INDUCTION OF FIBRINOGEN BINDING AND PLATELET-AGGREGATION AS A POTENTIAL INTRINSIC PROPERTY OF VARIOUS GLYCOPROTEIN IIB IIIA (ALPHA(IIB)BETA(3)) INHIBITORS/

Citation
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
Citations number
39
Categorie Soggetti
Hematology
Journal title
BloodACNP
ISSN journal
00064971
Volume
92
Issue
9
Year of publication
1998
Pages
3240 - 3249
Database
ISI
SICI code
0006-4971(1998)92:9<3240:IOFBAP>2.0.ZU;2-E
Abstract
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.