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 is a platelet agonist; elicits multiple responses in platelets Thrombin Fibrinogen Thrombin begets thrombin Prothrombin Platelet aggregation Key Message: Thrombin promotes clotting. Thrombin drives the explosive burst of thrombin, formed mostly after the clot is seen. While the fibrin and platelet clot can be seen, there is no visual sign of the large amount of thrombin that is produced and active. Although much pharmacologic attention has been focused on the clot, specifically fibrin and platelet aggregation, until recently no good alternative for attenuating the thrombin (whether soluble or clot-bound) had been available. There are several phases to the formation of a clot: Amplification phase; thrombin activates more platelets that promote assembly of coagulation factors and formation of clotting factor complexes Propagation phase; assembled coagulation factor complexes on activated platelets produce large amounts of thrombin. Thrombin also converts fibrinogen to fibrin strands that hold the clot together. During this process, thrombin binds to fibrin, where it remains enzymatically active and capable of triggering local thrombus growth Regulating its own production via positive and negative feedback loops to further promote thrombin generation Stabilizing the fibrin clot through activation of factor XIII and inhibiting fibrinolytic pathways Thus, thrombin plays a crucial role in platelet activation and is the link between tissue injury and cellular response. Thrombin also elicits multiple responses in platelets, endothelial cells, and other cells. Because of the central role that thrombin plays, use of an effective thrombin-specific inhibitor is important in PCI. 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. Heparin (long strand) binds to AT, causing a shape change that increases the ability of AT to inhibit thrombin. Angiomax® (bivalirudin) inhibits thrombin directly with high affinity and specificity. Angiomax provides rapid, effective thrombin inhibition to prevent thrombosis and platelet effects. Key Message: Angiomax inhibits thrombin directly; therefore, it does not promote coagulation. On the left panel, heparin is not labeled but is represented by the long strand. Several “antithrombin” agents have been developed to prevent coagulation for many clinical circumstances. Heparin is a ubiquitous agent in the hospital and outpatient settings that is an imprecise and inefficient anticlotting agent. Indirect inhibition by heparin requires the presence of antithrombin (AT), the actual inhibitor in the clotting cascade. The panel on the left shows heparin (see the long strand) binding to AT and causing a shape change that increases the ability of AT to inhibit thrombin. Angiomax inhibits thrombin directly with high affinity and specificity. The panel on the right shows Angiomax binding to thrombin. Angiomax provides rapid, effective thrombin inhibition to prevent thrombosis and platelet effects. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284.

Angiomax® (Bivalirudin) Inhibits Clot-Bound Thrombin The heparin-AT complex is not effective against clot-bound thrombin. This reservoir of active thrombin continues to activate platelets and trigger further clotting. Angiomax, with a high affinity for thrombin, displaces thrombin from fibrin. Angiomax effectively inhibits clot-bound and circulating thrombin. Key Message: Angiomax inhibits both circulating and clot-bound thrombin, therefore limiting the explosive burst of thrombin generation. The heparin-AT complex is not effective against clot-bound thrombin. The left panel shows a reservoir of active thrombin that continues to activate platelets and trigger further clotting. The right panel shows that Angiomax, with a high affinity for thrombin, displaces thrombin from fibrin. It demonstrates that Angiomax effectively inhibits clot-bound and circulating thrombin. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284. 9

Heparin Fails to Effectively Inhibit Clot-Bound Thrombin Clinical levels of unfractionated heparin (UFH) inhibit only 20% to 60% of clot-bound thrombin 50 100 0.1 0.2 0.4 1.0 2.0 3.0 4.0 Soluble thrombin Clot-bound thrombin Inhibition (%) Key Message: Heparin, at therapeutic levels, fails to effectively inhibit clot-bound thrombin. Although heparin is the most widely used anticoagulant in PCI, it has many limitations resulting from its mechanism of action. This graph shows the relative ability of heparin to inhibit clot-bound thrombin at concentrations expected in the cath lab (about 1.0 U/mL). A heparin concentration of 0.4 U/mL corresponds approximately with a 5,000-unit bolus and a 1.0 U/mL concentration corresponds with a 10,000-unit bolus. Clot-bound thrombin is an important source of clot extension and propagation of thrombin production. Heparin is not able to effectively inhibit platelet-associated factor Xa as well. Heparin Concentration (Units/mL) Reproduced with permission of Weitz JI et al. J Clin Invest. 1990;86:388.

Angiomax® (Bivalirudin) Inhibits Clot-Bound and Circulating Thrombin Mean % inhibition of fibrinopeptide A production by Angiomax 87% 100% 96% 0% 20% 40% 60% 80% 0.5 M 1.0 M Key Message: Angiomax inhibits both circulating and clot-bound thrombin. Angiomax inhibits fibrinopeptide A – a marker of thrombin activity – for both soluble and clot-bound thrombin. Soluble Thrombin Clot-Bound Thrombin Data on file. The Medicines Company.