Prostaglandin E1 potentiates the effects of P2Y12 blockade on ADP-mediated platelet aggregation in vitro: Insights using short thromboelastography.
In addition to adenosine diphosphate (ADP), a number of platelet function tests including the VerifyNow P2Y12 assay (VN-P2Y12) employ prostaglandin E1 (PGE1) to improve specificity for P2Y12 blockade by mitigating the contribution of the P2Y1 pathway on ADP-mediated platelet aggregation. Using short thromboelastography (s-TEG), we have previously shown that VN-P2Y12 overestimates the functional effect of clopidogrel in some individuals. We investigated whether PGE1 systematically increases the inhibitory effects of P2Y12 blockade on ADP-mediated platelet aggregation in an in vitro model. Using s-TEG, we measured ADP-induced platelet aggregation either in the presence or absence of PGE1 (11 or 22 nM) in blood samples taken from healthy volunteers pre-incubated with prasugrel active metabolite (PAM; 0, 1, 3 or 10 µM). Individually, both PGE1 (p < 0.02) and PAM (p < 0.0001) inhibited ADP-mediated platelet aggregation in a dose-dependent manner, as expected. Furthermore, inclusion of PGE1 augmented inhibition of ADP-mediated platelet aggregation in response to PAM (p < 0.02) in a dose-dependent manner such that a 10-fold higher dose of PAM was required to attain equivalent inhibition of ADP-mediated platelet aggregation to that achieved by 1 µM PAM in the presence of 11 nM PGE1. In conclusion, PGE1 potentiates the anti-aggregatory effects of P2Y12 blockade on ADP-mediated platelet aggregation. Assays that employ PGE1 with ADP may therefore overestimate therapeutic response to prasugrel in a proportion of individuals, potentially making them unsuitable candidates for guiding delivery of personalized antiplatelet therapy.
a University Hospital Southampton NHS Foundation Trust , Southampton , UK .
Vikram
V
Khanna
Paul C J
PC
Armstrong
Timothy D
TD
Warner
Nick
N
Curzen
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000527:Alprostadil / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D004357:Drug Synergism; D064368:Healthy Volunteers; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D013916:Thrombelastography
D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000527:Alprostadil
Adenosine diphosphate; prasugrel active metabolite; prostaglandin E1; short thrombelastography; verifyNow