Heparin Binds Plasma Proteins: AngiomaxHeparin Binds Plasma Proteins: Angiomax®® (Bivalirudin) (Bivalirudin) Binds Binds SpecificallySpecifically to Thrombin to Thrombin

Heparin Binds Plasma Proteins: AngiomaxHeparin Binds Plasma Proteins: Angiomax®® (Bivalirudin) (Bivalirudin) Binds Binds SpecificallySpecifically to Thrombin 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 onlyto 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.

Consequences of Nonspecific BindingConsequences of Nonspecific BindingConsequences of Nonspecific BindingConsequences 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.Weitz JI et al. Thromb Res. 2002;106:V275-V284.Williams RT et al. Circulation. 2003;107:2307-2312.

Heparin Increases Platelet ActivationHeparin Increases Platelet ActivationHeparin Increases Platelet ActivationHeparin 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.

Heparin Has a Direct Effect on PlateletsHeparin Has a Direct Effect on PlateletsHeparin Has a Direct Effect on PlateletsHeparin 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 P<0.001

Max

imu

m A

gg

reg

atio

n (

%)

ADP (0.3125 µM) TRAP (0.625 µM)0

5

10

15

20

Pre-heparin

Heparin

TRAP=thrombin receptor agonist peptide.

34%

38%

34%

42%

25

30

35

40

45

UFH Angiomax

Per

cen

tag

e

AngiomaxAngiomax®® (Bivalirudin) Significantly (Bivalirudin) Significantly Decreases Platelet ReactivityDecreases Platelet Reactivity

AngiomaxAngiomax®® (Bivalirudin) Significantly (Bivalirudin) Significantly Decreases Platelet ReactivityDecreases 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.