title: Cangrelor attenuates coated-platelet formation.
abstract: P2Y(12) inhibitors were introduced clinically as effective inhibitors of adenosine-5'-diphosphate (ADP) mediated platelet activation and aggregation. This class of pharmacological agents has enjoyed considerable success. Cangrelor is a recently developed P2Y(12) inhibitor that has the advantage of being an active drug not requiring metabolic conversion, although it is not orally available. Coated-platelets are a subclass of activated platelets generated on dual agonist activation with collagen plus thrombin; the primary hallmark of coated-platelets is their ability to support prothrombinase activity. Interestingly, we recently observed that the relatively weak agonist ADP potentiates the production of coated-platelets by the very strong agonists collagen plus thrombin, a previously unknown role for ADP. The authors sought in this study to determine if P2Y(12) inhibitors, such as cangrelor, were capable of attenuating this augmentation of coated-platelet generation. Cangrelor, at physiologically relevant concentrations, was able to eliminate the ADP-dependent increase in coated-platelet production with an IC(50) of 1.4 nM. Cangrelor, however, had no effect on thrombin-dependent platelet activation as measured by P-selectin expression. Although this in vitro study does not address the question of whether the effectiveness of cangrelor in vivo is partially due to an attenuation of coated-platelet production in addition to its documented antiaggregatory effects, it does reveal an unexpected action of cangrelor. Additional studies will be required to determine if all P2Y(12) inhibitors are equally effective in attenuating coated-platelet production.
authors.affiliation: Department of Clinical and Administrative Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Norgard
authors.forename: Callie L
authors.initials: CL
authors.lastname: Hann
authors.forename: George L
authors.initials: GL
authors.lastname: Dale
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000097:blood; D058925:Receptors, Purinergic P2Y12
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor