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Papers In Press, published online ahead of print June 17, 2002
Dept. of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110
Corresponding Author: enrico{at}biochem.wustl.edu
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 one 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.
J. Biol. Chem, 10.1074/jbc.C200237200
Submitted on April 16, 2002
Revised on June 14, 2002
Accepted on June 14, 2002
The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo
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