Enhanced Protein C Activation and Inhibition of Fibrinogen Cleavage by a Thrombin Modulator

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Science  06 Sep 1996:
Vol. 273, Issue 5280, pp. 1389-1391
DOI: 10.1126/science.273.5280.1389


A modulator of the enzymatic activity of human thrombin, designated LY254603, was identified that enhances the thrombin-catalyzed generation of the anticoagulant factor activated protein C, yet inhibits thrombin-dependent fibrinogen clotting. By means of mutant substrates, it was shown that LY254603 mediates the change in enzymatic substrate specificity through an alteration in thrombin's S3 substrate recognition site, a mechanism that appeared to be independent of allosteric changes induced by either sodium ions or by thrombomodulin. This compound may represent the prototype of a class of agents that specifically modulates the balance between thrombin's procoagulant and anticoagulant functions.