Systemic and transcardiac platelet activity in acute myocardial infarction in man: Resistance to prostacyclin

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore an understanding of factors that influence platelet performance is important. This study was undertaken (1) to characterize during evolving myocardial infarction platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and (2) to evaluate the effects of prostacyclin (PGI₂), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving myocardial infarction were studied. Twenty-two patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI₂, 13 ± 4.5 ng/kg/min (mean ± SD), for 90 min. In 15 patients with anterior myocardial infarction, transcardiac platelet function and response to PGI₂ were studied. Plasma levels of β-thromboglobulin (β-TG) and of thromboxane B₂ (TxB₂), in vivo measures of platelet activity, were elevated three- and 10-fold. 6-Keto-prostaglandin F(1α), the stable end product of PGI₂, was less than 10 pg/ml, reflecting a leftward shift of the TxB₂/PGI₂ ratio. Platelets circulating during evolving myocardial infarction ('ischemic platelets') were hyperaggregable in response to ADP and relatively resistant to PGI₂, both in vivo and in vitro. Concentrations of platelet cyclic AMP and the cyclic AMP response to PGI₂ were diminished. The platelet hyperreactivity, expressed by plasma β-TG, platelet aggregation, and PGI₂-induced inhibition of aggregation, was most intense early during infarct evolution and decreased with time. The increased platelet performance resulted in 'platelet fatigue', indicated by decreased contents of β-TG of the ischemic platelet and decreased TxA₂ production in response to collagen. However, the ischemic platelet produced twice normal TxA₂ in response to arachidonic acid (stimulus and substrate), demonstrating a heightened metabolic capacity. TxA₂ was produced across the ischemic/infarcting compartment in 10 of 15 patients with anterior myocardial infarction. The antiplatelet effect of PGI₂ was greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving myocardial infarction, characterized by a proaggregatory environment, heightened platelet reactivity in both the peripheral and coronary circulation, and relative resistance to PGI₂. The clinical consequences of the data are that the patient in the acute phase of myocardial infarction may benefit from suspension of platelet function and requires significantly greater doses of PGI₂ than normal subjects. The data also suggest future directions for therapeutic manipulation of platelet hyperreactivity in the setting of acute myocardial ischemia.