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. 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 micromol/l. The IC50s 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.
Albany College of Pharmacy, Albany, NY, USA. mousas@acp.edu
Shaker A
SA
Mousa
Mark S
MS
Forsythe
Jeffrey M
JM
Bozarth
D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D005337:Fibrin / Q000187:drug effects; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013916:Thrombelastography
D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D005337:Fibrin