Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age

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. Methods and Results-On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46Ϯ17 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; Pϭ0.007) 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. (Circulation. 2008;118:1659-1667.)

Impact of Incident Venous Thromboembolism on Risk of Arterial Thrombotic Diseases

“…Concordantly, some inherited thrombophilias have also been associated with arterial thrombosis. 32,33 Furthermore, several risk factors for VTE, including high levels of coagulation factors VIII, IX, and XI, plasminogen activator inhibitor-1, and von Willebrand factor, have been reported as risk factors for arterial cardiovascular disease. 34,35 It is also possible that the observed association is not explained by common risk factors but is restricted to the events themselves or treatment thereof.…”

Genetic characterization of antithrombin, protein C and protein S deficiencies in Polish patients

“…2,3,7 Evidence linking natural anticoagulant deficiencies with arterial thromboembolism, mostly ischemic stroke, is conflicting and largely derived from case reports. 2,8,9 AT is the main endogenous anticoagulant serpin (serine -protease inhibitor) that primarily inactivates thrombin and activated factor (F) X. The gene encoding AT (SERPINC1) is located on chromosome 1q25.1 and consists of 7 exons and 6 introns spanning 13,574 bp (ENSG00 000 117 601).…”

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game

“…In addition to isolated case reports (37)(38)(39), a large cohort of relatives of VTE patients with PC, PS or ATIII deficiency (ns468) had a higher incidence of arterial thrombosis compared to subjects who were not deficient. The risk of arterial thrombosis was especially high in individuals -55 years of age; adjusted hazard ratios for PC and PS deficiencies were 6.9 (95% CI, 2.1-22.2) and 4.6 (95% CI, 1.1-18.3), respectively (40). In the ARIC cohort which enrolled more than 13,000 patients with coronary events or ischemic stroke, and had a follow-up time of almost 17 years, low PC concentrations were associated with the development of stroke (41).…”

“…The mature protein contains a Gla-domain (amino acids 1-37) with the nine glutamic acid residues that are carboxylated during posttranslational maturation. A short amphipathic helix (amino acids [38][39][40][41][42][43][44][45] connects the Gla-domain to the first epidermal growth factor (EGF) domain (amino acids . The second EGF domain (amino acids 92-136) is followed by the activation peptide domain (amino acids 137-184).…”