CLARIFICATION OF THE RISK FOR VENOUS THROMBOSIS ASSOCIATED WITH HEREDITARY PROTEIN-S DEFICIENCY BY INVESTIGATION OF A LARGE KINDRED WITH A CHARACTERIZED GENE DEFECT

Background: Protein S is an important regulatory protein of the coagul ation cascade. The risk for venous thrombosis associated with protein S deficiency has been uncertain because all previous risk estimates us ed phenotypic evaluation alone, which can be ambiguous. Objective: To quantitate the risk for thrombosis associated with a characterized pro tein S gene mutation that causes a Gly295-->Val substitution and prote in S deficiency. Design: Retrospective study of a single extended fami ly. Setting: University hospital referral center. Participants: A 122- member protein S-deficient family, in which 44 members had a recently characterized gene defect. Measurements: Comprehensive history of thro mbosis, history of exposure to acquired risk factors for thrombosis, l evels of total and free protein S antigen, and genotype for the mutati on causing the Gly295-->Val substitution. Results: Kaplan-Meier analys is of thrombosis-free survival showed that the probability of remainin g free of thrombosis at 30 years of age is 0.5 (95% CI, 0.33 to 0.66) for carriers of the Gly295-->Val mutation compared with 0.97 (CI, 0.93 to 1.0) for normal family members (P < 0.001). In a multivariate Cox regression model that included smoking and obesity, the mutation was a strong independent risk factor for thrombosis (hazard ratio, 11.5 [CI , 4.33 to 30.6]; P < 0.001). For free (but not total) protein S antige n levels, the distributions of persons with and persons without the mu tation did not overlap. Conclusions: Protein S deficiency, as defined by the presence of a causative gene mutation or a reduced level of fre e protein S antigen; is a strong independent risk factor for venous th rombosis in a clinically affected family.