title: The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes.
abstract: BACKGROUND
  Venous thromboembolism (VTE) is thought to result from interactions between multiple genetic and environmental risk factors.
  
  
  OBJECTIVE
  To assess the contribution of multiple thrombophilic defects and exogenous risk factors to the absolute risk for VTE.
  
  
  METHODS
  Retrospective family cohort study.
  
  
  METHODS
  Single university hospital.
  
  
  METHODS
  468 relatives of 91 probands with a symptomatic hereditary deficiency of protein S, protein C, or antithrombin.
  
  
  METHODS
  All relatives were tested for 10 thrombophilic deficiencies and defects in addition to the index deficiency and were assessed for exogenous risk factors (surgery, trauma, immobilization, use of oral contraceptives, and pregnancy). The authors compared annual incidences and relative risks for VTE in deficient and nondeficient relatives.
  
  
  RESULTS
  Annual incidences of VTE in relatives with 0, 1, and 2 or more additional thrombophilic deficiencies or defects were 1.16 (95% CI, 0.60 to 2.03), 1.75 (CI, 1.17 to 2.53), and 2.64 (CI, 1.67 to 3.96) per 100 person-years, respectively, compared with 0.06 (CI, 0.002 to 0.33) per 100 person-years in nondeficient relatives without additional deficiencies or defects. Adjusted relative risks were 16.3 (CI, 2.0 to 131.0), 50.3 (6.5 to 389.7), and 102.8 (12.5 to 843.4). Of deficient relatives, 38% with no additional defect, 57% with 1 additional defect, and 81% with 2 or more additional defects had VTE at age 65 years compared with 5% of nondeficient relatives (P < 0.001). In deficient relatives with additional deficiencies or defects, exogenous risk factors increased the risk for VTE from 1.20% to 2.51% per year (relative risk, 2.1 [CI, 1.1 to 4.2]).
  
  
  CONCLUSIONS
  This was a retrospective study without the ability to distinguish interactions between specific thrombophilic deficiencies and defects.
  
  
  CONCLUSIONS
  Additional thrombophilic defects and exogenous risk factors increase the risk for VTE in persons with hereditary deficiencies of protein S, protein C, or antithrombin and provide evidence that multiple genetic and environmental risk factors contribute to VTE.
authors.affiliation: University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan-Leendert P
authors.initials: JL
authors.lastname: Brouwer
authors.forename: Nic J G M
authors.initials: NJ
authors.lastname: Veeger
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.forename: Jan
authors.initials: J
authors.lastname: van der Meer
mesh_terms: D000368:Aged; D000991:Antithrombins / Q000172:deficiency; D018572:Disease-Free Survival; D004777:Environment; D006801:Humans; D008875:Middle Aged; D020151:Protein C Deficiency / Q000150:complications; D018455:Protein S Deficiency / Q000150:complications; D012189:Retrospective Studies; D012307:Risk Factors; D013923:Thromboembolism / Q000209:etiology* / Q000235:genetics; D020246:Venous Thrombosis / Q000209:etiology* / Q000235:genetics
chemical_list: D000991:Antithrombins