title: P2Y12 receptor blockade augments glycoprotein IIb-IIIa antagonist inhibition of platelet activation, aggregation, and procoagulant activity.
abstract: BACKGROUND
  New antiplatelet agents that provide greater, more consistent inhibition of the platelet ADP receptor P2Y12 may be used in combination with glycoprotein (GP) IIb-IIIa antagonists, but their combined effect on platelet function and procoagulant activity is not well studied. Therefore, the objective of this study was to evaluate the independent and complementary effects of P2Y12 and GPIIb-IIIa inhibition on platelet function and procoagulant activity.
  
  
  RESULTS
  Healthy donor blood was treated with the active metabolite of prasugrel (R-138727 5 μmol/L), GPIIb-IIIa antagonists (abciximab 3 μg/mL or eptifibatide 0.9 μg/mL), and combinations thereof, exposed to physiologically relevant agonists (collagen and ADP) and then evaluated for markers of platelet activation and procoagulant activity. Significant interactions between R-138727 and GPIIb-IIIa antagonists were observed. R-138727 and the GPIIb-IIIa antagonists had additive inhibitory effects on collagen-stimulated platelet aggregation and on the collagen plus ADP-stimulated level of activated platelet surface GPIIb-IIIa. R-138727 and abciximab each inhibited collagen plus ADP-stimulated platelet phosphatidylserine expression and prothrombin cleavage, and the combination produced greater inhibition than achieved with abciximab alone. In contrast, eptifibatide did not inhibit, but instead enhanced, collagen plus ADP-stimulated prothrombin cleavage. Addition of R-138727 reduced prothrombin cleavage in eptifibatide-treated samples, suggesting a novel mechanism for potential benefit from combined prasugrel and eptifibatide treatment.
  
  
  CONCLUSIONS
  The complementary effects of abciximab and R-138727 on platelet activation, aggregation, and procoagulant activity suggest their combined use may, to a greater degree than with either agent alone, reduce thrombus formation in vivo.
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, Japan.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Berny-Lang
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
authors.forename: Marc R
authors.initials: MR
authors.lastname: Barnard
authors.forename: Alan D
authors.initials: AD
authors.lastname: Michelson
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
mesh_terms: D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology*; D000077542:Eptifibatide; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; C548576:P2RY12 protein, human; D010455:Peptides; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C510685:R-138727; D058925:Receptors, Purinergic P2Y12; D000077542:Eptifibatide; D000077284:Abciximab
keywords: glycoprotein IIb‐IIIa receptor antagonists; platelets; prasugrel