15 - Platelet phospholipases A₂

Summary

Introduction

The major physiological role of platelets is in the cessation of bleeding following damage to the vasculature. Ordinarily, platelets circulate within intact blood vessels in a quiescent state, but undergo extremely rapid and powerful activation upon exposure to the subendothelial matrix leading to formation of a platelet aggregate or vascular plug. This rapid response is achieved by the stimulatory action of a range of diverse agonists including extracellular matrix proteins, e.g. collagen, and products of the coagulation cascade, e.g. thrombin. Activation is reinforced through release of agonists from platelet granules, notably ADP, and liberation of thromboxane A₂ (TxA₂), the major product of the metabolism of arachidonic acid (AA) in the platelet. The positive feedback action of ADP and TxA₂ is of direct clinical relevance. The Antiplatelet Trialists' Collaboration published a summary of 20 randomized trials in 1988, concluding that antiplatelet therapy significantly reduces (by ∼ 25%) the risk of cardiovascular death, non-fatal myocardial infarction and nonfatal stroke in patients with unstable angina or a past history of heart attack, transient ischemic attack, or stroke. A follow-up report by the same group, confirmed the efficacy of platelet inhibition in a broader spectrum of pathological conditions. More recently, the CAPRIE study has shown that the ADP receptor antagonist, clopidogrel, and aspirin have a similar therapeutic benefit in individuals with a history of thrombotic disease. Aspirin, however, remains the drug of choice in the majority of cases primarily for reasons of cost.