 19, 407–412 (2013).

    Article  PubMed  Google Scholar 

  104. den Exter, P. L., Kooiman, J. & Huisman, M. V. Validation of the Ottawa prognostic score for the prediction of recurrent venous thromboembolism in patients with cancer-associated thrombosis. J. Thromb. Haemost. 11, 998–1000 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Heit, J. A. Estimating the incidence of symptomatic postoperative venous thromboembolism: the importance of perspective. JAMA 307, 306–307 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Cohen, A. T. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb. Haemost. 98, 756–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Centers for Disease Control and Prevention (CDC). Venous thromboembolism in adult hospitalizations—United States, 2007–2009. MMWR Morb. Mortal. Wkly Rep. 61, 401–404 (2012).

  108. Cohoon, K. P. et al. Costs of venous thromboembolism associated with hospitalization for medical illness. Am. J. Manag. Care 21, e255–e263 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. Cohoon, K. P. et al. Direct medical costs attributable to venous thromboembolism among persons hospitalized for major surgery: a population-based longitudinal study. Surgery 157, 423–431 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  110. ISTH Steering Committee for World Thrombosis Day. Thrombosis: a major contributor to the global disease burden. J. Thromb. Haemost. 12, 1580–1590 (2014).

  111. Heit, J. A. et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Arch. Intern. Med. 159, 445–453 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Goldhaber, S. Z., Visani, L. & De Rosa, M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 353, 1386–1389 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Janata, K. et al. Mortality of patients with pulmonary embolism. Wien. Klin. Wochenschr. 114, 766–772 (2002).

    PubMed  Google Scholar 

  114. Andresen, M. S. et al. Mortality and recurrence after treatment of VTE: long term follow-up of patients with good life-expectancy. Thromb. Res. 127, 540–546 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Søgaard, K. K., Schmidt, M., Pedersen, L., Horváth-Puhó, E. & Sørensen, H. T. 30-year mortality after venous thromboembolism: a population-based cohort study. Circulation 130, 829–836 (2014).

    Article  PubMed  Google Scholar 

  116. Agnelli, G. & Becattini, C. Acute pulmonary embolism. N. Engl. J. Med. 363, 266–274 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Konstantinides, S. et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 96, 882–888 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Horlander, K. T., Mannino, D. M. & Leeper, K. V. Pulmonary embolism mortality in the United States, 1979–1998: an analysis using multiple-cause mortality data. Arch. Intern. Med. 163, 1711–1717 (2003).

    Article  PubMed  Google Scholar 

  119. Tsai, J., Grosse, S. D., Grant, A. M., Hooper, W. C. & Atrash, H. K. Trends in in-hospital deaths among hospitalizations with pulmonary embolism. Arch. Intern. Med. 172, 960–961 (2012).

    Article  PubMed  Google Scholar 

  120. Barsoum, M. K. et al. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb. Res. 126, 373–378 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Heit, J. A. et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch. Intern. Med. 160, 809–815 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Cushman, M. et al. Fibrin fragment D-dimer and the risk of future venous thrombosis. Blood 101, 1243–1248 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Smeeth, L. et al. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 367, 1075–1079 (2006).

    Article  PubMed  Google Scholar 

  124. Sweetland, S. et al. Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study. BMJ 339, b4583 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Bezemer, I. D., van der Meer, F. J., Eikenboom, J. C., Rosendaal, F. R. & Doggen, C. J. The value of family history as a risk indicator for venous thrombosis. Arch. Intern. Med. 169, 610–615 (2009).

    Article  PubMed  Google Scholar 

  126. Roach, R. E., Lijfering, W. M., Flinterman, L. E., Rosendaal, F. R. & Cannegieter, S. C. Increased risk of CVD after VT is determined by common etiologic factors. Blood 121, 4948–4954 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Cannegieter, S. C. et al. Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study. Blood 125, 229–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Heit, J. A. et al. Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin. Proc. 76, 1102–1110 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Noboa, S., Mottier, D., Oger, E. & EPI-GETBO Study Group. Estimation of a potentially preventable fraction of venous thromboembolism: a community-based prospective study. J. Thromb. Haemost. 4, 2720–2722 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Samama, M. M. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch. Intern. Med. 160, 3415–3420 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Geerts, W. H. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133, 381S–453S (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Sweetland, S. et al. Smoking, surgery, and venous thromboembolism risk in women: United Kingdom cohort study. Circulation 127, 1276–1282 (2013).

