Steven Coutre

Publication Details

  • CONVERSION OF THROMBIN INTO AN ANTICOAGULANT BY PROTEIN ENGINEERING NATURE Gibbs, C. S., Coutre, S. E., Tsiang, M., Li, W. X., Jain, A. K., Dunn, K. E., Law, V. S., Mao, C. T., MATSUMURA, S. Y., MEJZA, S. J., Paborsky, L. R., Leung, L. L. 1995; 378 (6555): 413-416

    Abstract:

    At sites of vascular injury, thrombin interacts with multiple procoagulant substrates, to mediate both fibrin clotting and platelet aggregation. But upon binding to thrombomodulin on the vascular endothelium, thrombin instead activates protein C, thereby functioning as an anticoagulant and attenuating clot formation. Upon infusion in vivo, both the procoagulant and anticoagulant effects of thrombin were observed. Preliminary studies indicating that thrombin's protein C activating and fibrinogen clotting activities could be dissociated by mutagenesis suggested to us that a thrombin variant that lacked procoagulant activity while retaining anticoagulant function might be an attractive antithrombotic agent. Using protein engineering, we introduced a single substitution, E229A, that substantially shifted thrombin's specificity in favour of the anticoagulant substrate, protein C. In monkeys, this modified thrombin functioned as an endogenous protein C activator demonstrating dose-dependent, reversible anticoagulation without any indication of procoagulant activity. Notably, template bleeding times were not prolonged, suggesting a reduced potential for bleeding complications.

    View details for Web of Science ID A1995TF89300066

    View details for PubMedID 7477382

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