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Research ArticleCardiovascular

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

Patrick André, Francis DeGuzman, Helena Haberstock-Debic, Scott Mills, Yvonne Pak, Mayuko Inagaki, Anjali Pandey, Stanley Hollenbach, David R. Phillips and Pamela B. Conley
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 22-30; DOI: https://doi.org/10.1124/jpet.110.178574
Patrick André
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Francis DeGuzman
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Helena Haberstock-Debic
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Scott Mills
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Yvonne Pak
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Mayuko Inagaki
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Anjali Pandey
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Stanley Hollenbach
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David R. Phillips
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Pamela B. Conley
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Abstract

Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y12 and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl3-induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y12(−/−) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y12. Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y12(−/−) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y12 activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y12-independent off-target effects at the vessel wall, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.

Footnotes

  • All coauthors are employees and shareholders of Portola Pharmaceuticals.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.110.178574.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    TRITON-TIMI 38
    Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction
    WT
    wild-type
    PRP
    platelet-rich plasma
    TRAP
    thrombin receptor activating peptide
    aPTT
    activated partial thromboplastin time
    PT
    prothrombin time
    α,β-metATP
    α,β-methyleneadenosine 5′-triphosphate.

  • Received December 22, 2010.
  • Accepted March 29, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleCardiovascular

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

Patrick André, Francis DeGuzman, Helena Haberstock-Debic, Scott Mills, Yvonne Pak, Mayuko Inagaki, Anjali Pandey, Stanley Hollenbach, David R. Phillips and Pamela B. Conley
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 22-30; DOI: https://doi.org/10.1124/jpet.110.178574

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Research ArticleCardiovascular

Thienopyridines, but Not Elinogrel, Result in Off-Target Effects at the Vessel Wall That Contribute to Bleeding

Patrick André, Francis DeGuzman, Helena Haberstock-Debic, Scott Mills, Yvonne Pak, Mayuko Inagaki, Anjali Pandey, Stanley Hollenbach, David R. Phillips and Pamela B. Conley
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 22-30; DOI: https://doi.org/10.1124/jpet.110.178574
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