Protease and cyclooxygenase inhibitors synergistically prevent activation of human platelets

Thrombin induces platelet aggregation and formation of a fibrin clot in platelet-rich plasma; leupeptin, a protease inhibitor, partially inhibits platelet aggregation, but it does not inhibit fibrin clot formation. Indomethacin does not inhibit either thrombin-induced platelet aggregation or fibrin clot formation. However, when the two drugs are given together, a synergistic inhibition of thrombin-induced platelet aggregation occurs, while fibrin clot formation remains unaffected. Thrombin-induced stimulation of the release of serotonin in washed human platelets is also synergistically inhibited by the combined actions of leupeptin and indomethacin. Thrombin and collagen, added simultaneously, induce full platelet aggregation and release of serotonin. Neither leupeptin nor indomethacin inhibits platelet responses elicited by both agonists; however, when leupeptin and indomethacin are given together, a synergistic inhibition of thrombin- and collagen-induced response is observed. These findings might be relevant in prophylaxis and treatment of thromboembolic disease.