Preserved thrombin‐inducible platelet activation in thienopyridine‐treated patients

Abstract

Abundant thrombin generation may be a major reason for subsequent thromboembolic events in patients with cardiovascular disease receiving dual antiplatelet therapy. We therefore investigated the susceptibility of thienopyridine responders and nonresponders to thrombin receptor-activating peptide (TRAP)-6- and adenosine diphosphate (ADP)-inducible platelet activation. Response to clopidogrel or prasugrel was determined by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) in 317 patients undergoing angioplasty and stenting for cardiovascular disease. Baseline, TRAP-6-, and ADP-inducible P-selectin expression, activated glycoprotein IIb/IIIa (GPIIb/IIIa) and monocyte-platelet aggregate (MPA) formation were measured as sensitive parameters of platelet activation. In patients with high on-treatment residual ADP-inducible platelet reactivity (HRPR), baseline P-selectin expression, GPIIb/IIIa and MPA formation were similar to those in patients without HRPR (all P > 0.05). After platelet activation with TRAP-6 or ADP, patients with HRPR by both assays exhibited significantly higher levels of P-selectin expression, GPIIb/IIIa and MPA formation than patients with an adequate thienopyridine-mediated platelet inhibition (all P ≤ 0.02). However, high levels of TRAP-6-inducible P-selectin, GPIIb/IIIa and MPA formation also occurred in 20.4%, 19.1% and 20.1% of the good responders by the VASP assay, and in 19.6%, 16.6% and 20.6% of the good responders by MEA, respectively. Thienopyridine nonresponders are more susceptible to thrombin- and ADP-inducible platelet activation than patients with good platelet inhibition. However, even patients with adequate thienopyridine-mediated platelet inhibition often show a preserved responsiveness to thrombin. These patients may benefit from additional thrombin receptor blockage or inhibition of thrombin generation.