fibrin and roxifiban

The effect of platelet glycoprotein IIb/IIIa antagonists on the dynamics of platelet/fibrin clot formation and strength was determined using thrombelastography (TEG) under conditions of recalcification or tissue factor addition. In the present investigation, the effect of roxifiban (class I) on ex vivo clot dynamics using recalcified blood was tested in normal, healthy volunteers (n = 7) dosed with 1 mg BID roxifiban for 9 days. Roxifiban inhibited platelet aggregation induced by 20 mumol/l adenosine diphosphate by 60-90% but did not significantly affect any of the TEG parameters either at peak, trough, or subtrough drug levels. Addition of 30 nmol/l roxifiban free acid (XV459; which is ineffective by itself to modify TEG parameters) to human blood obtained from roxifiban-treated subjects resulted in 45-60% (P < 0.01) inhibition of clot strength (maximum amplitude), 90-100% (P < 0.01) inhibition of initial kinetic of clot development (angle alpha), and 50-70% (P < 0.01) inhibition of early clot initiation (K). These data suggest that a subthreshold blood level of 40-50 nmol/l roxifiban active form was achieved in those subjects, as estimated from an in vitro calibration with XV459. These data indicate (not studied) that roxifiban, at a targeted clinical dosing regimen, failed to achieve sufficient exposure to modulate platelet-mediated clot retraction.

Topics: Amidines; Aspirin; Blood Coagulation; Calcium Chloride; Cross-Over Studies; Fibrin; Humans; Isoxazoles; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reference Values; Thrombelastography

In the present study, the in vitro efficacy of different platelet glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists on platelet-fibrin-mediated clot strength under shear was compared with the antiaggregatory efficacy by using tissue factor (TF) thromboelastography (TEG). The ability of platelets to augment the elastic properties of blood clots under shear conditions was measured by computerized TEG under conditions of maximal platelet activation accelerated by recombinant TF. Under these conditions, platelets significantly enhance clot strength 8-fold (relative to platelet-free fibrin clots). This effect was inhibited to a different extent by various platelet GPIIb/IIIa receptor antagonists; this inhibition appears to be dependent on the transmission of platelet contractile force to fibrin via the GPIIb/IIIa receptors. The GPIIb/IIIa antagonists with high binding affinity for resting and activated platelets and slow platelet dissociation rates (class I) but not those with fast platelet dissociation rates (class II) demonstrated potent and comparable inhibition of platelet aggregation and TF-TEG clot strength. Platelet GPIIb/IIIa antagonists of class I, such as XV459 (free-acid form of roxifiban), DMP802, XV454, and c7E3, demonstrated comparable inhibitory dose responses of TF-TEG clot strength and platelet aggregation, with an IC(50) of 50 to 70 nmol/L. In contrast, platelet GPIIb/IIIa antagonists from class II, with comparable antiaggregatory efficacy, such as DMP728, YZ202 (free-acid form of orbofiban), YZ211 (free-acid form of sibrafiban), YZ751, and other antagonists, have a much lower efficacy in altering the strength of TF-mediated clot formation (IC(50) >1.0 micromol/L). These data suggest differential efficacy among different GPIIb/IIIa antagonists in inhibiting platelet-fibrin clot retraction despite of equivalent antiaggregatory potency.

Topics: Abciximab; Alanine; Amidines; Antibodies, Monoclonal; Blood Coagulation; Blood Platelets; Elasticity; Fibrin; Humans; Immunoglobulin Fab Fragments; Isoxazoles; Nephelometry and Turbidimetry; Oxazoles; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Recombinant Proteins; Sulfonamides; Thrombelastography; Thromboplastin; Viscosity