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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, R E; Ireland, H; Lane, D A; Zöller, B LU ; García de Frutos, P and Dahlbäck, B LU (1998) In Annals of Internal Medicine 128(1). p.8-14
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,... (More)

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 clinical affected family.

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published
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keywords
Adolescent, Adult, Aged, Aged, 80 and over, Chi-Square Distribution, Child, Disease-Free Survival, Female, Heterozygote, Humans, Male, Middle Aged, Mutation, Phenotype, Protein S Deficiency, Regression Analysis, Risk Factors, Thrombophlebitis, Journal Article, Research Support, Non-U.S. Gov't
in
Annals of Internal Medicine
volume
128
issue
1
pages
7 pages
publisher
American College of Physicians
external identifiers
  • scopus:0031964419
ISSN
0003-4819
DOI
0.7326/0003-4819-128-1-199801010-00002
language
English
LU publication?
yes
id
b102906f-429e-4d2b-9c3d-09f1f12f9cc2
date added to LUP
2017-10-19 15:13:27
date last changed
2017-11-20 09:17:10
@article{b102906f-429e-4d2b-9c3d-09f1f12f9cc2,
  abstract     = {<p>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.</p><p>OBJECTIVE: To quantitate the risk for thrombosis associated with a characterized protein S gene mutation that causes a Gly295--&gt;Val substitution and protein S deficiency.</p><p>DESIGN: Retrospective study of a single extended family.</p><p>SETTING: University hospital referral center.</p><p>PARTICIPANTS: A 122-member protein S-deficient family, in which 44 members had a recently characterized gene defect.</p><p>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--&gt;Val substitution.</p><p>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--&gt;Val mutation compared with 0.97 (CI, 0.93 to 1.0) for normal family members (P &lt; 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 &lt; 0.001). For free (but not total) protein S antigen levels, the distributions of persons with and persons without the mutation did not overlap.</p><p>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.</p>},
  author       = {Simmonds, R E and Ireland, H and Lane, D A and Zöller, B and García de Frutos, P and Dahlbäck, B},
  issn         = {0003-4819},
  keyword      = {Adolescent,Adult,Aged,Aged, 80 and over,Chi-Square Distribution,Child,Disease-Free Survival,Female,Heterozygote,Humans,Male,Middle Aged,Mutation,Phenotype,Protein S Deficiency,Regression Analysis,Risk Factors,Thrombophlebitis,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {8--14},
  publisher    = {American College of Physicians},
  series       = {Annals of Internal Medicine},
  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},
  url          = {http://dx.doi.org/0.7326/0003-4819-128-1-199801010-00002},
  volume       = {128},
  year         = {1998},
}