Introduction: Hereditary deficiencies of protein S, protein C or antithrombin are strong risk factors for venous thromboembolism (VTE). Whether these deficiencies are associated with arterial thromboembolism (ATE) and whether history of VTE in these subjects predisposes to subsequent ATE has yet to be determined.
Methods: Based on pedigree analysis we enrolled a total 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 VTE, ATE, anticoagulants use and atherosclerosis risk factors (i.e. diabetes, hypertension, hyperlipidemia, and smoking) were collected. In addition to the index deficiencies participants were also tested for other thrombophilic defects; including factor V Leiden, prothrombin G20210A, increased FVIII and lupus anticoagulants. Primary study outcome was objectively verified symptomatic ATE. As the assumption for proportional hazards for the final model was not met over the entire observation period, we opted for a piecewise Cox model with a cut off point set at 55 years of age.
Results: Of 552 subjects (mean age±SD, 46±17 years; 52% women), 308 had either protein S (35%), protein C (39%) or antithrombin deficiency (26%). Age, atherosclerosis risk factors and other thrombophilic defects were similar (P>0.23) between deficient and non-deficient subjects. A total of 44 arterial thromboembolic events had occurred, corresponding to an overall annual incidences of 0.34% (95% CI, 0.23–0.49) in deficient and 0.17% (0.09–0.28) in non-deficient subjects, hazard ratio 2.3 (1.2–4.5; P=0.01). However, the risk hazards varied over lifetime; while risk of ATE conferred by these deficiencies was 5.4 (1.6–18.4; P=0.006) before age 55 years, it was 1.3 (0.6–2.9; P=0.51) thereafter. After adjusting for atherosclerosis risk factors and clustering of ATE within families, deficient subjects had 4.7-fold (1.5–14.2; P=0.007) higher risk of ATE before age 55 years, versus 1.1 (0.5–2.6; P=0.84) thereafter, compared to non-deficient family members. For separate deficiencies these were 4.6 (1.1 – 18.3), 6.9 (2.1 – 22.2) and 1.1 (0.1 – 10.9) in protein S-, protein C- and antithrombin-deficient subjects, respectively, before age 55 years. History of VTE was not related to subsequent ATE, hazard ratio 1.1 (0.5 – 2.2).
Conclusions: Compared to non-deficient family members, subjects with protein S or protein C deficiencies but not antithrombin deficiency have an increased risk for ATE before age 55 years, independent of prior VTE. After age 55 years conventional atherosclerosis risk factors accounted for ATE. In thrombophilic families, deficiencies of protein S and protein C should be considered in atherothrombotic risk assessment before age 55 years.
Disclosures: No relevant conflicts of interest to declare.