title: Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age: results from a large family cohort study.
abstract: BACKGROUND
  Whether hereditary protein S, protein C, or antithrombin deficiency is associated with arterial thromboembolism (ATE) and whether history of venous thromboembolism in these subjects predisposes them to subsequent ATE have yet to be determined.
  
  
  RESULTS
  On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46+/-17 years), belonging to 84 different kindreds, in this retrospective family cohort study. Detailed information on previous episodes of venous thromboembolism, ATE, anticoagulant use, and atherosclerosis risk factors was collected. Primary study outcome was objectively verified symptomatic ATE. Of 552 subjects, 308 had protein S (35%), protein C (39%), or antithrombin (26%) deficiency. Overall, annual incidences of ATE were 0.34% (95% confidence interval [CI], 0.23 to 0.49) in deficient versus 0.17% (95% CI, 0.09 to 0.28) in nondeficient subjects; the hazard ratio was 2.3 (95% CI, 1.2 to 4.5). Because the risk hazards varied over lifetime, we performed a time-dependent analysis. After adjusting for atherosclerosis risk factors and clustering within families, we found that deficient subjects had a 4.7-fold (95% CI, 1.5 to 14.2; P=0.007) higher risk for ATE before 55 years of age versus 1.1 (95% CI, 0.5 to 2.6) thereafter compared with nondeficient family members. For separate deficiencies, the risks were 4.6- (95% CI, 1.1 to 18.3), 6.9- (95% CI, 2.1 to 22.2), and 1.1- (95% CI, 0.1 to 10.9) fold higher in protein S-, protein C-, and antithrombin-deficient subjects, respectively, before 55 years of age. History of venous thromboembolism was not related to subsequent ATE (hazard ratio, 1.1; 95% CI, 0.5 to 2.2).
  
  
  CONCLUSIONS
  Compared with nondeficient family members, subjects with protein S or protein C deficiency but not antithrombin deficiency have a higher risk for ATE before 55 years of age that is independent of prior venous thromboembolism.
authors.affiliation: Division of Hemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
authors.forename: Bakhtawar K
authors.initials: BK
authors.lastname: Mahmoodi
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: Jan
authors.initials: J
authors.lastname: van der Meer
mesh_terms: D000328:Adult; D017677:Age Distribution; D000991:Antithrombins / Q000235:genetics; D015331:Cohort Studies; D018572:Disease-Free Survival; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010375:Pedigree; D016016:Proportional Hazards Models; D011486:Protein C / Q000235:genetics*; D017293:Protein S / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D019851:Thrombophilia / Q000453:epidemiology / Q000235:genetics; D054556:Venous Thromboembolism / Q000453:epidemiology* / Q000235:genetics*
chemical_list: D000991:Antithrombins; D011486:Protein C; D017293:Protein S