Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism

Journal of Thrombosis and Haemostasis

Volumn 11, Issue 10, 2013, Pages 1867-1876

  Nylander, S ^a   Femia, E A ^b   Scavone, M ^b   Berntsson, P ^a   Asztely A K ^a   Nelander, K ^a   Lofgren L ^a   Nilsson, R G ^a   Cattaneo, M ^b  

^a ASTRAZENECA R AND D   (Sweden)

^b UNIVERSITY OF MILAN   (Italy)

Author keywords

Adenosine; Adenosine A2A receptor; Equilibrative nucleoside transporter 1; Platelet aggregation; Receptors, purinergic P2Y12; Ticagrelor

Indexed keywords

4 [2 [7 AMINO 2 (2 FURYL) 1,2,4 TRIAZOLO[2,3 A][1,3,5]TRIAZIN 5 YLAMINO]ETHYL]PHENOL; ADENOSINE; ADENOSINE A2A RECEPTOR; DIPYRIDAMOLE; HYPOXANTHINE; PRASUGREL; PURINERGIC P2Y12 RECEPTOR; TICAGRELOR;

ADULT; AGED; ARTICLE; BLOOD; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG CLEARANCE; FEMALE; HUMAN; HUMAN EXPERIMENT; IC 50; IN VITRO STUDY; MALE; METABOLITE; NORMAL HUMAN; PRIORITY JOURNAL; THROMBOCYTE AGGREGATION; THROMBOCYTE FUNCTION; THROMBOCYTE RICH PLASMA;

ADENOSINE; ADENOSINE A2A RECEPTOR; EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1; PLATELET AGGREGATION; RECEPTORS, PURINERGIC P2Y12; TICAGRELOR;

ADENOSINE; ADULT; AGED; FEMALE; HUMANS; HYPOXANTHINE; MALE; MIDDLE AGED; PLATELET AGGREGATION INHIBITORS; PURINERGIC P2Y RECEPTOR ANTAGONISTS; YOUNG ADULT;

EID: 84876228478     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/jth.12360     Document Type: Article

References (26)

1. van Giezen JJJ, Humphries RG. Preclinical and Clinical Studies with Selective Reversible Direct P2Y12 Antagonists. Semin Thromb Hemost 2005; 31: 195-204.
2. van Giezen JJJ, Nilsson L, Berntsson P, Wissing BM, Giordanetto F, Tomlinson W, Greasley PJ. Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7: 1556-65.
3. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-57.
4. Ellsworth ML, Ellis CG, Goldman D, Stephenson AH, Dietrich HH, Sprague RS. Erythrocytes: oxygen sensors and modulators of vascular tone. Physiology (Bethesda) 2009; 24: 107-16.
5. Fredholm BB. Physiological and pathophysiological roles of adenosine. Sleep Biol Rythms 2011; 9: 24-8.
6. Noji T, Karasawa A, Kusaka H. Adenosine uptake inhibitors. Eur J Pharmacol 2004; 495: 1-16.
7. Fredholm BB. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 2007; 14: 1315-23.
8. King AE, Ackley MA, Cass CE, Young JD, Baldwin SA. Nucleoside transporters: from scavengers to novel therapeutic targets. Trends Pharmacol Sci 2006; 27: 416-25.
9. Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma of human and dog blood. Am J Physiol 1989; 256: C799-806.
10. van Giezen JJJ, Sidaway J, Glaves P, Kirk I, Bjorkman JA. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther 2012; 17: 164-72.
11. Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, Gan LM. Ticagrelor Enhances Adenosine-Induced Coronary Vasodilatory Responses in Humans. J Am Coll Cardiol 2013; 61: 723-7.
12. Noè L, Peeters K, Izzi B, van Geet C, Freson K. Regulators of platelet cAMP levels: clinical and therapeutic implications. Curr Med Chem 2010; 17: 2897-905.
13. Ongini E, Fredholm BB. Pharmacology of adenosine A2A receptors. Trends Pharmacol Sci 1996; 17: 364-72.
14. Schwarz UR, Walter U, Eigenthaler M. Taming platelets with cyclic nucleotides. Biochem Pharmacol 2001; 62: 1153-61.
15. Cattaneo M. The platelet P2Y(12) receptor for adenosine diphosphate: congenital and drug-induced defects. Blood 2011; 117: 2102-12.
16. Cattaneo M, Lecchi A, Lombardi R, Gachet C, Zighetti ML. Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet 'primary secretion defect' are heterozygous for a defect of P2CYC receptors. Arterioscler Thromb Vasc Biol 2000; 20: E101-6.
17. Cattaneo M, Lecchi A, Randi AM, McGregor JL, Mannucci PM. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood 1992; 80: 2787-96.
18. Cattaneo M, Cerletti C, Harrison P, Hayward CP, Kenny D, Nugent D, Nurden P, Rao AK, Schmaier AH, Watson SP, Lussana F, Pugliano MT, Michelson AD. Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the platelet physiology subcommittee of SSC/ISTH. J Thromb Haemost 2003; doi: 10.1111/jth.12231 [Epub ahead of print].
19. Cattaneo M, Lecchi A, Zighetti ML, Lussana F. Platelet aggregation studies: autologous platelet-poor plasma inhibits platelet aggregation when added to platelet-rich plasma to normalize platelet count. Haematologica 2007; 92: 694-7.
20. Deussen A. Metabolic flux rates of adenosine in the heart. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 351-63.
21. Deussen A, Stappert M, Schafer S, Kelm M. Quantification of extracellular and intracellular adenosine production: understanding the transmembranous concentration gradient. Circulation 1999; 99: 2041-7.
22. Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110: 925-34.
23. Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun 2012; 418: 754-8.
24. Cattaneo M, Lecchi A. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin. J Thromb Haemost 2007; 5: 577-82.
25. Iyù D, Glenn JR, White AE, Fox SC, Heptinstall S. Adenosine derived from ADP can contribute to inhibition of platelet aggregation in the presence of a P2Y12 antagonist. Arterioscler Thromb Vasc Biol 2011; 31: 416-22.
26. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50: 1852-6.