The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo |
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Authors: | Gruber Andras Cantwell Angelene M Di Cera Enrico Hanson Stephen R |
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Institution: | Department of Biomedical Engineering and Yerkes Regional Primate Research Center, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, Georgia 30322, USA. |
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Abstract: | 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. |
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