Article    Table of Contents                    Full Text of this article Free    Figures/Tables List  Services    Send comment/rapid response letter    Notify a friend about this article    Alert me when this article is cited    Add to Personal Archive    Download to Citation Manager    ACP Search                            Get Permissions  Google Scholar    Search for Related Content  PubMed Articles in PubMed by Author:    Simmonds, R. E.    Dahlback, B.    Related Articles in PubMed    PubMed Citation    PubMed

ARTICLE

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

1 January 1998 | Volume 128 Issue 1 | Pages 8-14

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 Gly295Val 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 Gly295Val 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 Gly295Val 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.

Author and Article Information

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.

This article has been cited by other articles:

				B. Dahlback Advances in understanding pathogenic mechanisms of thrombophilic disorders Blood, July 1, 2008; 112(1): 19 - 27. [Abstract] [Full Text] [PDF]

				B. Hurtado, X. Munoz, M. C. Mulero, G. Navarro, P. Domenech, P. Garcia de Frutos, M. Perez-Riba, and N. Sala Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency Haematologica, April 1, 2008; 93(4): 574 - 580. [Abstract] [Full Text] [PDF]

				R. Sitruk-Ware, G. Plu-Bureau, J. Menard, J. Conard, S. Kumar, J.-C. Thalabard, B. Tokay, and P. Bouchard Effects of Oral and Transvaginal Ethinyl Estradiol on Hemostatic Factors and Hepatic Proteins in a Randomized, Crossover Study J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2074 - 2079. [Abstract] [Full Text] [PDF]

				F. Saller, B. O. Villoutreix, A. Amelot, T. Kaabache, B. F. Le Bonniec, M. Aiach, S. Gandrille, and D. Borgel The {gamma}-carboxyglutamic acid domain of anticoagulant protein S is involved in activated protein C cofactor activity, independently of phospholipid binding Blood, January 1, 2005; 105(1): 122 - 130. [Abstract] [Full Text] [PDF]

				S. M. Rezende, R. E. Simmonds, and D. A. Lane Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex Blood, February 15, 2004; 103(4): 1192 - 1201. [Abstract] [Full Text] [PDF]

				S. R Deitcher and M. P. Gomes Hypercoagulable state testing and malignancy screening following venous thromboembolic events Vascular Medicine, February 1, 2003; 8(1): 33 - 46. [Abstract] [PDF]

				A. Tripodi and P. M. Mannucci Laboratory Investigation of Thrombophilia Clin. Chem., September 1, 2001; 47(9): 1597 - 1606. [Abstract] [Full Text] [PDF]

				T. K. Giri, T. Yamazaki, N. Sala, B. Dahlback, and P. G. de Frutos Deficient APC-cofactor activity of protein S Heerlen in degradation of factor Va Leiden: a possible mechanism of synergism between thrombophilic risk factors Blood, July 15, 2000; 96(2): 523 - 531. [Abstract] [Full Text] [PDF]

				M. Makris, M. Leach, N. J. Beauchamp, M. E. Daly, P. C. Cooper, K. K. Hampton, P. Bayliss, I. R. Peake, G. J. Miller, and F. E. Preston Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S Blood, March 15, 2000; 95(6): 1935 - 1941. [Abstract] [Full Text] [PDF]

				Y. Espinosa-Parrilla, T. Yamazaki, N. Sala, B. Dahlback, and P. G. de Frutos Protein S secretion differences of missense mutants account for phenotypic heterogeneity Blood, January 1, 2000; 95(1): 173 - 179. [Abstract] [Full Text] [PDF]

				E.M. Faioni, F. Franchi, P. Bucciarelli, M. Margaglione, V. De Stefano, G. Castaman, G. Finazzi, and P.M. Mannucci Coinheritance of the HR2 Haplotype in the Factor V Gene Confers an Increased Risk of Venous Thromboembolism to Carriers of Factor V R506Q (Factor V Leiden) Blood, November 1, 1999; 94(9): 3062 - 3066. [Abstract] [Full Text] [PDF]

				A. A. Zimmerman, R. S. Watson, and J. K. Williams Protein S Deficiency Presenting as an Acute Postoperative Arterial Thrombosis in a Four-Year-Old Child Anesth. Analg., March 1, 1999; 88(3): 535 - 535. [Full Text] [PDF]

				T. Li, C.-T. Yang, D. Jin, and D. W. Stafford Identification of a Drosophila Vitamin K-dependent gamma -Glutamyl Carboxylase J. Biol. Chem., June 9, 2000; 275(24): 18291 - 18296. [Abstract] [Full Text] [PDF]