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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

Rachel E. Simmonds, PhD; Helen Ireland, PhD; David A. Lane, PhD; Bengt Zoller, MD, PhD; Pablo Garcia de Frutos, PhD; and Bjorn Dahlback, MD, PhD
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From Imperial College School of Medicine at Charing Cross Hospital, London, United Kingdom; University Hospital, University of Lund, Lund, Sweden; and University of Lund, Malmo, Sweden. Acknowledgment: The authors thank Elizabeth Thompson for technical assistance. Grant Support: By a studentship and grants from the Special Trustees of Charing Cross Hospital and Medical School, the Swedish Medical Council (no. 07143), le Louis Jeantet Fondation de Medicine, the Osterlund Trust, the King Gustaf V and Queen Victoria Trust, the Albert Pahlsson Trust, the Johan and Greta Kock Trust, and the Goran Gustavsson Trust; research funds from University Hospital, Malmo, Sweden; and the Ann Lisa and Sven-Eric Lundgrens Trust for Medical Research, the Crafood Trust, Stiftelsen for blodsjukdomarsbekampande, Carin Trygger Trust (Swedish Medical Society), Carl-Bertil Laurell's Nordic Fund, and the Swedish Society for Medical Research. Requests for Reprints: Rachel E. Simmonds, PhD, Department of Haematology, Imperial College School of Medicine at Charing Cross Hospital, St. Dunstan's Road, Hammersmith, London W6 8RP, United Kingdom. Current Author Addresses: Drs. Simmonds, Ireland, and Lane: Department of Haematology, Imperial College School of Medicine at Charing Cross Hospital, St. Dunstan's Road, Hammersmith, London W6 8RP, United Kingdom.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1998;128(1):8-14. doi:10.7326/0003-4819-128-1-199801010-00002
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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.


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Figure 1.
Histogram of the current ages of the investigated persons in the study family.

The total number of persons in each age range is shown. Striped bars represent persons who carried the Gly295→Val mutation; white bars indicate persons who were normal at this site.

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Figure 3.
Phenotypic data, including total and free protein S antigen levels, in family members who did not receive anticoagulation and in an unrelated control group.

Dashed lines represent the lower limits of the normal ranges. Column A represents family members who lack the Gly295→Val mutation; column B represents family members with the Gly295→Val mutation; and column C represents an unrelated, normal control group. It is clear that measurement of free rather than total protein S antigen is fully predictive of the presence of the mutation that causes protein S deficiency.

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Figure 2.
Kaplan-Meier analysis of thrombosis-free survival showing the probability of remaining free of thrombosis at a certain age.asteriskP

The lower panel indicates the number of family members who remain at risk at 10-year intervals. Data for 78 family members who lacked the Gly295→Val mutation and 44 heterozygous Gly295→Val carriers ( ) are shown. The difference between the curves is statistically significant ( < 0.001). The probability that a carrier of the mutation would remain free of venous thrombosis at 30 years was 0.5 (95% CI, 0.33 to 0.66) compared with 0.97 (CI, 0.93 to 1.0) for normal family members. The curve for affected family members reaches zero because no tested family member with the Gly295→Val mutation older than 71 years of age remained free of thrombosis.

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