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Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect

Simmonds, RE; Ireland, H; Lane, DA; Zoller, B; de Frutos, PG; Dahlback, B; (1998) 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 , 128 (1) 8 - +.

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Abstract

Background: 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.Objective: To quantitate the risk for thrombosis associated with a characterized protein S gene mutation that causes a Gly295-->Val substitution and protein S deficiency.Design: Retrospective study of a single extended family.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 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.Results: 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.Conclusions: 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.

Type:Article
Title:Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect
Keywords:protein S deficiency, thrombophlebitis, heterozygote, mutation, hereditary diseases, C4B-BINDING PROTEIN, C DEFICIENCY, PLASMA-LEVELS, FACTOR-X, THROMBOPHILIA, ORGANIZATION, COMPLEX, DISEASE, OUTPATIENTS, RESISTANCE
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science

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