    Article  PubMed  Google Scholar 

  133. White, R. H., Zhou, H. & Romano, P. S. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb. Haemost. 90, 446–455 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Edmonds, M. J., Crichton, T. J., Runciman, W. B. & Pradhan, M. Evidence-based risk factors for postoperative deep vein thrombosis. ANZ J. Surg. 74, 1082–1097 (2004).

    Article  PubMed  Google Scholar 

  135. Goldhaber, S. Z., Tapson, V. F. & DVT FREE Steering Committee. A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am. J. Cardiol. 93, 259–262 (2004).

    Article  PubMed  Google Scholar 

  136. Anderson, F. A. Jr, Hirsh, J., White, K., Fitzgerald, R. H. Jr & Hip and Knee Registry Investigators. Temporal trends in prevention of venous thromboembolism following primary total hip or knee arthroplasty 1996–2001: findings from the Hip and Knee Registry. Chest 124 (Suppl. 6), 349S–356S (2003).

    Article  PubMed  Google Scholar 

  137. White, R. H., Gettner, S., Newman, J. M., Trauner, K. B. & Romano, P. S. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N. Engl. J. Med. 343, 1758–1764 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Parkin, L. et al. Body mass index, surgery, and risk of venous thromboembolism in middle-aged women: a cohort study. Circulation 125, 1897–1904 (2012).

    Article  PubMed  Google Scholar 

  139. Mantilla, C. B., Horlocker, T. T., Schroeder, D. R., Berry, D. J. & Brown, D. L. Risk factors for clinically relevant pulmonary embolism and deep venous thrombosis in patients undergoing primary hip or knee arthroplasty. Anesthesiology 99, 552–560 (2003).

    Article  PubMed  Google Scholar 

  140. Zakai, N. A., Wright, J. & Cushman, M. Risk factors for venous thrombosis in medical inpatients: validation of a thrombosis risk score. J. Thromb. Haemost. 2, 2156–2161 (2004).

    Article  CAS  PubMed  Google Scholar 

  141. Chopard, P., Spirk, D. & Bounameaux, H. Identifying acutely ill medical patients requiring thromboprophylaxis. J. Thromb. Haemost. 4, 915–916 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Barbar, S. et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J. Thromb. Haemost. 8, 2450–2457 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Rothberg, M. B., Lindenauer, P. K., Lahti, M., Pekow, P. S. & Selker, H. P. Risk factor model to predict venous thromboembolism in hospitalized medical patients. J. Hosp. Med. 6, 202–209 (2011).

    Article  PubMed  Google Scholar 

  144. Spyropoulos, A. C. et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 140, 706–714 (2011).

    Article  PubMed  Google Scholar 

  145. Woller, S. C. et al. Derivation and validation of a simple model to identify venous thromboembolism risk in medical patients. Am. J. Med. 124, 947–954.e2 (2011).

    Article  PubMed  Google Scholar 

  146. Zakai, N. A., Callas, P. W., Repp, A. B. & Cushman, M. Venous thrombosis risk assessment in medical inpatients: the medical inpatients and thrombosis (MITH) study. J. Thromb. Haemost. 11, 634–641 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Samama, M. M., Combe, S., Conard, J. & Horellou, M. H. Risk assessment models for thromboprophylaxis of medical patients. Thromb. Res. 129, 127–132 (2012).

    Article  CAS  PubMed  Google Scholar 

  148. Rothberg, M. B. Venous thromboembolism prophylaxis for medical patients: who needs it? JAMA Intern. Med. 174, 1585–1586 (2014).

