Polypharmacologic interactions in the management of thrombosis.

Pathologic evidence indicates that thrombosis in coronary arteries is most frequently initiated by fissures in atheromatous plaques and that the associated hemorrhage induces platelet aggregation. Less frequently, thrombosis may be initiated by arterial spasm or by pathologic abnormalities affecting the platelets or the mechanisms of plasma coagulation. For the rational development of antithrombotic drugs on the basis of aggregation inhibitors, the cause (or causes) of plaque fissure and of the ensuing platelet aggregation need therefore to be elucidated. Our current research is based on the working hypothesis that fissuring occurs when plaques have acquired a particular composition that can be disrupted by the cumulative effect of continuously varying hemodynamic forces (reminiscent of fatigue failure in artificial materials), and that fissure-associated hemorrhage, like hemorrhage anywhere else, initiates platelet aggregation via a concurrence of hemodynamic and biochemical mechanisms. Detailed studies are currently being directed toward establishing the sequence of events that determine the contributions of adenosine diphosphate, thromboxane A2, and other endogenous agents in promoting hemostatic platelet aggregation in real life and, by implication, arterial thrombosis. Important recent evidence has demonstrated repeated thrombosis in unstable angina patients. In such patients, aspirin diminishes by about half the incidence of myocardial infarction and death. Presumably, it prevents the formation of platelet thrombi, which would tend to be produced in the turbulent blood flowing through arterial segments severely narrowed by hemorrhage plaques or in spasm. Several other platelet-active drugs are also under investigation.