Thoughts evoked by MATCH and other trials.

Abstract

Many different processes are involved in platelet activation. Most drugs affect one of these chemical reactions. Theoretically, platelet functions (secretion, aggregation, and adhesion) can be reduced most effectively by using >1 agent or by inhibiting the final step in the attachment of the platelet to fibrin at the level of the glycoprotein IIb/IIIa (GpIIb/IIIa) receptor. Preliminary experience with oral and intravenous GpIIb/IIIa inhibitors has shown that bleeding is an important problem. In MATCH, 2 platelet function inhibitors, clopidogrel and aspirin, did prevent slightly more strokes (but not with statistical significance) but at the price of significantly more excess bleeding. Killing platelets causes bleeding. Platelets seem to swim happily in the blood until they reach an area of irregular or damaged endothelium, for example, on the surface of an ulcerated atherosclerotic plaque in a large artery. They then stick to that irregular surface and to each other in an attempt to heal the vascular irregularity. The white platelet–fibrin thrombus can break loose and embolize. The platelet plug also activates the coagulation cascade, promoting the formation of a red erythrocyte–fibrin-rich clot. Perhaps rather than killing the platelet, it might be better to inhibit platelet attachment to the endothelium. Antiplatelet drugs might do this but have not been tested thoroughly for their effect on endothelial–platelet interaction. Theoretically, antiplatelet agents should work by inhibiting formation of white clots. These tend to form on irregular …