    Article  PubMed  Google Scholar 

  149. Chew, H. K., Wun, T., Harvey, D., Zhou, H. & White, R. H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch. Intern. Med. 166, 458–464 (2006).

    Article  PubMed  Google Scholar 

  150. Blom, J. W. et al. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J. Thromb. Haemost. 4, 529–535 (2006).

    Article  CAS  PubMed  Google Scholar 

  151. Kucuk, O., Kwaan, H. C., Gunnar, W. & Vazquez, R. M. Thromboembolic complications associated with L-asparaginase therapy. Etiologic role of low antithrombin III and plasminogen levels and therapeutic correction by fresh frozen plasma. Cancer 55, 702–706 (1985).

    Article  CAS  PubMed  Google Scholar 

  152. Liebman, H. A., Wada, J. K., Patch, M. J. & McGehee, W. Depression of functional and antigenic plasma antithrombin III (AT-III) due to therapy with L-asparaginase. Cancer 50, 451–456 (1982).

    Article  CAS  PubMed  Google Scholar 

  153. Zangari, M. et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 98, 1614–1615 (2001).

    Article  CAS  PubMed  Google Scholar 

  154. Knight, R., DeLap, R. J. & Zeldis, J. B. Lenalidomide and venous thrombosis in multiple myeloma. N. Engl. J. Med. 354, 2079–2080 (2006).

    Article  CAS  PubMed  Google Scholar 

  155. Meier, C. R. & Jick, H. Tamoxifen and risk of idiopathic venous thromboembolism. Br. J. Clin. Pharmacol. 45, 608–612 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Baron, J. A., Gridley, G., Weiderpass, E., Nyrén, O. & Linet, M. Venous thromboembolism and cancer. Lancet 351, 1077–1080 (1998).

    Article  CAS  PubMed  Google Scholar 

  157. Piccioli, A. et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. J. Thromb. Haemost. 2, 884–889 (2004).

    Article  CAS  PubMed  Google Scholar 

  158. Tafur, A. J. et al. The association of active cancer with venous thromboembolism location: a population-based study. Mayo Clin. Proc. 86, 25–30 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Carrier, M. et al. Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism? Ann. Intern. Med. 149, 323–333 (2008).

    Article  PubMed  Google Scholar 

  160. Khorana, A. A., Kuderer, N. M., Culakova, E., Lyman, G. H. & Francis, C. W. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 111, 4902–4907 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Ay, C. et al. Prediction of venous thromboembolism in cancer patients. Blood 116, 5377–5382 (2010).

    Article  CAS  PubMed  Google Scholar 

  162. Merrer, J. et al. Complications of femoral and subclavian venous catheterization in critically ill patients: a randomized controlled trial. JAMA 286, 700–707 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Decousus, H. et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann. Intern. Med. 152, 218–224 (2010).

    Article  PubMed  Google Scholar 

  164. Goldhaber, S. Z. et al. Risk factors for pulmonary embolism. The Framingham Study. Am. J. Med. 74, 1023–1028 (1983).

    Article  CAS  PubMed  Google Scholar 

  165. Cogo, A. et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch. Intern. Med. 154, 164–168 (1994).

    Article  CAS  PubMed  Google Scholar 

  166. Dalen, J. E. Economy class syndrome: too much flying or too much sitting? Arch. Intern. Med. 163, 2674–2676 (2003).

    Article  PubMed  Google Scholar 

  167. Kuipers, S. et al. The absolute risk of venous thrombosis after air travel: a cohort study of 8,755 employees of international organisations. PLoS Med. 4, e290 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Chandra, D., Parisini, E. & Mozaffarian, D. Meta-analysis: travel and risk for venous thromboembolism. Ann. Intern. Med. 151, 180–190 (2009).

    Article  PubMed  Google Scholar 

  169. Watson, H. G. & Baglin, T. P. Guidelines on travel-related venous thrombosis. Br. J. Haematol. 152, 31–34 (2011).

    Article  PubMed  Google Scholar 

  170. Ray, J. G. et al. Use of statins and the subsequent development of deep vein thrombosis. Arch. Intern. Med. 161, 1405–1410 (2001).

