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

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Abstract
Objective: To determine whether glycoprotein (GP) IIb–IIIa inhibitors can paradoxically augment activation of platelets, activation of GP IIb–IIIa, α-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. α-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 α-granules (by confocal microscopy), consistent with potentiation of agonist-induced release of α-granular products associated with uptake of proteins. Conclusions: Specific types of GP IIb–IIIa inhibitors can paradoxically augment agonist-induced release of α-granules despite inhibiting agonist-induced fibrinogen binding.

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