Rachel E. Simmonds, PhD; Helen Ireland, PhD; David A. Lane, PhD; Bengt Zoller, MD, PhD; Pablo Garcia de Frutos, PhD; Bjorn Dahlback, MD, PhD
Simmonds RE, Ireland H, Lane DA, Zoller B, de Frutos PG, Dahlback B. Clarification of the Risk for Venous Thrombosis Associated with Hereditary Protein S Deficiency by Investigation of a Large Kindred with a Characterized Gene Defect. Ann Intern Med. 1998;128:8-14. doi: 10.7326/0003-4819-128-1-199801010-00002
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Published: Ann Intern Med. 1998;128(1):8-14.
Protein S is an important regulatory protein of the coagulation cascade. The risk for venous thrombosis associated with protein S deficiency has been uncertain because all previous risk estimates used phenotypic evaluation alone, which can be ambiguous.
To quantitate the risk for thrombosis associated with a characterized protein S gene mutation that causes a Gly295→Val substitution and protein S deficiency.
Retrospective study of a single extended family.
University hospital referral center.
A 122-member protein S-deficient family, in which 44 members had a recently characterized gene defect.
Comprehensive history of thrombosis, history of exposure to acquired risk factors for thrombosis, levels of total and free protein S antigen, and genotype for the mutation causing the Gly295→Val substitution.
Kaplan-Meier analysis of thrombosis-free survival showed that the probability of remaining 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 antigen levels, the distributions of persons with and persons without the mutation did not overlap.
Protein S deficiency, as defined by the presence of a causative gene mutation or a reduced level of free protein S antigen, is a strong independent risk factor for venous thrombosis in a clinically affected family.
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Hematology/Oncology, Venous Thromboembolism, Coagulopathies.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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