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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 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 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 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 Thrombosis and Hemostasis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant Laurent O. Mosnier1, Antonella Zampolli1, Edward J. Kerschen2, Reto A. Schuepbach3, Yajnavalka Banerjee1, José A. Fernández1, Xia V. Yang1, Matthias Riewald3, Hartmut Weiler2, Zaverio M. Ruggeri1, and John H. Griffin1 1 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; 2 Blood Research Institute, Milwaukee, WI; and 3 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 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 endothelial protein C receptor and protease-activated receptor-1. APC mutants with selectively altered and opposite activity profiles, that is, greatly reduced anticoagulant activity or greatly reduced cytoprotective activities, are compared here. 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 APC's 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 protease domain mutations 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's 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: E. Di Cera Know your APC Blood, June 4, 2009; 113(23): 5699 - 5700. [Full Text] [PDF]

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