P2Y12 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 P2Y12 inhibits a broad spectrum of platelet aggregation pathways. However, vWF release may reduce prasugrel's effects under high-shear conditions.
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Research Article|
July 23 2012
Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial
Alexander O. Spiel;
Alexander O. Spiel
*Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
†Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
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Ulla Derhaschnig;
Ulla Derhaschnig
*Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
†Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
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Michael Schwameis;
Michael Schwameis
*Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
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Johann Bartko;
Johann Bartko
*Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
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Jolanta M. Siller-Matula;
Jolanta M. Siller-Matula
*Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
‡Department of Cardiology, Medical University of Vienna, Vienna, Austria
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Bernd Jilma
*Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Correspondence: Dr Bernd Jilma (email [email protected]).
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Publisher: Portland Press Ltd
Received:
April 20 2012
Revision Received:
May 24 2012
Accepted:
May 30 2012
Accepted Manuscript online:
May 30 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 123 (10): 591–600.
Article history
Received:
April 20 2012
Revision Received:
May 24 2012
Accepted:
May 30 2012
Accepted Manuscript online:
May 30 2012
Citation
Alexander O. Spiel, Ulla Derhaschnig, Michael Schwameis, Johann Bartko, Jolanta M. Siller-Matula, Bernd Jilma; Effects of prasugrel on platelet inhibition during systemic endotoxaemia: a randomized controlled trial. Clin Sci (Lond) 1 November 2012; 123 (10): 591–600. doi: https://doi.org/10.1042/CS20120194
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