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

Abstract

To cite this article: Nylander S, Femia EA, Scavone M, Berntsson P, Aszt ely A-K, Nelander K, L€ ofgren L, Nilsson RG, Cattaneo M. Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y 12 antagonism. J Thromb Haemost 2013; 11: 1867-76.Summary. Background: Ticagrelor, a P2Y 12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells. Objective: To test whether ticagrelor inhibits platelet aggregation (PA) in whole blood (WB) by increasing the extracellular levels of adenosine, which inhibits PA via the A 2A receptor. Methods: Collagen-induced PA was measured in WB or platelet-rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y 12 deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A 2A antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y 12 antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared. Results: For PA in WB, adenosine contributed to drug-induced inhibition of PA; the adenosine contribution was similar for dipyridamole and ticagrelor but was significantly greater for ticagrelor than for PAM (P < 0.01). For PA in PRP (no adenosine uptake by erythrocytes), adenosine contributed to inhibition of PA in the presence/absence of all tested drugs. ZM241385 reversed the inhibition by adenosine in WB and PRP. Similar results were obtained with WB and PRP from P2Y 12 -deficient patients. Adenosine (7.1 lmol L -1 ) added to WB, was detectable for 0.5 min in the presence of vehicle or PAM, for 3-6 min in the presence of ticagrelor, and for > 60 min in the presence of dipyridamole. Conclusion: This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.

Acute Coronary Syndrome: Focus on Antiplatelet Therapy

“…9 and the promotion of fibrin cross-linking to stabilize the thrombus. The P2Y 12 antagonists clopidogrel, prasugrel, and ticagrelor inhibit ADP-induced P2Y 12 receptor activation, thereby preventing GPIIb/IIIa complex activation and reducing platelet aggregation. 9 Clopidogrel and prasugrel are both orally administered, thienopyridine-based, irreversibly binding P2Y 12 inhibitors, which must be converted into an active metabolite to allow binding to the P2Y 12 receptor.…”

“…In addition to P2Y 12 inhibition, ticagrelor also increases extracellular adenosine levels by inhibiting the equilibrative nucleoside transporter-1. 11 As well as being an additional mechanism for the antiplatelet effects of ticagrelor, 12 the increase in local adenosine levels enhances adenosine-mediated coronary blood flow. [13][14][15] Guideline Update: NSTE-ACS The AHA/ACC Task Force on Practice Guidelines has published a 2014 update for the care of patients with NSTE-ACS.…”

“…In NSTE-ACS, dual antiplatelet therapy with aspirin and a P2Y 12 inhibitor remains the cornerstone of treatment, and aspirin is recommended as first-line, indefinite therapy. 6 Several sections of the guidelines that include guidance on how to manage antiplatelet therapies in patients with NSTE-ACS were updated to include the newest P2Y 12 receptor antagonist, ticagrelor, in addition to clopidogrel and prasugrel.…”

“…6,27 ) The guidelines recommend that PPIs be prescribed in patients receiving triple antithrombotic therapy with a vitamin K antagonist, aspirin, and a P2Y 12 receptor inhibitor who have a history of gastrointestinal bleeding, and that use of PPIs may be considered in patients without a history of gastrointestinal bleeding who are receiving P2Y 12 agents. 6 In case study 1, the interventional cardiologist decides to change the P2Y 12 inhibitor to ticagrelor, a decision based on the reduction in vascular death, myocardial infarction, or stroke found for ticagrelor relative to clopidogrel in the PLATO trial. 20 The patient receives a loading dose of ticagrelor 180 mg by mouth and then 90 mg twice a day.…”

“…19 Interestingly, the rate of major bleeding did not differ between patients receiving ticagrelor along with clopidogrel and patients receiving just clopidogrel, 20 and no significant interaction was found between clopidogrel given before randomization or as a loading dose and bleeding events. 30 The other possible choices of P2Y 12 inhibitor are continuation of clopidogrel or initiation of prasugrel, if considered appropriate. Moderate-to high-risk patients with ACS and scheduled PCI were examined in the TRITON-TIMI 38 trial, which compared clopidogrel with prasugrel (Table 3).…”