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Chapter 6. Thrombin and Factor Xa Inhibition

1996; Elsevier BV; Linguagem: Inglês

10.1016/s0065-7743(08)60445-5

1557-8437

Jeremy J. Edmunds, Stephen T. Rapundalo,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

Publisher Summary This chapter discusses the recent studies on experimental and clinical pharmacology of thrombin and factor Xa inhibitors. Several recent studies have utilized defined biochemical systems, particularly plasma, to characterize the mechanism of action profiles for a variety of anti-thrombin agents. Following the promising anti-thrombotic efficacy, afforded by the direct thrombin inhibitors hirudin and hirulog, recent attention has focused on the design of low molecular weight thrombin active site inhibitors. These inhibitors address the limitations of previous anti-thrombotics, including bleeding propensity, serine protease selectivity, lack of significant oral bioavailability, and inability to inhibit clot-bound thrombin. An alternative anti-thrombotic strategy has also emerged in the form of inhibitors of factor Xa, the penultimate serine protease in the blood coagulation cascade. The factor Xa inhibitors known to date can be classified into three types— namely, endogenous inhibitors that are present in the blood including anti-thrombin III (ATIII) and tissue factor pathway inhibitor (TFPI), inhibitors isolated from the salivary glands of blood sucking insects and animals, and rational drug designed inhibitors comprising of peptides and nonpeptides. This enzyme, as a part of a prothrombinase complex composed of nonenzymatic co-factor Va, calcium ions, and a phospholipid membrane surface regulates the generation of thrombin from its zymogen prothrombin. Polypeptide factor Xa inhibitors have demonstrated that specific inhibition of factor Xa is a valid anti-thrombotic strategy, and hence low molecular weight agents that selectively inhibit factor Xa or clot-bound factor Xa are currently being developed. Factor Xa inhibitors offer the attractive potential to suppress thrombin generation, while, as competitive inhibitors, allowing some platelet aggregation. This translates to a reduced bleeding tendency and presents an exciting area for drug development.