The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo

J Biol Chem. 2002 Aug 2;277(31):27581-4. doi: 10.1074/jbc.C200237200. Epub 2002 Jun 17.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Anticoagulants / pharmacology*
  • Antithrombins / pharmacology*
  • Blood Platelets / drug effects
  • Blood Platelets / physiology*
  • Fibrin / metabolism
  • Mutagenesis, Site-Directed
  • Papio
  • Protein C / metabolism*
  • Thrombin / pharmacology*


  • Anticoagulants
  • Antithrombins
  • Protein C
  • Fibrin
  • Thrombin