Platelet and vascular function during coronary thrombolysis with tissue-type plasminogen activator.

Abstract

Platelet activation may limit the response to tissue-type plasminogen activator (t-PA) during coronary thrombolysis in humans. As an index of platelet activation, we assessed thromboxane A2 biosynthesis during coronary thrombolysis with intravenous t-PA in patients with acute myocardial infarction. Urinary 2,3-dinor-thromboxane B2, a metabolite of thromboxane A2, was increased to a peak of 3,327+±511 pg/mg creatinine (n=12) following administration of intravenous t-PA and remained elevated for 48 hours. This increase was abolished by pretreatment with aspirin 325 mg orally (n=6), indicating de novo biosynthesis of thromboxane A2 rather than washout of preformed metabolites during reperfusion. Prostacyclin (PGI2) biosynthesis, determined by excretion of 2,3-dinor-6-keto-PGFia, also increased after t-PA administration. However, this increase was less pronounced in patients who reperfused (28+±3.3 ng.hr/mg creatinine) than in patients who failed to reperfuse (118+±30 ng-hr/mg creatinine, p<0.05). These data provide evidence of platelet activation during coronary thrombolysis with t-PA. In patients who reperfuse, the reduction in PGI2 biosynthesis may be a marker of reperfusion injury to the vasculature and may further amplify platelet activation. (Circulation 1989;80:1718-1725 P latelet activation plays a major role in limiting the response to tissue-type plasminogen activator (t-PA) in experimental models of coronary thrombosis.1-4 In particular, platelets delay reperfusion and induce reocclusion.1,4 Platelet activation is also increased in patients with acute myocardial infarction treated with intravenous streptokinase,5 and antiplatelet therapy enhances the response to streptokinase, accelerating reperfusion6 and further reducing mortality.7 However, streptokinase directly activates human platelets.5 In contrast, t-PA inhibits platelet function in vitro.8 Although t-PA has been reported to increase platelet aggregation ex vivo,9 this increase may reflect an

Dietary fish oil accelerates the response to coronary thrombolysis with tissue-type plasminogen activator. Evidence for a modest platelet inhibitory effect in vivo.

“…TxA biosynthesis increased during thrombosis with a further increase after reperfusion with rt-PA, which is consistent with previous observations in this animal model16 and in humans. 28 In the control group, excretion of the TxA2 metabolite increased from 2,229±302 to 4,422±798 pg/mg creatinine (p<0.002) during thrombosis and increased further to a maximum of 59,703±18,000 pg/mg creatinine (p<0.001) after administration of rt-PA ( Figure 5). Trace amounts of the TxA3 metabolite were evident in the control animals; these increased to low, but clearly detectable, levels during thrombolysis ( Figure 5).…”

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

“…4,[30][31][32] The clinically observed thrombi contain numerous platelets, and there is evidence that circulating platelets can be activated in the diseased arterial segment, causing increases in transmyocardial thromboxane concentrations.33-35 When the circulating platelets are activated but not enmeshed in the thrombus, they can form small intramyocardial aggregates, which Davies et a136 have described in patients with unstable angina who experienced sudden ischemic cardiac death. Additionally, there have been recent reports suggesting even greater platelet activation during the infusion of thrombolytic agents, that is, streptokinase and rt-PA. 37,38 Platelet aggregates interacting with a damaged endothelial surface or exposed subendothelial component are a major factor early in coronary artery thrombosis and subsequent rethrombosis. 39 The release of thromboxane and serotonin from the activated platelets is one mechanism proposed as a cause of reocclusion.…”

Streptokinase induces intravascular release of platelet-activating factor in patients with acute myocardial infarction and stimulates its synthesis by cultured human endothelial cells.

“…Group A consisted of 14 patients who were treated with SK (1.5 MU in 100 mL physiological saline infused intravenously over 60 minutes). Group B included 11 patients given a control infusion of 100 mL physiological saline over a period of 60 minutes who had the following contraindications to fibrinolytic therapy: 3 patients had very recent stroke, 1 (Table).…”