ABSTRACT
While much work in antithrombotic therapeutic approaches has focused on inhibition of thrombin, the central role that Factor Xa plays in the coagulation response to vascular injury also makes it an ideal pharmacological target for antithrombotic drug development. The recent report of the x-ray crystal structure of native Factor Xa allows, for the first time, a well-founded structure-based drug design approach for inhibitors. Thrombin generation is itself, however, the result of Factor Xa in complex with Factor Va on a phospholipid surface acting on prothrombin. Several small, potent, and naturally occurring Factor Xa inhibitors—tick anticoagulant protein, tissue factor pathway inhibitor, antistasin, Ecotin—have been isolated and characterized. In addition to ticks and leeches, other hematophagous organisms such as hook-worms have also evolved potent and selective Factor Xa inhibitors as anticoagulant strategies. Ecotin, a protein isolated from Escherichia coli, is a promiscuous protease inhibitor that potently inhibits kallikrein, urokinase, Factor XIIa, granzyme B, trypsin, chymotrypsin, and elastase.