    Article  CAS  PubMed  Google Scholar 

  171. Lacut, K. et al. Statins but not fibrates are associated with a reduced risk of venous thromboembolism: a hospital-based case-control study. Fundam. Clin. Pharmacol. 18, 477–482 (2004).

    Article  CAS  PubMed  Google Scholar 

  172. Glynn, R. J. et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N. Engl. J. Med. 360, 1851–1861 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Doggen, C. J. et al. Serum lipid levels and the risk of venous thrombosis. Arterioscler. Thromb. Vasc. Biol. 24, 1970–1975 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Prandoni, P. et al. An association between atherosclerosis and venous thrombosis. N. Engl. J. Med. 348, 1435–1441 (2003).

    Article  PubMed  Google Scholar 

  175. Marcucci, R. et al. Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism. Am. J. Med. 115, 601–605 (2003).

    Article  CAS  PubMed  Google Scholar 

  176. Tsai, A. W. et al. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch. Intern. Med. 162, 1182–1189 (2002).

    Article  PubMed  Google Scholar 

  177. Sørensen, H. T., Horvath-Puho, E., Pedersen, L., Baron, J. A. & Prandoni, P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 370, 1773–1779 (2007).

    Article  PubMed  Google Scholar 

  178. Zöller, B., Li, X., Sundquist, J. & Sundquist, K. Venous thromboembolism does not share strong familial susceptibility with coronary heart disease: a nationwide family study in Sweden. Eur. Heart J. 32, 2800–2805 (2011).

    Article  PubMed  Google Scholar 

  179. Barsoum, M. K. et al. Are myocardial infarction and venous thromboembolism associated? Population-based case-control and cohort studies. Thromb. Res. 134, 593–598 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Folsom, A. R. & Chamberlain, A. Lipoprotein(a) and venous thromboembolism. Am. J. Med. 121, e17 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Chamberlain, A. M., Folsom, A. R., Heckbert, S. R., Rosamond, W. D. & Cushman, M. High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE). Blood 112, 2675–2680 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Chasan-Taber, L. & Stampfer, M. J. Epidemiology of oral contraceptives and cardiovascular disease. Ann. Intern. Med. 128, 467–477 (1998).

    Article  CAS  PubMed  Google Scholar 

  183. Rosendaal, F. R. Risk factors for venous thrombotic disease. Thromb. Haemost. 82, 610–619 (1999).

    Article  CAS  PubMed  Google Scholar 

  184. Gomes, M. P. & Deitcher, S. R. Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review. Arch. Intern. Med. 164, 1965–1976 (2004).

    Article  CAS  PubMed  Google Scholar 

  185. Grady, D. et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann. Intern. Med. 132, 689–696 (2000).

    Article  CAS  PubMed  Google Scholar 

  186. Grady, D., Hulley, S. B. & Furberg, C. Venous thromboembolic events associated with hormone replacement therapy. JAMA 278, 477 (1997).

    Article  CAS  PubMed  Google Scholar 

  187. Heit, J. A. et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann. Intern. Med. 143, 697–706 (2005).

    Article  PubMed  Google Scholar 

  188. Adomaityte, J., Farooq, M. & Qayyum, R. Effect of raloxifene therapy on venous thromboembolism in postmenopausal women. A meta-analysis. Thromb. Haemost. 99, 338–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  189. van Hylckama Vlieg, A., Helmerhorst, F. M. & Rosendaal, F. R. The risk of deep venous thrombosis associated with injectable depot-medroxyprogesterone acetate contraceptives or a levonorgestrel intrauterine device. Arterioscler. Thromb. Vasc. Biol. 30, 2297–2300 (2010).

