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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1740-1744. Prepublished online as a Blood First Edition Paper on June 3, 2004; DOI 10.1182/blood-2004-01-0110. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-01-0110v1 104/6/1740    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 Hemostasis, Thrombosis, and Vascular Biology Apoptosis Signal Transduction Gene Expression Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Activated protein C variants with normal cytoprotective but reduced anticoagulant activity Laurent O. Mosnier, Andrew J. Gale, Subramanian Yegneswaran, and John H. Griffin From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA. Recombinant activated protein C (APC), a well-defined anticoagulant enzyme, reduced mortality in severe sepsis patients in a phase 3 trial. However, 2 potent anticoagulants, antithrombin III and recombinant tissue factor pathway inhibitor, failed to do so, implying the physiologic relevance of APC's less well-defined anti-inflammatory and antiapoptotic activities. Recombinant APC therapy conveys an increased risk of serious bleeding complications due to APC anticoagulant activity. To generate recombinant APC variants with reduced risk of bleeding due to reduced anticoagulant activity, we dissected APC's anticoagulant activity from its cytoprotective activity by site-directed mutagenesis. Using staurosporine-induced endothelial cell apoptosis assays, we show here that Ala mutations (RR229/230AA and KKK191_ 193AAA) in 2 APC surface loops that severely reduce anticoagulant activity result in 2 APC variants that retain normal antiapoptotic activity that requires protease activated receptor-1 and endothelial cell protein C receptor. Thus, it is possible to reduce anticoagulant activity while preserving antiapoptotic activity of recombinant APC variants. We suggest that therapeutic use of such APC variants may reduce serious bleeding risks while providing the beneficial effects of APC acting directly on cells. (Blood. 2004;104: 1740-1744) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: APC stripped bare Roger J. S. Preston and David A. Lane Blood 2004 104: 1595-1596. [Full Text] [PDF] This article has been cited by other articles: L. O. Mosnier, A. Zampolli, E. J. Kerschen, R. A. Schuepbach, Y. Banerjee, J. A. Fernandez, X. V. Yang, M. Riewald, H. Weiler, Z. M. Ruggeri, et al. Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant Blood, June 4, 2009; 113(23): 5970 - 5978. [Abstract] [Full Text] [PDF] Y. Wang, M. Thiyagarajan, N. Chow, I. Singh, H. Guo, T. P. Davis, and B. V. Zlokovic Differential Neuroprotection and Risk for Bleeding From Activated Protein C With Varying Degrees of Anticoagulant Activity Stroke, May 1, 2009; 40(5): 1864 - 1869. [Abstract] [Full Text] [PDF] R. J. S. Preston, S. Tran, J. A. Johnson, F. N. Ainle, S. Harmon, B. White, O. P. Smith, P. V. Jenkins, B. Dahlback, and J. S. 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O'Donnell Dissociation of Activated Protein C Functions by Elimination of Protein S Cofactor Enhancement J. Biol. Chem., November 7, 2008; 283(45): 30531 - 30539. [Abstract] [Full Text] [PDF] L. O. Mosnier, X. V. Yang, and J. H. Griffin Activated Protein C Mutant with Minimal Anticoagulant Activity, Normal Cytoprotective Activity, and Preservation of Thrombin Activable Fibrinolysis Inhibitor-dependent Cytoprotective Functions J. Biol. Chem., November 9, 2007; 282(45): 33022 - 33033. [Abstract] [Full Text] [PDF] 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] L. Yang, J.-S. Bae, C. Manithody, and A. R. Rezaie Identification of a Specific Exosite on Activated Protein C for Interaction with Protease-activated Receptor 1 J. Biol. 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