title: Comparison of the effect of different platelet GPIIb/IIa antagonists on the dynamics of platelet/fibrin-mediated clot strength induced using thromboelastography.
abstract: The effect of various platelet glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists on the dynamics of platelet-fibrin clot formation and strength induced by various stimuli was measured by thromboelastography (TEG). 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 tissue factor (TF), lipopolysaccharide (LPS), Factor Xa, and thrombin-induced clot strength, in contrast to antagonists that dissociate rapidly from GPIIb/IIIa (Class II antagonists). For example, the Class I antagonist XV459 (the free acid form of roxifiban) inhibited TF, endotoxin, Factor Xa, and thrombin-induced maximal clot strength and platelet aggregation with an IC(50)=30-70 nM, whereas the IC(50) of the Class II antagonist YZ211 (the free acid form of sibrafiban) for altering clot formation and strength was 0.3-4.7 microM. Moreover, the IC(50)'s of sibrafiban, and another Class II antagonist, orbofiban, for inhibiting platelet-fibrin clot formation and strength were substantially greater than their clinically achievable concentrations. Further, although aspirin treatment improved the efficacy of all GPIIb/IIIa antagonists, it did not alter the differences between Classes I and II antagonists. Thus, these data indicate that there are differences in the efficacy of various GPIIb/IIIa antagonists in inhibiting platelet-fibrin clot formation and strength. They also suggest that inhibiting platelet aggregation may not be the sole determinant for the in vivo efficacy of various GPIIb/IIIa antagonists.
authors.affiliation: Du Pont Pharmaceuticals Company, 141 & Henry Clay Road, Experimental Station, E400/3470, Wilmington, DE 19880-0400, USA. shakera.mousa@dupontpharma.com
authors.forename: S A
authors.initials: SA
authors.lastname: Mousa
authors.forename: M S
authors.initials: MS
authors.lastname: Forsythe
mesh_terms: D001696:Biomechanical Phenomena; D001777:Blood Coagulation / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000145:classification / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013916:Thrombelastography
chemical_list: D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex