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 GpIII antagonists failed in achieving clinical benefits. This raises 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 GPIIb/IIIa (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 (IC50) = 70 n mol/l, whereas the IC50 of the class II antagonists such as the free acid forms of orbofiban sibrafiban, lotrafiban, integrilin or aggrastat ranged from 1 to 15 p mol/l. The IC(50)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.