    Article  CAS  PubMed  Google Scholar 

  190. Smith, N. L. et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA 292, 1581–1587 (2004).

    Article  CAS  PubMed  Google Scholar 

  191. James, A. H. Venous thromboembolism in pregnancy. Arterioscler. Thromb. Vasc. Biol. 29, 326–331 (2009).

    Article  CAS  PubMed  Google Scholar 

  192. Danilenko-Dixon, D. R. et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based, case-control study. Am. J. Obstet. Gynecol. 184, 104–110 (2001).

    Article  CAS  PubMed  Google Scholar 

  193. Roach, R. E. et al. The risk of venous thrombosis in individuals with a history of superficial vein thrombosis and acquired venous thrombotic risk factors. Blood 122, 4264–4269 (2013).

    Article  CAS  PubMed  Google Scholar 

  194. Sultan, A. A. et al. Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom. Blood 121, 3953–3961 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Ludvigsson, J. F., Welander, A., Lassila, R., Ekbom, A. & Montgomery, S. M. Risk of thromboembolism in 14,000 individuals with coeliac disease. Br. J. Haematol. 139, 121–127 (2007).

    Article  PubMed  Google Scholar 

  196. Shantsila, E., Lip, G. Y. & Chong, B. H. Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management. Chest 135, 1651–1664 (2009).

    Article  CAS  PubMed  Google Scholar 

  197. Tsai, A. W. et al. Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). Am. J. Hematol. 72, 192–200 (2003).

    Article  CAS  PubMed  Google Scholar 

  198. den Heijer, M., Lewington, S. & Clarke, R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J. Thromb. Haemost. 3, 292–299 (2005).

    Article  CAS  PubMed  Google Scholar 

  199. van Zaane, B. et al. Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: a case-control study. Blood 115, 4344–4349 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Severinsen, M. T. et al. Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br. J. Haematol. 152, 360–362 (2011).

    Article  PubMed  Google Scholar 

  201. Boyle, S., White, R. H., Brunson, A. & Wun, T. Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 121, 4782–4790 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Grainge, M. J., West, J. & Card, T. R. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 375, 657–663 (2010).

    Article  PubMed  Google Scholar 

  203. Dentali, F. et al. JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis. Blood 113, 5617–5623 (2009).

    Article  CAS  PubMed  Google Scholar 

  204. Barbui, T. et al. Thrombosis in primary myelofibrosis: incidence and risk factors. Blood 115, 778–782 (2010).

    Article  CAS  PubMed  Google Scholar 

  205. Folsom, A. R. et al. Chronic kidney disease and venous thromboembolism: a prospective study. Nephrol. Dial. Transplant. 25, 3296–3301 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Kayali, F., Najjar, R., Aswad, F., Matta, F. & Stein, P. D. Venous thromboembolism in patients hospitalized with nephrotic syndrome. Am. J. Med. 121, 226–230 (2008).

    Article  PubMed  Google Scholar 

  207. Brodsky, R. A. Paroxysmal nocturnal hemoglobinuria: stem cells and clonality. Hematology Am. Soc. Hematol. Educ. Program 2008, 111–115 (2008).

    Article  Google Scholar 

  208. Bacani, A. K., Gabriel, S. E., Crowson, C. S., Heit, J. A. & Matteson, E. L. Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events? Arthritis Rheum. 64, 53–61 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Holmqvist, M. E. et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA 308, 1350–1356 (2012).

    Article  CAS  PubMed  Google Scholar 

  210. Arnulf, I. et al. Obstructive sleep apnea and venous thromboembolism. JAMA 287, 2655–2656 (2002).

    Article  PubMed  Google Scholar 

  211. Peng, Y. H. et al. Association between obstructive sleep apnea and deep vein thrombosis / pulmonary embolism: a population-based retrospective cohort study. Thromb. Res. 134, 340–345 (2014).

    Article  CAS  PubMed  Google Scholar 

  212. Austin, H. et al. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood 110, 908–912 (2007).

    Article  CAS  PubMed  Google Scholar 

  213. Merkel, P. A. et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann. Intern. Med. 142, 620–626 (2005).

    Article  PubMed  Google Scholar 

  214. Sanson, B. J. et al. The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study. Blood 94, 3702–3706 (1999).

    CAS  PubMed  Google Scholar 

  215. Folsom, A. R., Cushman, M., Tsai, M. Y., Heckbert, S. R. & Aleksic, N. Prospective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism. Am. J. Hematol. 71, 285–290 (2002).

    Article  CAS  PubMed  Google Scholar 

  216. Vossen, C. Y. & Rosendaal, F. R. The protective effect of the factor XIII Val34Leu mutation on the risk of deep venous thrombosis is dependent on the fibrinogen level. J. Thromb. Haemost. 3, 1102–1103 (2005).

    Article  CAS  PubMed  Google Scholar 

  217. Vossen, C. Y. et al. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler. Thromb. Vasc. Biol. 25, 1992–1997 (2005).

    Article  CAS  PubMed  Google Scholar 

  218. Bombeli, T., Piccapietra, B., Boersma, J., Fehr, J. Decreased anticoagulant response to tissue factor pathway inhibitor in patients with venous thromboembolism and otherwise no evidence of hereditary or acquired thrombophilia. Thromb. Haemost. 91, 80–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  219. Broze, G. J. Jr & Miletich, J. P. Human Protein Z. J. Clin. Invest. 73, 933–938 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Yin, Z. F. et al. Prothrombotic phenotype of protein Z deficiency. Proc. Natl Acad. Sci. USA 97, 6734–6738 (2000).

    Article  CAS  PubMed  Google Scholar 

  221. Han, X., Fiehler, R. & Broze, G. J. Jr. Isolation of a protein Z-dependent plasma protease inhibitor. Proc. Natl Acad. Sci. USA 95, 9250–9255 (1998).

    Article  CAS  PubMed  Google Scholar 

  222. Han, X., Huang, Z. F., Fiehler, R. & Broze, G. J. Jr. The protein Z-dependent protease inhibitor is a serpin. Biochemistry 38, 11073–11078 (1999).

    Article  CAS  PubMed  Google Scholar 

  223. Souri, M., Koseki-Kuno, S., Iwata, H., Kemkes-Matthes, B. & Ichinose, A. A naturally occurring E30Q mutation in the Gla domain of protein Z causes its impaired secretion and subsequent deficiency. Blood 105, 3149–3154 (2005).

    Article  CAS  PubMed  Google Scholar 

  224. Uitte de Willige, S. et al. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen gamma' levels. Blood 106, 4176–4183 (2005).

    Article  CAS  PubMed  Google Scholar 

  225. Press, R. D., Bauer, K. A., Kujovich, J. L. & Heit, J. A. Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch. Pathol. Lab. Med. 126, 1304–1318 (2002).

    PubMed  Google Scholar 

  226. Folsom, A. R. et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 99, 2720–2725 (2002).

    Article  CAS  PubMed  Google Scholar 

  227. Juul, K., Tybjaerg-Hansen, A., Schnohr, P. & Nordestgaard, B. G. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann. Intern. Med. 140, 330–337 (2004).

    Article  CAS  PubMed  Google Scholar 

  228. Chandler, W. L., Rodgers, G. M., Sprouse, J. T. & Thompson, A. R. Elevated hemostatic factor levels as potential risk factors for thrombosis. Arch. Pathol. Lab. Med. 126, 1405–1414 (2002).

    CAS  PubMed  Google Scholar 

  229. van Hylckama Vlieg, A. & Rosendaal, F. R. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly. J. Thromb. Haemost. 1, 2677–2678 (2003).

    Article  CAS  PubMed  Google Scholar 

  230. Wells, P. S., Langlois, N. J., Webster, M. A., Jaffey, J. & Anderson, J. A. Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada—is it necessary to define a new upper reference range for factor VIII? Thromb. Haemost. 93, 842–846 (2005).

    Article  CAS  PubMed  Google Scholar 

  231. McGlennen, R. C. & Key, N. S. Clinical and laboratory management of the prothrombin G20210A mutation. Arch. Pathol. Lab. Med. 126, 1319–1325 (2002).

