INDUCTION OF FIBRINOGEN BINDING AND PLATELET-AGGREGATION AS A POTENTIAL INTRINSIC PROPERTY OF VARIOUS GLYCOPROTEIN IIB IIIA (ALPHA(IIB)BETA(3)) INHIBITORS/
K. Peter et al., INDUCTION OF FIBRINOGEN BINDING AND PLATELET-AGGREGATION AS A POTENTIAL INTRINSIC PROPERTY OF VARIOUS GLYCOPROTEIN IIB IIIA (ALPHA(IIB)BETA(3)) INHIBITORS/, Blood, 92(9), 1998, pp. 3240-3249
The blockade of platelet integrin glycoprotein (GP) IIb/IIIa is a prom
ising new antiplatelet strategy. The binding of ligands or of the liga
nd-mimetic peptide RGD causes a conformational change of GP IIb/IIIa f
rom the nonactivated to the activated state. Because several blocking
agents/inhibitors are ligand-mimetics, the current study evaluates whe
ther these agents have the intrinsic property to activate GP IIb/IIIa.
Fibrinogen binding to GP IIb/IIIa on platelets or on CHO cells expres
sing recombinant GP IIb/IIIa was evaluated by flow cytometry or I-125-
labeled fibrinogen. Incubation with the monoclonal antibody (MoAb) fra
gment c7E3 (abciximab) results in fibrinogen binding to GP IIb/IIIa an
d in the access of ligand-induced binding sites.,At low concentrations
(0.01 to 0.1 mu g/mL), this intrinsic activating property of c7E3 can
result in platelet aggregation. The disintegrin flavorodin and the RG
D analogue fradafiban also induce fibrinogen binding, whereas the bloc
king MoAbs 2G12 and P2 and the activation-specific MoAb PAC-1 do not.
Aspirin and indomethacin cannot block c7E3-induced fibrinogen binding
to GP IIb/IIIa, but can inhibit c7E3-induced platelet aggregation. Thu
s, we conclude that GP IIb/IIIa inhibitors can demonstrate an intrinsi
c activating property, which can result in fibrinogen binding to GP II
b/IIIa and consequently in platelet aggregation. Cyclooxygenase inhibi
tors can inhibit platelet aggregation caused by GP IIb/IIIa inhibitors
, Further studies will have to evaluate the clinical relevance of the
potential intrinsic activating property of GP IIb/IIIa inhibitors and
define consequences for the future drug development and evaluation of
these potent antiplatelet agents. (C) 1998 by The American Society of
Hematology.