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Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y 12 antagonism
Author(s) -
Nylander S.,
Femia E. A.,
Scavone M.,
Berntsson P.,
Asztély A.K.,
Nelander K.,
Löfgren L.,
Nilsson R. G.,
Cattaneo M.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12360
Subject(s) - ticagrelor , p2y12 , adenosine , prasugrel , dipyridamole , pharmacology , chemistry , antagonist , platelet , adenosine receptor , adenosine a2a receptor , purinergic signalling , nucleoside , platelet aggregation inhibitor , medicine , clopidogrel , receptor , agonist , biochemistry , platelet aggregation , aspirin
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 ZM 241385 (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. ZM 241385 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 μmol 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.