    CAS  PubMed  Google Scholar 

  232. Koster, T., Blann, A. D., Briët, E., Vandenbroucke, J. P. & Rosendaal, F. R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 345, 152–155 (1995).

    Article  CAS  PubMed  Google Scholar 

  233. MacCallum, P. K. et al. Clotting factor VIII and risk of deep-vein thrombosis. Lancet 345, 804 (1995).

    Article  CAS  PubMed  Google Scholar 

  234. Kraaijenhagen, R. A. et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb. Haemost. 83, 5–9 (2000).

    Article  CAS  PubMed  Google Scholar 

  235. Bank, I. et al. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis. J. Thromb. Haemost. 3, 79–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  236. van Hylckama Vlieg, A., van der Linden, I. K., Bertina, R. M. & Rosendaal, F. R. High levels of factor IX increase the risk of venous thrombosis. Blood 95, 3678–3682 (2000).

    CAS  PubMed  Google Scholar 

  237. Meijers, J. C., Tekelenburg, W. L., Bouma, B. N., Bertina, R. M. & Rosendaal, F. R. High levels of coagulation factor XI as a risk factor for venous thrombosis. N. Engl. J. Med. 342, 696–701 (2000).

    Article  CAS  PubMed  Google Scholar 

  238. Ohira, T. et al. ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). J. Thromb. Haemost. 5, 1455–1461 (2007).

    Article  CAS  PubMed  Google Scholar 

  239. Cushman, M., O'Meara, E. S., Folsom, A. R. & Heckbert, S. R. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood 114, 2878–2883 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Smith, N. L. et al. 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 121, 1382–1392 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Trégouët, D. A. 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 113, 5298–5303 (2009).

    Article  CAS  PubMed  Google Scholar 

  242. de Haan, H. G. et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood 120, 656–663 (2012).

    Article  CAS  PubMed  Google Scholar 

  243. Cohen, W. et al. ABO blood group and von Willebrand factor levels partially explained the incomplete penetrance of congenital thrombophilia. Arterioscler. Thromb. Vasc. Biol. 32, 2021–2028 (2012).

    Article  CAS  PubMed  Google Scholar 

  244. Heit, J. A. et al. A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q. J. Thromb. Haemost. 10, 1521–1531 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Tang, W. 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. 37, 512–521 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Tripodi, A., Chantarangkul, V., Martinelli, I., Bucciarelli, P. & Mannucci, P. M. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism. Blood 104, 3631–3634 (2004).

    Article  CAS  PubMed  Google Scholar 

  247. Folsom, A. R., Cushman, M., Heckbert, S. R., Rosamond, W. D. & Aleksic, N. Prospective study of fibrinolytic markers and venous thromboembolism. J. Clin. Epidemiol. 56, 598–603 (2003).

    Article  PubMed  Google Scholar 

  248. Lisman, T., de Groot, P. G., Meijers, J. C. & Rosendaal, F. R. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 105, 1102–1105 (2005).

    Article  CAS  PubMed  Google Scholar 

  249. André, P., Hartwell, D., Hrachovinová, I., Saffaripour, S. & Wagner, D. D. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc. Natl Acad. Sci. USA 97, 13835–13840 (2000).

    Article  PubMed  Google Scholar 

  250. Reitsma, P. H. & Rosendaal, F. R. Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study. J. Thromb. Haemost. 2, 619–622 (2004).

    Article  CAS  PubMed  Google Scholar 

  251. Souto, J. C. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 101, 1546–1551 (2000).

    Article  CAS  PubMed  Google Scholar 

  252. de Lange, M., Snieder, H., Ariëns, R. A., Spector, T. D. & Grant, P. J. The genetics of haemostasis: a twin study. Lancet 357, 101–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  253. Vossen, C. Y. et al. Heritability of plasma concentrations of clotting factors and measures of a prethrombotic state in a protein C-deficient family. J. Thromb. Haemost. 2, 242–247 (2004).

