Vol 26, No 6 (2019)
Original articles — Basic science and experimental cardiology
Published online: 2018-04-17

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P2Y12 antagonist ticagrelor inhibits the release of procoagulant extracellular vesicles from activated platelets

Aleksandra Gasecka12, Rienk Nieuwland2, Edwin van der Pol3, Najat Hajji2, Agata Ćwiek1, Kinga Pluta1, Michał Konwerski1, Krzysztof J. Filipiak1
Pubmed: 29671861
Cardiol J 2019;26(6):782-789.

Abstract

Background: Activated platelets release platelet extracellular vesicles (PEVs). Adenosine diphosphate
(ADP) receptors P2Y1 and P2Y12 both play a role in platelet activation, The present hypothesis herein
is that the inhibition of these receptors may affect the release of PEVs.
Methods: Platelet-rich plasma from 10 healthy subjects was incubated with saline, P2Y1 antagonist
MRS2179 (100 μM), P2Y12 antagonist ticagrelor (1 μM), and a combination of both antagonists.
Platelets were activated by ADP (10 μM) under stirring conditions at 37°C. Platelet reactivity was
assessed by impedance aggregometry. Concentrations of PEVs– (positive for CD61 but negative for
P-selectin and phosphatidylserine) and PEVs+ (positive for all) were determined by a state-of-the-art
flow cytometer. Procoagulant activity of PEVs was measured by a fibrin generation test.
Results: ADP-induced aggregation (57 ± 13 area under curve {AUC] units) was inhibited 73%
by the P2Y1 antagonist, 86% by the P2Y12 antagonist, and 95% when combined (p < 0.001 for all).
The release of PEVs– (2.9 E ± 0.8 × 108/mL) was inhibited 48% in the presence of both antagonists
(p = 0.015), whereas antagonists alone were ineffective. The release of PEVs+ (2.4 ± 1.6 × 107/mL)
was unaffected by the P2Y1 antagonist, but was 62% inhibited by the P2Y12 antagonist (p = 0.035),
and 72% by both antagonists (p = 0.022). PEVs promoted coagulation in presence of tissue factor.
Conclusions: Inhibition of P2Y1 and P2Y12 receptors reduces platelet aggregation and affects the
release of distinct subpopulations of PEVs. Ticagrelor decreases the release of procoagulant PEVs from
activated platelets, which may contribute to the observed clinical benefits in patients treated with ticagrelor.

