This Article Full Text Full Text (PDF) All Versions of this Article: 118/16/1659    most recent CIRCULATIONAHA.108.780759v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahmoodi, B. K. Articles by van der Meer, J. Search for Related Content PubMed PubMed Citation Articles by Mahmoodi, B. K. Articles by van der Meer, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Genetics Home Reference Related Collections Risk Factors Arterial thrombosis Coagulation Thrombophilia Thrombosis risk factors Related Article

(Circulation. 2008;118:1659-1667.)
© 2008 American Heart Association, Inc.

Vascular Medicine

Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age

Results From a Large Family Cohort Study

Bakhtawar K. Mahmoodi, BSc; Jan-Leendert P. Brouwer, MD; Nic J.G.M. Veeger, MSc; Jan van der Meer, MD, PhD

From the Division of Hemostasis, Thrombosis and Rheology, Department of Hematology (B.K.M., J.-L.P.B., N.J.G.M.V., J.v.d.M.), and Trial Coordination Center, Department of Epidemiology (N.J.G.M.V.), University Medical Center Groningen, Groningen, the Netherlands.

Reprint requests to Jan van der Meer, Division of Hemostasis, Thrombosis and Rheology, Department of Hematology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. E-mail j.van.der.meer{at}int.umcg.nl

Received March 18, 2008; accepted August 5, 2008.

Background— Whether hereditary protein S, protein C, or antithrombin deficiency is associated with arterial thromboembolism (ATE) and whether history of venous thromboembolism in these subjects predisposes them to subsequent ATE have yet to be determined.

Methods and Results— On the basis of pedigree analysis, we enrolled a total of 552 subjects (52% women; mean age, 46±17 years), belonging to 84 different kindreds, in this retrospective family cohort study. Detailed information on previous episodes of venous thromboembolism, ATE, anticoagulant use, and atherosclerosis risk factors was collected. Primary study outcome was objectively verified symptomatic ATE. Of 552 subjects, 308 had protein S (35%), protein C (39%), or antithrombin (26%) deficiency. Overall, annual incidences of ATE were 0.34% (95% confidence interval [CI], 0.23 to 0.49) in deficient versus 0.17% (95% CI, 0.09 to 0.28) in nondeficient subjects; the hazard ratio was 2.3 (95% CI, 1.2 to 4.5). Because the risk hazards varied over lifetime, we performed a time-dependent analysis. After adjusting for atherosclerosis risk factors and clustering within families, we found that deficient subjects had a 4.7-fold (95% CI, 1.5 to 14.2; P=0.007) higher risk for ATE before 55 years of age versus 1.1 (95% CI, 0.5 to 2.6) thereafter compared with nondeficient family members. For separate deficiencies, the risks were 4.6- (95% CI, 1.1 to 18.3), 6.9- (95% CI, 2.1 to 22.2), and 1.1- (95% CI, 0.1 to 10.9) fold higher in protein S–, protein C–, and antithrombin-deficient subjects, respectively, before 55 years of age. History of venous thromboembolism was not related to subsequent ATE (hazard ratio, 1.1; 95% CI, 0.5 to 2.2).

Conclusions— Compared with nondeficient family members, subjects with protein S or protein C deficiency but not antithrombin deficiency have a higher risk for ATE before 55 years of age that is independent of prior venous thromboembolism.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 118: 1605-1606. [Extract] [Full Text]

This article has been cited by other articles:

				B. K. Mahmoodi, R. T. Gansevoort, and H. C. Kluin-Nelemans Antiphospholipid Syndrome, Microalbuminuria, and Risk of Venous Thromboembolism--Reply JAMA, September 2, 2009; 302(9): 945 - 946. [Full Text] [PDF]

				M. J. Heeb, D. Prashun, J. H. Griffin, and B. N. Bouma Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor FASEB J, July 1, 2009; 23(7): 2244 - 2253. [Abstract] [Full Text] [PDF]