Antithrombin Therapy in the Management of ACS C. Michael Gibson, MS, MD Director, TIMI Data Coordinating Center Interventional Cardiologist & Chief of Clinical Research, Beth Israel Deaconess Medical Center Associate Professor of Medicine, Harvard Medical School
Thrombin Promotes Clotting • Thrombin is the link between tissue injury, coagulation, and platelet response Platelet activation Thrombin is a critical mediator in hemostasis and thrombosis Thrombin Fibrinogen Thrombin begets thrombin Thrombin is a platelet agonist; elicits multiple responses in platelets Prothrombin Platelet aggregation Plasma clotting factors Fibrin Coughlin SR. Nature. 2000; 407: 258 -264. Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002; 22: 1381 -1389.
Indirect vs Direct Thrombin Inhibition Indirect inhibition by heparin requires the presence of antithrombin (AT), the actual inhibitor. Angiomax® (bivalirudin) inhibits thrombin directly with high affinity and specificity. Heparin (long strand) binds to AT, causing a shape change that increases the ability of AT to inhibit thrombin. Angiomax provides rapid, effective thrombin inhibition to prevent thrombosis and platelet effects. Hirsh J et al. Chest. 2001; 119(1 suppl): 64 S-94 S. Weitz JI et al. Thromb Res. 2002; 106: V 275 -V 284.
Angiomax® (Bivalirudin) Inhibits Clot-Bound Thrombin The heparin-AT complex is not effective against clot-bound thrombin. Angiomax, with a high affinity for thrombin, displaces thrombin from fibrin. This reservoir of active thrombin continues to activate platelets and trigger further clotting. Angiomax effectively inhibits clotbound and circulating thrombin. Hirsh J et al. Chest. 2001; 119(1 suppl): 64 S-94 S. Weitz JI et al. Thromb Res. 2002; 106: V 275 -V 284. 9
Heparin Fails to Effectively Inhibit Clot-Bound Thrombin • Clinical levels of unfractionated heparin (UFH) inhibit only 20% to 60% of clot-bound thrombin Soluble thrombin Clot-bound thrombin Inhibition (%) 100 50 0 0. 1 0. 2 0. 4 1. 0 2. 0 Heparin Concentration (Units/m. L) Reproduced with permission of Weitz JI et al. J Clin Invest. 1990; 86: 388. 3. 0 4. 0
Angiomax® (Bivalirudin) Inhibits Clot-Bound and Circulating Thrombin Mean % inhibition of fibrinopeptide A production by Angiomax 100% 96% 100% 87% 0. 5 M 80% 1. 0 M 60% 40% 20% 0% Soluble Thrombin Data on file. The Medicines Company. Clot-Bound Thrombin
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