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References

  1. Linden MD, Jackson DE. Platelets: pleiotropic roles in atherogenesis and atherothrombosis. Int J Biochem Cell Biol. 2010; 42(11): 1762–1766.
  2. Hechler B, Gachet C. Purinergic receptors in thrombosis and inflammation. Arterioscler Thromb Vasc Biol. 2015; 35(11): 2307–2315.
  3. Yanachkov IB, Chang H, Yanachkova MI, et al. New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors. Eur J Med Chem. 2016; 107: 204–218.
  4. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018; 39(2): 119–177.
  5. van der Pol E, Böing AN, Harrison P, et al. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012; 64(3): 676–705.
  6. Rank A, Nieuwland R, Delker R, et al. Cellular origin of platelet-derived microparticles in vivo. Thromb Res. 2010; 126(4): e255–e259.
  7. Jurk K, Kehrel BE. Platelets: physiology and biochemistry. Semin Thromb Hemost. 2005; 31(4): 381–392.
  8. Vajen T, Mause SF, Koenen RR. Microvesicles from platelets: novel drivers of vascular inflammation. Thromb Haemost. 2015; 114(2): 228–236.
  9. Falati S, Liu Q, Gross P, et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med. 2003; 197(11): 1585–1598.
  10. Heemskerk JWM, Mattheij NJA, Cosemans JM. Platelet-based coagulation: different populations, different functions. J Thromb Haemost. 2013; 11(1): 2–16.
  11. Boulanger CM, Loyer X, Rautou PE, et al. Extracellular vesicles in coronary artery disease. Nat Rev Cardiol. 2017; 14(5): 259–272.
  12. Badimon L, Suades R, Fuentes E, et al. Role of Platelet-Derived Microvesicles As Crosstalk Mediators in Atherothrombosis and Future Pharmacology Targets: A Link between Inflammation, Atherosclerosis, and Thrombosis. Front Pharmacol. 2016; 7: 293.
  13. Zaldivia MTK, McFadyen JD, Lim B, et al. Platelet-Derived Microvesicles in Cardiovascular Diseases. Front Cardiovasc Med. 2017; 4: 74.
  14. Gasecka A, Böing AN, Filipiak KJ, et al. Platelet extracellular vesicles as biomarkers for arterial thrombosis. Platelets. 2017; 28(3): 228–234.
  15. Gąsecka A, van der Pol E, Nieuwland R, et al. Extracellular vesicles in post-infarct ventricular remodelling. Kardiol Pol. 2018; 76(1): 69–76.
  16. Tomaniak M, Gąsecka A, Filipiak KJ. Cell-derived microvesicles in cardiovascular diseases and antiplatelet therapy monitoring - A lesson for future trials? Current evidence, recent progresses and perspectives of clinical application. Int J Cardiol. 2017; 226: 93–102.
  17. Morel O, Jesel L, Freyssinet JM, et al. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol. 2011; 31(1): 15–26.
  18. Coumans FAW, Brisson AR, Buzas EI, et al. Methodological Guidelines to Study Extracellular Vesicles. Circ Res. 2017; 120(10): 1632–1648.
  19. van der Pol E, van Gemert MJC, Sturk A, et al. Single vs. swarm detection of microparticles and exosomes by flow cytometry. J Thromb Haemost. 2012; 10(5): 919–930.
  20. van der Pol E, Coumans FAW, Sturk A, et al. Refractive index determination of nanoparticles in suspension using nanoparticle tracking analysis. Nano Lett. 2014; 14(11): 6195–6201.
  21. Berckmans RJ, Sturk A, van Tienen LM, et al. Cell-derived vesicles exposing coagulant tissue factor in saliva. Blood. 2011; 117(11): 3172–3180.
  22. Arraud N, Linares R, Tan S, et al. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost. 2014; 12(5): 614–627.
  23. Hechler B, Gachet C. Purinergic receptors in thrombosis and inflammation. Arterioscler Thromb Vasc Biol. 2015; 35(11): 2307–2315.
  24. Böing AN, Stap J, Hau CM, et al. Active caspase-3 is removed from cells by release of caspase-3-enriched vesicles. Biochim Biophys Acta. 2013; 1833(8): 1844–1852.
  25. Behan MWH, Fox SC, Heptinstall S, et al. Inhibitory effects of P2Y12 receptor antagonists on TRAP-induced platelet aggregation, procoagulant activity, microparticle formation and intracellular calcium responses in patients with acute coronary syndromes. Platelets. 2005; 16(2): 73–80.
  26. Judge HM, Buckland RJ, Sugidachi A, et al. The active metabolite of prasugrel effectively blocks the platelet P2Y12 receptor and inhibits procoagulant and pro-inflammatory platelet responses. Platelets. 2008; 19(2): 125–133.
  27. Judge HM, Buckland RJ, Holgate CE, et al. Glycoprotein IIb/IIIa and P2Y12 receptor antagonists yield additive inhibition of platelet aggregation, granule secretion, soluble CD40L release and procoagulant responses. Platelets. 2005; 16(7): 398–407.
  28. Tatsumi K, Mackman N. Tissue factor and atherothrombosis. J Atheroscler Thromb. 2015; 22(6): 543–549.
  29. Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017; 377(12): 1119–1131.
  30. Medical University of Warsaw. Antiplatelet therapy effect on platelet extracellular vesicles (AFFECT EV). NLM Identifier: NCT02931045. https://clinicaltrials.gov/ct2/show/NCT02931045 (Accessed: 18.02.2018).