Synergism Between Platelet Aggregating Agents: Possible Trigger Mechanisms During Hemostatic Plug And/Or Thrombus Formation

number of in-vitro studies have shown that various pair-combinations of aggregating agents such as ADP, epinephrine, collagen, thrombin, arachidonate and ionophore A 23187 can produce synergistic responses to induce platelet aggregation and release reactions. We have also produced synergistic effects by combining much lower doses of 3 or more aggregating agents and found markedly enhanced responses. It appears that the potential for synergistic effects is based both on the combination of the various agents and on the amount of each agent used for stimulation. Epinephrine is the most potent agent among them, although fibrinogen and Ca++ play a very important role. Indomethacin, ASA, PGE 1, and synthetic serine protease inhibitors (carboxylate and sulphonate analog) completely inhibit the platelet aggregation and release response. Of particular interest is the fact that addition of as little as 0.04% of the usual aggregating dose of epinephrine in the presence of 4% of collagen, 2% of thrombin and 10% of the normal plasma level of fibrinogen will initiate a marked response both of platelet aggregation and ATP release. This suggests a possible mechanism whereby acute insults such as stress or exercise, with release of epinephrine, can precipitate a thrombotic event in a patient who has normal or near-normal circulating levels of fibrinogen but who also has exposure of a very limited amount of the vascular endothelium (thereby exposing collagen). Since the effects of the acute insults of epinephrine secretion can be blocked by the presence of indomethacin, ASA, PGE 1 and specific serine protease inhibitors, prostaglandin synthesis must play a major role in this reaction.