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Prepublished online as a Blood First Edition Paper on February 27, 2003; DOI 10.1182/blood-2002-10-3254. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-10-3254v1 101/12/4823    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 Levi, M. Articles by Carmeliet, P. Search for Related Content PubMed PubMed Citation Articles by Levi, M. Articles by Carmeliet, P. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4823-4827 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C–deficient mice Marcel Levi, Janine Dörffler-Melly, Pieter Reitsma, Harry Büller, Sandrine Florquin, Tom van der Poll, and Peter Carmeliet From the Departments of Vascular Medicine/Internal Medicine and Pathology and the Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, the Netherlands; the Division of Angiology, Inselspital Bern, Switzerland; and the Center for Transgene Technology and Gene Therapy, University of Leuven, Flanders Interuniversitary Institute for Biotechnology, Belgium. In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/–) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/–mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/– mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor- (TNF-), interleukin-6 (IL-6), and IL-1, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/– mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Niessen, C. Furlan-Freguia, J. A. Fernandez, L. O. Mosnier, F. J. Castellino, H. Weiler, H. Rosen, J. H. Griffin, and W. 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