Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism. (10th October 2013)

• Record Type: Journal Article
• Authors: Nylander, S.; Femia, E. A.; Scavone, M.; Berntsson, P.; Asztély, A.‐K.; Nelander, K.; Löfgren, L.; Nilsson, R. G.; Cattaneo, M.
• Is Part Of: Journal of thrombosis and haemostasis. Volume 11:Number 10(2013:Oct.)
• Page Start: 1867
• Page End: 1876
• Publication Date: 2013-10-10
• Subjects: Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.12360
• Languages: English
• ISSNs: 1538-7933

Abstract

<abstract abstract-type="main" id="jth12360-abs-0001"> <title>Summary</title> <sec id="jth12360-sec-0001" sec-type="section"> <title>Background</title> <p>Ticagrelor, a P2Y<sub>12</sub> antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells.</p> </sec> <sec id="jth12360-sec-0002" sec-type="section"> <title>Objective</title> <p>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<sub>2A</sub> receptor.</p> </sec> <sec id="jth12360-sec-0003" sec-type="section"> <title>Methods</title> <p>Collagen‐induced PA was measured in WB or platelet‐rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y<sub>12</sub> deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A<sub>2A</sub> antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y<sub>12</sub> antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared.</p> </sec> <sec id="jth12360-sec-0004" sec-type="section"> <title>Results</title> <p>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 (<italic>P</italic> < 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<sub>12</sub>‐deficient patients. Adenosine (7.1 μmol L<sup>–1</sup>) 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.</p> </sec> <sec id="jth12360-sec-0005" sec-type="section"> <title>Conclusion</title> <p>This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.</p> </sec> </abstract>