Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction.

Abstract

We assessed thromboxane biosynthesis as an index of platelet activation in 6 patients with acute myocardial infarction receiving intravenous streptokinase. Urinary 2,3-dinor-thromboxane B2 and plasma 1 1-dehydro-thromboxane B2, major enzymatic metabolites of thromboxane A2, were markedly increased after intravenous streptokinase (11,063 ± 2758 pg/mg creatinine and 33 ± 10 pg/ml, respectively) compared with levels in patients not receiving thrombolytic therapy (502 ± 89 pg/mg creatinine and 3 0.7 pg/ml). Prostacyclin biosynthesis also increased markedly after streptokinase coincident with the increase in thromboxane A2 formation. Administration of aspirin between the time of onset of coronary thrombosis and reperfusion both in man and in a canine preparation demonstrated that this reflected thromboxane biosynthesis de novo and not metabolism of preformed inactive thromboxane B2 washed out from the coronary circulation. Since the platelet is the major source of thromboxane A2, these findings suggest that there is marked platelet activation after coronary thrombolysis with streptokinase. Studies in vitro demonstrated that streptokinase enhanced platelet activation in a dose-dependent manner, resulting in the secondary release of thromboxane A2. The increase in platelet activation and thromboxane A2 biosynthesis may limit the therapeutic effect of intravenous streptokinase in acute myocardial infarction.

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

“…TXA 2 is in large part derived from platelets, and increased TXA 2 formation is a marker of platelet activity. 44,45 Therefore, we saw no evidence that the reduction in PGI 2 enhanced platelet activity in vivo. Indeed, given its expression in proliferating VSMCs, it is possible that the COX-2 activity contributes to the progression of atherosclerosis.…”

Increased Formation of Distinct F 2 Isoprostanes in Hypercholesterolemia

“…Given that immunoassays are currently available only for iPF 2␣ -III, 38 this observation is relevant to clinical investigation. This is especially so because COX activation may coincide with oxidant stress in clinical settings such as ischemiareperfusion syndromes 39 and in cigarette smoking. 40 Recently, Davi et al 41 reported that urinary levels of immunoreactive iPF 2␣ -III are elevated in hypercholesterolemia.…”

“…Attempts to establish the efficacy of aspirin through clinical trials in cardiovascular disease were frustrated for more than a decade because populations were diluted with respect to likely benefit from the drug. 42 The development of methods to estimate thromboxane biosynthesis using urinary metabolites not only aided in the selection of low doses of aspirin for cardiovascular indications 42 but also identified unstable angina 43 and therapeutic thrombolysis 44 as biochemically rational targets for aspirin therapy, a contention borne out by the results of randomized clinical trials. 45,46 Clinical trials of antioxidants have been performed in the past without a clear in vivo biochemical rationale, either for the choice of clinical targets or for the selection of antioxidant doses of such compounds.…”

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.…”