Pharmacology of the interaction between platelets and vessel wall.

Abstract

The evaluation of agents inhibiting platelet function is difficult because, in addition to primary aggregation by thrombin, there are three amplification loops involving respectively arachidonate, ADP and PAF-acether (platelet activating factor). Each amplification loop seems eventually to act via a common pathway: the mobilization of calcium ions from the dense tubular system into the cytoplasm. Inhibition of this mobilization would prevent platelet aggregation by any agonist. This could be an ideal step with which to intervene pharmacologically. An intracellular increase in cAMP reduces cytoplasm calcium levels and therefore counteracts the effect of whatever agonist is used (Vermylen et al, 1982, 1983; Verstraete et al, 1985). Depending on the pro-aggregatory stimulus, the relative importance of a given pathway of platelet activation may shift. There is also uncertainty about which pathway of platelet activation predominates in a given clinical condition. The second problem relates to the pharmacology of the ideal drug for the inhibition of platelet function. It is very difficult to delineate the desired profile of such a drug considering the properties of the various compounds presently being studied (see Table 1). Prolongation of a shortened platelet survival in man was considered to be one of the key markers of an anti-aggregatory agent; this characteristic was found to be present after administration of sulphinpyrazone, clofibrate, ticlopidine, suloctidil, dipyridamole (in patients with artificial heart valves) and dipyridamole (in patients with venous thrombosis). The protective antithrombotic effect is most clearly demonstrated for aspirin; it is rather surprising that this drug does not prolong the shortened platelet survival in man, not even in those clinical conditions in which it effectively prevents thromboembolism.