Patients who present with acute coronary syndromes, particularly ST-segment elevation myocardial infarction (STEMI), have abnormalities in platelet size and function that predispose to thrombotic events. Both preprocedural platelet reactivity and mean platelet volume are directly correlated with the occurrence of adverse ischemic events and impaired microvascular reperfusion following primary percutaneous coronary intervention (PCI) for STEMI. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial demonstrated a similar ischemic event rate to 30 days with a significantly lower bleeding event rate (enhanced net clinical benefit) in favor of bivalirudin monotherapy (with provisional platelet glycoprotein [GP] IIb/IIIa receptor blockade) in comparison with unfractionated heparin plus GP IIb/IIIa blockade in patients undergoing primary PCI for STEMI. The bivalirudin monotherapy was associated with a highly significant greater incidence of acute stent thrombosis. This observation provides the opportunity for strategies that enhance periprocedural platelet inhibition to reduce stent thrombosis and to potentially improve the safety and efficacy of periprocedural adjunctive pharmacotherapy above that achieved by bivalirudin monotherapy alone.