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 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.


METHODS
Retrospective study of a single extended family.


METHODS
University hospital referral center.


METHODS
A 122-member protein S-deficient family, in which 44 members had a recently characterized gene defect.


METHODS
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 clinical affected family.
Simmonds
R E
RE
Imperial College School of Medicine, Charing Cross Hospital, London, United Kingdom.
Ireland
H
H
Lane
D A
DA
Zöller
B
B
García de Frutos
P
P
Dahlbäck
B
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D018455:Protein S Deficiency / Q000235:genetics*; D012044:Regression Analysis; D012307:Risk Factors; D013924:Thrombophlebitis / Q000209:etiology*