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Cardiovascular Research 2000 45(2):437-446; doi:10.1016/S0008-6363(99)00253-9
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Paradoxical inhibition of fibrinogen binding and potentiation of {alpha}-granule release by specific types of inhibitors of glycoprotein IIb–IIIa

David J Schneider*, Douglas J Taatjes and Burton E Sobel

Departments of Medicine and Pathology, The University of Vermont, Burlington, Colchester, VT 05446, USA

* Corresponding author. Tel.: +1-802-656-3734; fax: +1-802-656-8969 djschnei{at}zoo.uvm.edu

Objective: To determine whether glycoprotein (GP) IIb–IIIa inhibitors can paradoxically augment activation of platelets, activation of GP IIb–IIIa, {alpha}-granule degranulation, and lysosome release were induced after exposure of platelets to GP IIb–IIIa inhibitors. Methods: ADP-induced platelet activation was assessed after exposure of platelets to Abciximab, or to a non-peptide ligand, the free acid of Orbofiban (Orbofibana). Activation of GP IIb–IIIa was detected based on binding of fluorochrome labeled fibrinogen or a labeled monoclonal antibody, PAC-1. {alpha}-Granule degranulation was detected based on surface expression of P-selectin and lysosome release was detected based on surface expression of CD63. Results: Despite significant inter-individual variability in inhibition of fibrinogen binding in response to each of the GP IIb–IIIa inhibitors used, a concentration dependent decrease in fibrinogen binding was seen with each agent in samples from each subject. Binding of PAC-1 was inhibited in a parallel manner. Abciximab increased ADP-induced P-selectin expression. Orbofibana did not alter ADP-induced P-selectin expression. Neither agent altered ADP-induced CD63 expression. When platelets were exposed to Abciximab and Orbofibana, both Abciximab and Orbofibana were found in the {alpha}-granules (by confocal microscopy), consistent with potentiation of agonist-induced release of {alpha}-granular products associated with uptake of proteins. Conclusions: Specific types of GP IIb–IIIa inhibitors can paradoxically augment agonist-induced release of {alpha}-granules despite inhibiting agonist-induced fibrinogen binding.

KEYWORDS Atherosclerosis; Blood flow; Platelets; Receptors; Thrombosis/embolism


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