1. Heparin Binds Plasma Proteins: Angiomax ® (Bivalirudin) Binds Specifically to Thrombin Heparin (long strand) binds to other plasma proteins (colored molecules) and platelets, reducing heparin’s availability to bind to AT. Heparin-binding proteins are elevated in acute coronary syndrome (ACS). Angiomax (bright blue) binds only to thrombin (orange). Angiomax is not neutralized by other plasma proteins or platelets; it remains fully active near thrombus. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Wittkowsky AK. Pharmacother. 2002;22(6 Pt 2):97S-104S.

2. Consequences of Nonspecific Binding Heparin is neutralized by platelet factor 4, (PF4), which is present in high concentrations near vascular injury. Thrombin continues activating platelets. PF4/heparin complex antibodies activate platelets, causing thrombocytopenia as well as heparin-induced thrombocytopenia thrombosis syndrome (HIT/TS). Angiomax ® (bivalirudin) does not bind to PF4, and remains fully active. There is no risk of HIT/TS or other thrombotic events associated with PF4/heparin antibodies. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Williams RT et al. Circulation. 2003;107:2307-2312.

3. Heparin Increases Platelet Activation Heparin makes platelets more reactive to activation by other agonists, such as adenosine diphosphate (ADP). Heparin binds to the platelet GP IIb/IIIa receptor. Given the various ways heparin increases platelet activation, its use may actually increase the need for antiplatelet agents. Becker R et al. J Invasive Cardiol. 2003;(suppl):1-15. Sobel M et al. J Vasc Surg. 2001;33:587-594. Xiao Z et al. Circulation. 1998;97:251-256.

4. Heparin Has a Direct Effect on Platelets Heparin increases platelet activation in unstable angina patients Reproduced with permission of Xiao Z et al. Circulation. 1998;97:253. P<0.001 Maximum Aggregation (%) ADP (0.3125 µM) TRAP (0.625 µM) 0 5 10 15 20 Pre-heparin Heparin TRAP=thrombin receptor agonist peptide.

5. 34% 38% 34% 42% 25 30 35 40 45 UFHAngiomax Percentage Angiomax ® (Bivalirudin) Significantly Decreases Platelet Reactivity Platelet reactivity in response to 1 μM ADP Fibrin binding P-selectin expression P<0.0001 P=0.01 Aggarwal A et al. J Thromb Thrombolysis. 2002;13:161-165.