Beschreibung:
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<jats:bold>Introduction.</jats:bold>
Ticagrelor, a P2Y
<jats:sub>12</jats:sub>
antagonist, inhibits adenosine uptake by erythrocytes and increases adenosine-induced coronary blood flow.
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We hypothesiszed that ticagrelor inhibits platelet function not only by antagonizing P2Y
<jats:sub>12</jats:sub>
, but also by increasing the levels of adenosine, which inhibits platelets by interacting with the platelet A
<jats:sub>2A</jats:sub>
receptor.
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<jats:p>
<jats:bold>Methods.</jats:bold>
Collagen-induced platelet aggregation (PA) was measured in citrate-anticoagulated whole blood (WB) (Multiplate) or platelet-rich plasma (PRP) (light-transmission aggregometry) from 12 healthy controls and 2 patients with congenital deficiency of P2Y
<jats:sub>12</jats:sub>
, in the presence or absence of adenosine (7.1 μM), which marginally affected PA in WB, and the A
<jats:sub>2A</jats:sub>
inhibitor ZM241385. The effects on PA of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y
<jats:sub>12</jats:sub>
antagonist) and dipyridamole (DYP) (ENT-1 inhibitor) were compared. The effects of these drugs on the clearance of adenosine after its in vitro addition to WB were also studied.
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<jats:p>
<jats:bold>Results.</jats:bold>
PA in WB: Adenosine contributed to drug-induced inhibition of PA in healthy controls. The magnitude of the contribution (absolute difference in % aggregation) was greater in the presence of ticagrelor (20%, p <0.01) or DYP (18%, p <0.01) than in the presence of PAM (6%, p 0.02). PA in PRP: Adenosine markedly contributed to inhibition of PA in healthy controls in the presence of all tested drugs. In both WB and PRP ZM241385 reversed the inhibitory effect of adenosine. Data from P2Y
<jats:sub>12</jats:sub>
-deficient patients was in agreement, but due to low numbers no statistical analysis was performed. Adenosine, added at 7.1μM to WB in vitro, was detectable up to 0.5 min in the presence of vehicle or PAM, up to 3 min in the presence of ticagrelor, and up to 60 min in the presence of DYP. These results are compatible with the hypothesis that ticagrelor and DYP, but not PAM, increase the adenosine levels by inhibiting its uptake by erythrocytes.
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<jats:bold>Conclusion.</jats:bold>
This study provides the first evidence of an additional anti-platelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels in WB. It remains to be established if and to what extent this additional mechanism of action contributes to the strong clinical benefit observed with ticagrelor in patients with acute coronary syndromes.
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