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  • Title: Paradoxical inhibition of fibrinogen binding and potentiation of alpha-granule release by specific types of inhibitors of glycoprotein IIb-IIIa.
    Author: Schneider DJ, Taatjes DJ, Sobel BE.
    Journal: Cardiovasc Res; 2000 Jan 14; 45(2):437-46. PubMed ID: 10728364.
    Abstract:
    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 (Orbofiban(a)). 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. Orbofiban(a) did not alter ADP-induced P-selectin expression. Neither agent altered ADP-induced CD63 expression. When platelets were exposed to Abciximab and Orbofiban(a), both Abciximab and Orbofiban(a) 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.
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