NEW APPROACHES TO THE PREVENTION OF THROMBOTIC RESTENOSIS AFTER ANGIOPLASTY OR THROMBOLYSIS

Percutaneous transluminal coronary angioplasty (PTCA) and early coronary thrombolysis are now widely used to treat selected patients with atherosclerotic coronary artery disease and acute myocardial infarction, respectively. However. the efficacy of these procedures may be limited by the occurrence of thrombotic complications. Restenosis of the dilated vessel, which occurs in about 30% of the patients, is considered the Achilles' heel of PTCA. Experimental and clinical data suggest that restenosis after PTCA may be mediated by platelet attachment at the site of balloon dilation, with a consequent release of platelet-derived mitogen factors able to stimulate intimal hyperplasia. Similarly, a thrombotic reocclusion of the infarct-related coronary artery may significantly reduce the potential benefits of early thrombolysis. This reocclusion occurs in up to 30-35% of the patients successfully reperfused after suspension of the thrombolytic agent, despite the concomitant use of heparin. Increasing evidence indicates that intracoronary platelet activation and aggregation play a major role in the pathophysiology of reocclusion. First, it has been demonstrated that a marked increase in thromboxane A2 production occurs at the moment of reperfusion in patients with acute myocardial infarction undergoing successful thrombolysis. Second, in experimental models of coronary thrombosis, reocclusion after thrombolysis can be prevented or markedly delayed by antiplatelet interventions, such as administration of a monoclonal antibody against the platelet glycoprotein (GP) IIb and IIIa-the putative fibrinogen receptor on platelet membrane whose exposure seems to be an obligatory step for platelet aggregation to occur. Furthermore. our group has demonstrated that thromboxane A2 and serotonin, released during platelet activation, cooperatively mediate reocclusion, as simultaneous administration of a thromboxane A2 and a serotonin receptor antagonist prevents or markedly delays the occurrence of reocclusion in a canine model of coronary thrombosis. This combination of drug is also able to significantly shorten the time to thrombolysis. The initial promising results of PTCA and thrombolytic therapy have greatly altered the care of patients with coronary artery disease and acute myocardial infarction. However, despite the substantial progress made during the past few years, a number of unresolved issues still exists. Specifically, much more effort needs to be made with regard to reducing the incidence of restenosis after PTCA, shortening the interval between onset of ischemia and achievement of reperfusion and prevention of reocclusion after thrombolysis.