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The effect of P2Y12 inhibition on platelet activation assessed with aggregation- and flow cytometry-based assays.

Authors
  • Leunissen, Tesse C1, 2
  • Wisman, Peter Paul1, 2
  • van Holten, Thijs C1
  • de Groot, Philip G1
  • Korporaal, Suzanne J1
  • Koekman, Arnold C1
  • Moll, Frans L2
  • Teraa, Martin2, 3
  • Verhaar, Marianne C3
  • de Borst, Gert Jan2
  • Urbanus, Rolf T1
  • Roest, Mark1
  • 1 a Department of Clinical Chemistry and Hematology , University Medical Center Utrecht , The Netherlands. , (Netherlands)
  • 2 b Department of Vascular Surgery , University Medical Center Utrecht , The Netherlands. , (Netherlands)
  • 3 c Department of Nephrology and Hypertension , University Medical Center Utrecht , The Netherlands. , (Netherlands)
Type
Published Article
Journal
Platelets
Publisher
Informa UK (Taylor & Francis)
Publication Date
Sep 01, 2017
Volume
28
Issue
6
Pages
567–575
Identifiers
DOI: 10.1080/09537104.2016.1246713
PMID: 27885904
Source
Medline
Keywords
License
Unknown

Abstract

Patients on P2Y12 inhibitors may still develop thrombosis or bleeding complications. Tailored antiplatelet therapy, based on platelet reactivity testing, might reduce these complications. Several tests have been used, but failed to show a benefit of tailored antiplatelet therapy. This could be due to the narrowness of current platelet reactivity tests, which are limited to analysis of platelet aggregation after stimulation of the adenosine diphosphate (ADP)-pathway. However, the response to ADP does not necessarily reflect the effect of P2Y12 inhibition on platelet function in vivo. Therefore, we investigated whether measuring platelet reactivity toward other physiologically relevant agonists could provide more insight in the efficacy of P2Y12 inhibitors. The effect of in vitro and in vivo P2Y12 inhibition on αIIbβ3-activation, P-selectin and CD63-expression, aggregate formation, release of alpha, and dense granules content was assessed after stimulation of different platelet activation pathways. Platelet reactivity measured with flow cytometry in 72 patients on P2Y12 inhibitors was compared to VerifyNow results. P2Y12 inhibitors caused strongly attenuated platelet fibrinogen binding after stimulation with peptide agonists for protease activated receptor (PAR)-1 and -4, or glycoprotein VI ligand crosslinked collagen-related peptide (CRP-xl), while aggregation was normal at high agonist concentration. P2Y12 inhibitors decreased PAR-agonist and CRP-induced dense granule secretion, but not alpha granule secretion. A proportion of P2Y12-inhibitor responsive patients according to VerifyNow, displayed normal fibrinogen binding assessed with flow cytometry after stimulation with PAR-agonists or CRP despite full inhibition of the response to ADP, indicating suboptimal platelet inhibition. Concluding, measurement of platelet fibrinogen binding with flow cytometry after stimulation of thrombin- or collagen receptors in addition to ADP response identifies different patients as nonresponders to P2Y12 inhibitors, compared to only ADP-induced aggregation-based assays. Future studies should investigate the value of both assays for monitoring on-treatment platelet reactivity.

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