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Blood, 1 March 2007, Vol. 109, No. 5, pp. 1984-1991. Prepublished online as a Blood First Edition Paper on October 17, 2006; DOI 10.1182/blood-2006-07-037945. This Article Full Text (PDF) All Versions of this Article: blood-2006-07-037945v1 109/5/1984    most recent Alert me when this article is cited Alert me if a correction is posted 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 Lay, A. J Articles by Castellino, F. J Search for Related Content PubMed PubMed Citation Articles by Lay, A. J Articles by Castellino, F. J Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 27, 2006 Accepted October 9, 2006 Acute inflammation is exacerbated in mice genetically predisposed to a severe Protein C deficiency Angelina J Lay, Deborah Donahue, Meng-Ju Tsai, and Francis J Castellino* University of Notre Dame * Corresponding author; email: fcastell{at}nd.edu. The anticoagulant, activated Protein C (aPC), possesses antithrombotic, profibrinolytic, antiinflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. While infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Since a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Here, we show for the first time, that novel genetic dosing of PC strongly correlates with survival outcomes following endotoxin (LPS) challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low-PC mice, but is greatly reduced in WT cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic endpoints following a severe acute inflammatory challenge. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Song, X. Ye, H. Xu, and S. F. Liu Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice Blood, September 17, 2009; 114(12): 2521 - 2529. [Abstract] [Full Text] [PDF] M. Schouten, W. J. Wiersinga, M. Levi, and T. van der Poll Inflammation, endothelium, and coagulation in sepsis J. Leukoc. Biol., March 1, 2008; 83(3): 536 - 545. [Abstract] [Full Text] [PDF] M. A. Kowalska, S. A. Mahmud, M. P. Lambert, M. Poncz, and A. Slungaard Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge Blood, September 15, 2007; 110(6): 1903 - 1905. [Abstract] [Full Text] [PDF]

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