Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a
randomized controlled trial.
Author(s): Spiel AO, Derhaschnig U, Schwameis M, Bartko J, Siller-Matula JM, Jilma B.
Affiliation(s): Department of Clinical Pharmacology, Medical University of Vienna, Vienna,
Austria.
Publication date & source: 2012, Clin Sci (Lond). , 123(10):591-600
P2Y(12) receptor antagonists have become a mainstay for the treatment of CVD
(cardiovascular diseases). However, they have rarely been evaluated under
pathophysiological conditions apart from arterial diseases. We hypothesized
interactions between prasugrel and enhanced vWF (von Willebrand Factor) release
in a model of systemic inflammation, and compared the pharmacodynamic effects of
prasugrel against placebo on agonist-induced platelet aggregation and
shear-induced platelet plug formation. A total of 20 healthy male volunteers were
enrolled in a double-blind placebo-controlled two-way crossover trial. Each
volunteer received either placebo or a 60 mg loading dose of prasugrel 2 h before
endotoxin or placebo infusion. Platelet inhibition was measured with MEA
(multiple electrode aggregometry), the PFA-100 system and the VASP
(vasodilator-stimulated phosphoprotein) phosphorylation assay. Prasugrel blunted
various platelet aggregation pathways, including those induced by ADP (-81%), AA
(arachidonic acid) (-60%), ristocetin (-75%; P<0.001 for all) and, to a lesser
degree, collagen or TRAP (thrombin-receptor-activating peptide). Prasugrel
decreased shear-induced platelet plug formation, but vWF release during
endotoxaemia partly antagonized the inhibitory effect of prasugrel as measured
with the PFA-100 system. Endotoxaemia acutely decreased ristocetin and
TRAP-induced platelet aggregation, and enhanced ristocetin-induced aggregation
after 24 h. Strong in vivo blockade of P2Y(12) inhibits a broad spectrum of
platelet aggregation pathways. However, vWF release may reduce prasugrel's
effects under high-shear conditions.
|