© 2001 American Heart Association, Inc.
Thrombosis |
Comparative Antiplatelet Efficacy of a Novel, Nonpeptide GPIIb/IIIa Antagonist (XV454) and Abciximab (c7E3) in Flow Models of Thrombosis
From the Department of Chemical Engineering (J.P.A., N.T., O.J.T.M., D.P., K.K.), Johns Hopkins University, Baltimore, Md, and DuPont Pharmaceuticals Co (S.A.M.), Wilmington, Del.
Correspondence to Konstantinos Konstantopoulos, PhD, Department of Chemical Engineering, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218-2694. E-mail konst_k{at}jhu.edu
Abstract—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
70% receptor occupancy, which is lower than the 
85% previously
reported for abciximab. At similar levels of receptor blockade
(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.
Key Words: platelets • adhesion • aggregation • shear stress • XV454, abciximab
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