1. Antiplatelet Drugs - Principles Benedict R. Lucchesi, M.D., Ph.D. Department of Pharmacology University of Michigan Medical School

2. Collagen Tissue Factor Thrombin Platelet activation Prothrombin ADP TXA 2 Plasma Clotting cascade THROMBUS FibrinogenFibrin Platelet aggregation Thrombin is a critical mediator in coagulation Elicits multiple responses in platelets

3. Platelet Activation - Arterial Thrombus Formation Fibrinogen Platelet GPIIb/IIIa (Fibrinogen) Receptor Endothelial Cell - Injury Platelet 1 23 1=adhesion 2=activation & release 3=aggregation Release

5. Inhibitors of the Arachidonic Acid Pathway Cyclooxygenase Inhibitors Aspirin Ibuprofen Indomethacin Sulfinpyrazone Aspirin does impair the aggregation response to epinephrine, ADP or thrombin and does not affect subendothelial platelet adhesion.

6. Modifiers of Platelet Cyclic AMP Agents that increase cyclic AMP will inhibit platelet aggregation. Increases in cyclic AMP are achieved in two ways: stimulation of adenylate cyclase inhibition of phosphodiesterase Prostacyclin and Derivatives -Increases cAMP Therapeutic use limited by side effects Dipyridamole - PDE inhibitor Therapeutic efficacy is questionable

7. Nitrates Nitrates (nitroglycerin, isosorbide dinitrate, etc.) undergo conversion in the platelet to yield nitric oxide (NO). NO activated platelet guanylate cyclase (cGMP) resulting in an inhibition of platelet aggregation Nitrates may also increase synthesis of prostacyclin by the endothelial cells The full potential of nitrates as antiplatelet drugs is relatively unexplored.

8. Ticlopidine (Ticlid™) Clopidogrel (Plavix™) Prolongs bleeding time Inhibits platelet aggregation in response to ADP, but not to epinephrine, arachidonic acid, 5-HT, thrombin, etc. Antiplatelet effects develop slowly - 24 to 48 hours from initial dosing. Onset of action may be increased with large oral dose.

9. Antiplatelet Therapy in Patients with Ischemic Heart Disease Acetylsalicylic Acid (Aspirin) Ticlopidine (Ticlid™) Clopidogrel (Plavix™) Dipyridamole (Persantin™) Aspirin + Dipyridamole (Aggrenox™) Abciximab (7E3 Antibody; ReoPro™) Eptifibatide (Integrilin™) Tirofiban (Aggrestat™)

10. Ischemic Heart Disease and Platelet Function Patients with ischemic heart disease and abnormal coronary artery anatomy are at an increased risk for: – activation of circulating blood platelets – platelet vessel wall interactions – platelet adhesion and intravascular aggregation – episodic, transient interruptions in coronary artery blood flow - transient ischemic events – occlusive thrombus formation - prolonged regional myocardial ischemia - infarction.

11. Altered Platelet Function Mechanisms associated in arterial thrombus formation 1. exposure of the circulating blood to a thrombo- genic surface » injured endothelial surface and exposure of subendothelial structures - collagen » atheromatous lesions on vessel wall - leading to turbulent flow » rupture of the fibrous cap of the atheromatous lesion and exposure of lipids, collagen, thrombogenic contents.

12. Altered Platelet Function Mechanisms associated in arterial thrombus formation (continued) 2. A sequence of platelet related events, involving, » platelet adhesion » platelet aggregation » release of platelet components that promote further aggregation vasoconstriction activation of the coagulation cascade

13. Altered Platelet Function Mechanisms associated in arterial thrombus formation (continued) 3. Activation of the clotting mechanism with an important role for thrombin.... » formation of fibrin » stabilization of platelet aggregate/thrombus » activation of the platelet to enhance aggregation » activation of thrombomodulin/ProteinC/ inhibi- tion of fVIIIa and fVa

14. Altered Platelet Function Formation of an Arterial Thrombus Direction of blood flow White Head - Platelet Rich due to shear stress at site of injury and contact with subendothelial components Red Tail - RBC’s/Fibrin due to stasis beyond the point of occlusion