The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin

Andrew L. Frelinger III; Joseph A. Jakubowski; You FuLi; Marc R. Barnard; Marsha L. Fox; Matthew D. Linden; Atsuhiro Sugidachi; Kenneth J. Winters; Mark I. Furman; Alan D. Michelson

doi:10.1160/TH07-01-0010

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(01): 192-200
DOI: 10.1160/TH07-01-0010

Platelets and Blood Cells

Schattauer GmbH

The active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin

Authors

Andrew L. Frelinger III

¹Center for Platelet Function Studies

³Pediatrics and
Joseph A. Jakubowski

⁵Lilly Research Laboratories, Indianapolis, Indiana, USA
You FuLi

¹Center for Platelet Function Studies

³Pediatrics and
Marc R. Barnard

¹Center for Platelet Function Studies

³Pediatrics and
Marsha L. Fox

¹Center for Platelet Function Studies

³Pediatrics and
Matthew D. Linden

¹Center for Platelet Function Studies

³Pediatrics and
Atsuhiro Sugidachi

⁶Daiichi Sankyo Company Ltd., Tokyo, Japan
Kenneth J. Winters

⁵Lilly Research Laboratories, Indianapolis, Indiana, USA
Mark I. Furman

¹Center for Platelet Function Studies

²Division of Cardiovascular Medicine, and Departments of

⁴Medicine, University of Massachusetts Medical School, Worcester, Massachussetts, USA
Alan D. Michelson

¹Center for Platelet Function Studies

³Pediatrics and

⁴Medicine, University of Massachusetts Medical School, Worcester, Massachussetts, USA

Abstract

Summary

The novel thienopyridine prodrug prasugrel, a platelet P2Y₁₂ ADP receptor antagonist, requires in vivo metabolism for activity. Although pharmacological data have been collected on the effects of prasugrel on platelet aggregation,there are few data on the direct effects of the prasugrel’s active metabolite, R-138727, on other aspects of platelet function. Here we examined the effects of R-138727 on thrombo-inflammatory markers of platelet activation, and the possible modulatory effects of other blood cells, calcium, and aspirin. Blood (PPACK or citrate anticoagulated) from healthy donors pre- and post-aspirin was incubated with R-138727 and the response to ADP assessed in whole blood or platelet-rich plasma (PRP) by aggregometry and flow cytometric analysis of leukocyte-platelet aggregates,platelet surface P-selectin, and GPIIb-IIIa activation. Low-micromolar concentrations of R-138727 resulted in a rapid and consistent in-hibition of these ADP-stimulated thrombo-inflammatory markers.These rapid kinetics required physiological calcium levels, but were largely unaffected by aspirin. Lower IC⁵⁰ values in whole blood relative to PRP suggested that other blood cells affect ADP-induced platelet activation and hence the net inhibition by R-138727. R-138727 did not inhibit P2Y₁₂-mediated ADP-induced shape change, even at concentrations that completely inhibited platelet aggregation, confirming the specificity of R-138727 for P2Y₁₂. In conclusion, R-138727, the active metabolite of prasugrel, results in rapid, potent, consistent, and selective inhibition of P2Y₁₂-mediated up-regulation of thromboinflammatory markers of platelet activation.This inhibition is enhanced in the presence other blood cells and calcium,but not aspirin.

Keywords

Anticoagulants - aspirin - blood cells - platelets - prasugrel - receptors

Full Text

References

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