Glycoprotein (
GP) IIb/IIIa is pivotal in homotypic platelet aggregation and may also be involved in the heterotypic adhesion of leukocytes and
tumor cells to platelets. This study was primarily undertaken to compare the antiplatelet efficacy of a novel, nonpeptide GPIIb/IIIa antagonist,
XV454, to that of
abciximab in 2 flow models of platelet
thrombus formation: (1) direct shear-induced platelet aggregation imposed by a cone-and-plate rheometer and (2) platelet adhesion onto
von Willebrand factor (vWF)/
collagen I followed by aggregation in a perfusion system.
XV454 inhibited platelet aggregation in a concentration-dependent manner in both experimental models. Maximal inhibition of aggregation was achieved by
XV454 at approximately 70% receptor occupancy, which is lower than the >/=85% previously reported for
abciximab. At similar levels of receptor blockade (approximately 45%),
XV454 appeared to be relatively more effective than
abciximab in suppressing platelet aggregation. Neither
XV454 nor
abciximab inhibited platelet adhesion to
collagen. Pretreatment of surface-adherent platelets with either
XV454 or
abciximab inhibited the attachment of monocytic THP-1 cells under flow. In contrast, the rapidly reversible GPIIb/IIIa inhibitor
orbofiban failed to suppress these heterotypic interactions. These findings demonstrate that
XV454 is a potent GPIIb/IIIa antagonist with a long receptor-bound lifetime like
abciximab and may be beneficial for the treatment/prevention of thrombotic complications.