    Article  CAS  PubMed  Google Scholar 

  254. Morange, P. E. et al. Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort. Br. J. Haematol. 128, 91–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  255. Morange, P. E. & Trégouët, D. A. Current knowledge on the genetics of incident venous thrombosis. J. Thromb. Haemost. 11 (Suppl. 1), 111–121 (2013).

    Article  PubMed  Google Scholar 

  256. Oren, E., Smith, N. L., Doggen, C. J., Heckbert, S. R. & Lemaitre, R. N. Body mass index and the risk of venous thrombosis among postmenopausal women. J. Thromb. Haemost. 4, 2273–2275 (2006).

    Article  CAS  PubMed  Google Scholar 

  257. Severinsen, M. T. et al. Genetic susceptibility, smoking, obesity and risk of venous thromboembolism. Br. J. Haematol. 149, 273–279 (2010).

    Article  CAS  PubMed  Google Scholar 

  258. Vandenbroucke, J. P. et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 344, 1453–1457 (1994).

    Article  CAS  PubMed  Google Scholar 

  259. Wu, O. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb. Haemost. 94, 17–25 (2005).

    Article  CAS  PubMed  Google Scholar 

  260. Pomp, E. R., le Cessie, S., Rosendaal, F. R. & Doggen, C. J. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br. J. Haematol. 139, 289–296 (2007).

    Article  PubMed  Google Scholar 

  261. van Hylckama Vlieg, A. & Rosendaal, F. R. Interaction between oral contraceptive use and coagulation factor levels in deep venous thrombosis. J. Thromb. Haemost. 1, 2186–2190 (2003).

    Article  CAS  PubMed  Google Scholar 

  262. van Vlijmen, E. F. et al. Thrombotic risk during oral contraceptive use and pregnancy in women with factor V Leiden or prothrombin mutation: a rational approach to contraception. Blood 118, 2055–2061 (2011).

    Article  CAS  PubMed  Google Scholar 

  263. Martinelli, I. et al. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium. Thromb. Haemost. 87, 791–795 (2002).

    Article  CAS  PubMed  Google Scholar 

  264. Herrington, D. M. et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler. Thromb. Vasc. Biol. 22, 1012–1017 (2002).

    Article  CAS  PubMed  Google Scholar 

  265. Rosendaal, F. R. et al. Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis. Br. J. Haematol. 116, 851–854 (2002).

    Article  CAS  PubMed  Google Scholar 

  266. Cushman, M. et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 292, 1573–1580 (2004).

    Article  CAS  PubMed  Google Scholar 

  267. van Stralen, K. J., Rosendaal, F. R. & Doggen, C. J. Minor injuries as a risk factor for venous thrombosis. Arch. Intern. Med. 168, 21–26 (2008).

    Article  PubMed  Google Scholar 

  268. Lindahl, T. L., Lundahl, T. H., Nilsson, L. & Andersson, C. A. APC-resistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee—a prospective study. Thromb. Haemost. 81, 18–21 (1999).

    Article  CAS  PubMed  Google Scholar 

  269. Salvati, E. A. et al. The John Charnley Award: heritable thrombophilia and development of thromboembolic disease after total hip arthroplasty. Clin. Orthop. Relat. Res. 441, 40–55 (2005).

    Article  PubMed  Google Scholar 

  270. Blom, J. W., Doggen, C. J., Osanto, S. & Rosendaal, F. R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293, 715–722 (2005).

    Article  CAS  PubMed  Google Scholar 

  271. Libourel, E. J. et al. Co-segregation of thrombophilic disorders in factor V Leiden carriers; the contributions of factor VIII, factor XI, thrombin activatable fibrinolysis inhibitor andlipoprotein(a) to the absolute risk of venous thromboembolism. Haematologica 87, 1068–1073 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author was supported by grants from the National Heart, Lung, and Blood Institute under Award Number R01HL66216. Research support was also provided by the Mayo Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John A. Heit.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heit, J. Epidemiology of venous thromboembolism. Nat Rev Cardiol 12, 464–474 (2015). https://doi.org/10.1038/nrcardio.2015.83

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2015.83

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing