Differential efficacy of different platelet glycoprotein IIb/IIIa antagonists on platelet/fibrin-mediated clot dynamics under different conditions using thrombelastography: the critical need for anticoagulant.

Background Intravenous GpIIb/IIIa antagonists demonstrate various significant clinical benefits depending on the agent used. In contrast, oral delivery of GpIIb/IIIa antagonists failed in achieving clinical benefits. Thisraises the question about the differences among different GpII/IIIa antagonists. Methods The effect of various platelet glycoprotein (GP) IIb/IIIa antagonists on the dynamics of platelet/fibrin clot formation and strength was determined using thrombelastography under different conditions. Results GPIIb/IIIa antagonists with high affinity for resting and activated platelets and with slow rates of dissociation from GPIIb/IIIa (Class I antagonists) demonstrated potent and comparable inhibition of platelet aggregation and platelet-mediated clot strength under different conditions. In contrast to antagonists that dissociate rapidly from GPllb/llla (class II antagonists). Class I antagonists such as the free acid form of roxifiban inhibited platelet-mediated clot strength, with the inhibiting concentration required for 50% effect (IC 5 0 ) = 70 n mol/l, whereas the IC 5 0 of the class II antagonists such as the free acid forms of orbofiban, sibrafiban, lotrafiban, integrilin or aggrastat ranged from 1 to 15 μ mol/l. The IC 5 0 s for class II antagonists in inhibiting platelet/fibrin clot formation and strength were substantially greater (10-15 fold) than their clinically achievable concentrations. The limited efficacy for class II antagonists in inhibiting platelet-mediated clot dynamics was enhanced by the combination with heparin. Conclusions Thus, these data indicated that there are differences in the efficacy of various GPIIb/IIIa antagonists in inhibiting platelet/fibrin clot formation and strength, which might be corrected by heparin. Data also suggest that inhibition of platelet aggregation may not be the sole determinant for the in-vivo efficacy of various GPIIb/IIIa antagonists.