Variability of platelet aggregate dispersal with glycoprotein IIb-IIIa antagonists eptifibatide and abciximab.

Abstract

Utilization of glycoprotein IIb-IIIa (GPIIb-IIIa) inhibitors improves outcomes of patients with acute coronary syndromes (ACS), including those undergoing percutaneous coronary intervention (PCI). These results may be related to the ability of the inhibitors to destabilize coronary thrombi, reduce microembolization, and restore vessel patency. To evaluate in vitro the ability of GPIIb-IIIa antagonists, abciximab and eptifibatide, to promote the disaggregation of platelet-rich thrombus. Antagonist-induced disaggregation was assayed in plasma by aggregometry, as well as in whole blood by point of care and capillary perfusion systems. Fibrinogen dissociation from the platelet surface was quantified by flow cytometry. Significant disaggregation of 5 microm ADP-induced aggregates was observed after addition of either agent. The maximum extent and rate of disaggregation were significantly higher with eptifibatide than with abciximab. Both antagonists also dispersed 2 microg mL(-1) collagen-induced aggregates, again with eptifibatide having a greater effect. Eptifibatide, but not abciximab (up to 10 microg mL(-1)), was efficient at dissociating aggregates to single platelets in whole blood and dispersing aggregates that had been aged for 30 min before treatment. Eptifibatide also reduced existing thrombus burden in the perfusion model under arterial flow conditions. A key mechanism of aggregate dispersal was antagonist-induced displacement of platelet-bound fibrinogen, which was greater with eptifibatide, a competitive inhibitor of fibrinogen binding, than with the noncompetitive inhibitor, abciximab. These results suggest that drug concentration and residence time, along with thrombus extent and age, may be critical determinants in promoting timely recanalization.