A Mechanistic Model for Paradoxical Platelet Activation by Ligand-Mimetic αIIbβ3(GPIIb/IIIa) Antagonists

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Abstract
Objective— Integrins are attractive therapeutic targets. Inhibition of integrin αIIbβ3 effectively blocks platelet aggregation. However, limitations with intravenous αIIbβ3 antagonists and failure of oral αIIbβ3 antagonists prompted doubts on the current concept of ligand-mimetic integrin blockade. Methods and Results— Evaluating P-selectin expression on platelets by flow cytometry, we report a mechanism of paradoxical platelet activation by ligand-mimetic αIIbβ3 antagonists and define three requirements: (1) Induction of ligand-bound conformation of αIIbβ3, (2) receptor clustering, (3) prestimulation of platelets. Conformational change is inducible by clinically used ligand-mimetic αIIbβ3 antagonists, RGD-peptides, and anti-LIBS antibodies. In a mechanistic experimental model, clustering is achieved by crosslinking integrins via antibodies, and preactivation is induced by low-dose ADP. Finally, we demonstrate that platelet adhesion on collagen represents an in vivo correlate of platelet prestimulation an... Limitations with intravenous and failure of oral αIIbβ3 antagonists question the current concept of ligand-mimetic αIIbβ3 blockade. We provide a model explaining paradoxical platelet activation as consequence of αIIbβ3 antagonist-induced conformational change of αIIbβ3. Concomitant blockade of the ADP-receptor P2Y12, activation-specific and allosteric blockade are described/discussed as alternative αIIbβ3-blocking strategies.