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Originally published In Press as doi:10.1074/jbc.C200237200 on June 17, 2002

J. Biol. Chem., Vol. 277, Issue 31, 27581-27584, August 2, 2002
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ACCELERATED PUBLICATION
The Thrombin Mutant W215A/E217A Shows Safe and Potent Anticoagulant and Antithrombotic Effects in Vivo*

Andras GruberDagger , Angelene M. Cantwell§, Enrico Di Cera§, and Stephen R. HansonDagger

From the Dagger  Department of Biomedical Engineering and Yerkes Regional Primate Research Center, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, Georgia 30322 and the § Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110

Administration of the thrombin mutant W215A/E217A (WE), rationally designed for selective activation of the anticoagulant protein C, elicits safe and potent anticoagulant and antithrombotic effects in a baboon model of platelet-dependent thrombosis. The lowest dose of WE tested (0.011 mg/kg bolus) reduced platelet thrombus accumulation by 80% and was at least as effective as the direct administration of 40-fold more (0.45 mg/kg bolus) activated protein C. WE-treated animals showed no detectable hemorrhage or organ failure. No procoagulant activity could be detected for up to 1 week in baboon plasma obtained following WE administration. These results show that engineered thrombin derivatives that selectively activate protein C may represent useful therapeutic agents for the treatment of thrombotic disorders.

* This work was supported by National Institutes of Health Grants HL49413 and HL58141 (to E. D. C.), HL31469 (to S. R. H.), and RR00165 (to the Yerkes Regional Primate Research Center) and by National Science Foundation Grant EEC-9731643 (to the Georgia Institute of Technology).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 314-362-4185; Fax: 314-747-5354; E-mail: enrico@biochem.wustl.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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