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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1003-1009. Prepublished online as a Blood First Edition Paper on October 5, 2006; DOI 10.1182/blood-2006-06-032086. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-06-032086v1 109/3/1003    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zheng, X. Articles by Esmon, C. T. Search for Related Content PubMed PubMed Citation Articles by Zheng, X. Articles by Esmon, C. T. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Effects of membrane and soluble EPCR on the hemostatic balance and endotoxemia in mice Xunzhen Zheng1, Weihong Li1, Jian-Ming Gu3, Dongfeng Qu1, Gary L. Ferrell2, Naomi L. Esmon1,4, and Charles T. Esmon1,2,4,5 1 Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 2 the Howard Hughes Medical Institute, Oklahoma City, OK; 3 Berlex Biosciences, Richmond, CA; 4 Departments of Pathology and 5 Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK Recent studies have shown that endothelial protein C receptor (EPCR) polymorphisms and soluble EPCR levels are associated with thrombotic diseases. It is unknown whether membrane EPCR (mEPCR) heterozygosity and/or physiologically elevated sEPCR levels directly impact the hemostatic balance and the outcome of endotoxemia. In these studies, thrombin infusion experiments revealed that EPCR heterozygosity (Procr+/–) impaired protein C activation by approximately 30%. Infusion of factor Xa with phospholipid demonstrated that the Procr+/–genotype increased the coagulant response relative to wild-type mice. Challenge of the Procr+/– mice with lipopolysaccharide (LPS) did not significantly exaggerate their response compared with wild-type mice. We also generated mice in which one allele of full-length EPCR was replaced by sEPCR (Procrs/+). Compared with Procr+/– mice, Procrs/+ mice had 5-fold higher sEPCR and similar mEPCR levels. Procr+/– and Procrs/+ mice generated similar levels of activated protein C (APC) upon thrombin infusion. They also exhibited a similar coagulant response upon factor Xa/phospholipid infusion. Only supraphysiologic levels of sEPCR could influence protein C activation and exaggerate the coagulant response. In conclusion, mEPCR, but not physiologically elevated sEPCR, regulated protein C activation. Procr heterozygosity results in a mild increase of thrombosis tendency and little influence on the response to endotoxin. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. J. Kerschen, J. A. Fernandez, B. C. Cooley, X. V. Yang, R. Sood, L. O. Mosnier, F. J. Castellino, N. Mackman, J. H. Griffin, and H. Weiler Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C J. Exp. Med., October 1, 2007; 204(10): 2439 - 2448. [Abstract] [Full Text] [PDF]

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