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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5970-5978. Prepublished online as a Blood First Edition Paper on February 24, 2009; DOI 10.1182/blood-2008-10-183327. This Article Full Text (PDF) Supplemental Table and Figure All Versions of this Article: blood-2008-10-183327v1 113/23/5970    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 Mosnier, L. O. Articles by Griffin, J. H. Search for Related Content PubMed PubMed Citation Articles by Mosnier, L. O. Articles by Griffin, J. H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 8, 2008 Accepted February 6, 2009 Hyper-antithrombotic, non-cytoprotective Glu149Ala-activated protein C mutant Laurent O. Mosnier, Antonella Zampolli, Edward J. Kerschen, Reto A. Schuepbach, Yajnavalka Banerjee, Jose A. Fernandez, Xia V. Yang, Matthias Riewald, Hartmut Weiler, Zaverio M. Ruggeri, and John H. Griffin* Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States Blood Research Institute, Milwaukee, WI, United States Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, United States * Corresponding author; email: jgriffin{at}scripps.edu. Activated protein C (APC) reduces mortality in severe sepsis patients. APC exerts anticoagulant activities via inactivation of factors Va and VIIIa and cytoprotective activities via EPCR and PAR-1. APC mutants with selectively altered and opposite activity profiles, i.e., greatly reduced anticoagulant activity or greatly reduced cytoprotective activities, are here compared. Glu149Ala-APC exhibited enhanced in vitro anticoagulant and in vivo antithrombotic activity but greatly diminished in vitro cytoprotective effects and in vivo reduction of endotoxin-induced murine mortality. Thus, residue Glu149 and the C-terminal region of the APC light chain are identified as functionally important for expression of multiple APC activities. In contrast to Glu149Ala-APC, 5A-APC (Lys191-193Ala+Arg229/230Ala) with 5 mutations in APC's protease domain lacked in vivo antithrombotic activity, although it was potent in reducing endotoxin-induced mortality, as previously shown. These data imply that APC molecular species with potent antithrombotic activity but without robust cytoprotective activity are not sufficient to reduce mortality in endotoxemia, emphasizing the need for APC's cytoprotective actions, but not anticoagulant actions, to reduce endotoxin-induced mortality. Protein engineering can provide APC mutants that permit definitive mechanism of action studies for APC multiple activities and may also provide safer and more effective second generation APC mutants with reduced bleeding risk. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Know your APC Enrico Di Cera Blood 2009 113: 5699-5700. [Full Text] [PDF] This article has been cited by other articles: J. A. Fernandez, M. J. Heeb, X. Xu, I. Singh, B. V. Zlokovic, and J. H. Griffin Species-specific anticoagulant and mitogenic activities of murine protein S Haematologica, December 1, 2009; 94(12): 1721 - 1731. [Abstract] [Full Text] [PDF] E. Di Cera Know your APC Blood, June 4, 2009; 113(23): 5699 - 5700. [Full Text] [PDF]

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