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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 orcid ; 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
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
  • pmid:9424998
ISSN
0003-4819
DOI
10.7326/0003-4819-128-1-199801010-00002
language
English
LU publication?
yes
id
b102906f-429e-4d2b-9c3d-09f1f12f9cc2
date added to LUP
2017-10-19 15:13:27
date last changed
2025-10-14 10:00:45
@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}},
  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}},
  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/10.7326/0003-4819-128-1-199801010-00002}},
  doi          = {{10.7326/0003-4819-128-1-199801010-00002}},
  volume       = {{128}},
  year         = {{1998}},
}