The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo.
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.
Gruber
Andras
A
Department of Biomedical Engineering and Yerkes Regional Primate Research Center, Emory University School of Medicine and Georgia Institute of Technology, Atlanta, Georgia 30322, USA.
Cantwell
Angelene M
AM
Di Cera
Enrico
E
Hanson
Stephen R
SR
D019943:Amino Acid Substitution; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D005337:Fibrin / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010215:Papio; D011486:Protein C / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology*
D000925:Anticoagulants; D000991:Antithrombins; D011486:Protein C; D005337:Fibrin; D013917:Thrombin