Effects of Strong P2Y12 Receptor Inhibition by Prasugrel on Platelet Inhibition During Endotoxemia: A Randomized Controlled Trial

P2Y12 receptor antagonists have become a mainstay for the treatment of cardiovascular diseases. Yet, they have rarely been evaluated under pathophysiological conditions apart from arterial diseases.

We hypothesized interactions between prasugrel and enhanced von Willebrand Factor (VWF) release in a model of systemic inflammation, and compared the pharmacodynamic effects of prasugrel versus placebo on agonist-induced platelet aggregation and shear-induced platelet plug formation.

Subjects/Methods: Twenty healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Each volunteer received either placebo or a 60 mg-loading dose of prasugrel two hours before endotoxin infusion. Platelet inhibition was measured with Multiple Electrode Aggregometry (MEA), the Platelet Function Analyzer-100 (PFA-100) and the Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation assay, respectively. Results: Prasugrel reduced the platelet reactivity index in the VASP assay from 79% to 5–7%, and unequivocally prolonged the closure times of the Innovance cartridge to >300s, but also the CADP-CT to >300s in the majority of subjects. Prasugrel not only blunted platelet aggregation induced by ADP (−81%), but also other pathways including arachidonic acid (−60%), ristocetin (−75%; p<0.001 for all), and to a lesser degree collagen or thrombin receptor activating peptide (TRAP). Prasugrel decreased shear-induced platelet plug formation but VWF release during endotoxemia partly antagonized the inhibitory effect of prasugrel as measured with the PFA-100. Endotoxemia acutely decreased ristocetin and TRAP induced platelet aggregation, and enhanced ristocetin induced aggregation after 24h.

These data for the first time demonstrate that strong in vivo blockade of P2Y12 by prasugrel inhibits a broad spectrum of platelet aggregation pathways. However, VWF release may reduce prasugrel's effects under high shear conditions.

No relevant conflicts of interest to declare.