The clinical response to thrombolytic therapy in patients with acute myocardial infarction is limited by the failure to reperfuse the occluded vessel, severe residual stenosis and early reocclusion. Even when vessel patency is achieved, myocardial injury may continue because of impaired tissue perfusion and tissue damage induced specifically by reperfusion. This project examines the role of platelets in limiting the response to coronary thrombolysis and the mechanisms of platelet activation following administration of thrombolytic therapy. In preliminary studies we have demonstrated a massive increase in the formation of thromboxane (Tx) A2, the major cyclooxygenase product of arachidonic acid in platelets, following administration of streptokinase in patients with acute myocardial infarction. This suggests that marked platelet activation occurs during coronary thrombolysis. Two possible mechanisms of platelet activation following thrombolytic therapy were identified. Firstly, streptokinase was found to activate platelets directly by a mechanism dependent on its lytic activity. Secondly, reperfusion in a chronic canine model of coronary thrombosis was followed by cycles of gradual reocclusion and abrupt reperfusion which were platelet dependent. This in man, was associated with increased formation of prostacyclin, a potent platelet inhibitor, suggesting a role for these eicosanoids in modulating platelet activity in this setting. In these studies we propose to examine mechanisms and site of platelet activation during coronary thrombolysis in man. In addition, we will evaluate the role of platelets in limiting coronary reperfusion and myocardial salvage induced by thrombolytic agents in vivo. Finally, we will examine the role of eicosanoids in modulating platelet activation during coronary thrombolysis.
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