title: Thienopyridines, but not elinogrel, result in off-target effects at the vessel wall that contribute to bleeding.
abstract: Clinical studies with clopidogrel or prasugrel show that although increased inhibition of P2Y(12) and platelet function improves efficacy, bleeding is also increased. Other preclinical and clinical studies have suggested a greater therapeutic index (TI) with reversible inhibitors and disproportionate effects of thienopyridines on bleeding at high doses. We used multiple in vivo (FeCl(3)-induced arterial thrombosis in mesenteric arteries, blood loss after tail transsection, and platelet deposition and wound closure time in a micropuncture model in mesenteric veins) and ex vivo (light transmittance aggregometry, prothrombin time, and activated partial thromboplastin time) mouse models to 1) compare the TI of clopidogrel, prasugrel, and elinogrel, a reversible, competitive antagonist, with that in P2Y(12)(-/-) mice and 2) determine whether the bleeding consequences of the thienopyridines are attributed only to the inhibition of P2Y(12). Data indicated greater (elinogrel) and decreased (thienopyridines) TI compared with that in P2Y(12)(-/-) mice. The impaired TI associated with the thienopyridines was not attributed to non-P2Y(12) activities on platelet function or coagulation but was related to a direct effect at the vessel wall (inhibition of vascular tone). Further analysis showed that the prasugrel off-target effect was dose- and time-dependent and of a reversible nature. In conclusion, the TI of thienopyridines in the mouse may be decreased by P2Y(12)-independent off-target effects at the vessel wall, whereas that of elinogrel may be enhanced by the reversible, competitive nature of the antiplatelet agent.
authors: Portola Pharmaceuticals, Inc, 270 E. Grand Ave., South San Francisco, California 94080, USA.
authors: Patrick
authors: P
authors: André
authors: Francis
authors: F
authors: DeGuzman
authors: Helena
authors: H
authors: Haberstock-Debic
authors: Scott
authors: S
authors: Mills
authors: Yvonne
authors: Y
authors: Pak
authors: Mayuko
authors: M
authors: Inagaki
authors: Anjali
authors: A
authors: Pandey
authors: Stanley
authors: S
authors: Hollenbach
authors: David R
authors: DR
authors: Phillips
authors: Pamela B
authors: PB
authors: Conley
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006470:Hemorrhage / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D058919:Purinergic P2 Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D052999:Quinazolinones / Q000008:administration & dosage* / Q000009:adverse effects; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D058924:Thienopyridines / Q000008:administration & dosage* / Q000009:adverse effects; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology
chemical_list: C548577:P2ry12 protein, mouse; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D052999:Quinazolinones; D058925:Receptors, Purinergic P2Y12; D013449:Sulfonamides; D058924:Thienopyridines; C549473:elinogrel