Bivalirudin, thrombin and platelets: clinical implications and future directions.
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Our current understanding of hemostasis and the roles of coagulation and platelets has evolved in recent years from the old "coagulation cascade" and "platelet pathway" models to an inter-related, cell-based model that more accurately represents in-vivo processes and better reflects clinical observations. The new model makes it apparent that thrombin is a key effector and modulator of hemostasis, and that activation of coagulation and platelets cannot be viewed as separate processes. Thrombin is a potent platelet agonist, and recent data indicate that thrombin may be the most critical activator of tissue-factor-induced thrombosis. Minute quantities of thrombin generated at the site of plaque disruption or arterial injury activates platelets and amplifies its own production, resulting in an explosive burst of thrombin production after clot formation. Thrombin-induced activation of platelets and other cells may contribute to inflammatory processes that are increasingly recognized as playing an important role in acute coronary syndromes (ACS) and coronary interventions. Along with a clearer understanding of the biology of thrombosis and hemostasis, better methods for studying the mechanisms of coagulation and platelet activation and the interaction of these processes in vivo have provided a new understanding of the method by which antithrombotic agents work. The physiological basis of thrombosis and hemostasis has important implications for treatment strategies in ACS, and for outcomes of percutaneous coronary interventions (PCI). With this increased understanding, the limitations of heparin and the advantages of the direct thrombin inhibitor bivalirudin (Angiomax, The Medicines Company) become apparent--providing a mechanistic rationale for the clinical benefit recently demonstrated in the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) PCI trial.
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