title: Platelet activation biomarkers in Berkeley sickle cell mice and the response to prasugrel.
abstract: Vaso-occlusive crisis (VOC) is a common complication that occurs in sickle cell disease (SCD) patients. Although underlying mechanisms of VOC remain unclear, platelet activation has been associated with VOC. In the present study, plasma adenine nucleotide measurements using LC-ESI-MS/MS showed that plasma ADP in the Berkeley murine model of SCD was significantly higher (applox. 2.7-fold increase) compared with control mice. Assessment of platelet activation markers using flow cytometry indicated that in SCD mice at steady state (8 weeks old), circulating platelets were partially activated and this tended to increase with age (15 weeks old). The administration of prasugrel, a thienopiridyl P2Y12 antagonist, did not affect the activation state of circulating platelets suggesting P2Y12 independent mechanism of activation. In this murine SCD model, ex vivo addition of ADP or PAR4 TRAP resulted in further platelet activation as assessed by expression of activated GPIIb/IIIa and P-selectin both at 8 and 15 weeks. In 15 weeks old SCD mice, agonist-induced increases in activation markers were enhanced compared to control mice. Oral administration of prasugrel effectively inhibited ex vivo platelet activation consistent with clinical data in patients with SCD. In conclusion, in the Berkeley murine model of SCD, we found evidence of basal and agonist-stimulated platelet activation which could in part be attenuated by prasugrel. These data are consistent with observations made in patients with SCD and suggest possible utility of this murine model and prasugrel therapy in exploring treatment options for patients with SCD.
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Center for Pharmaceutical and Biomedical Analysis, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Samata
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Tomizawa
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. Electronic address: sugidachi.atsuhiro.r7@daiichisankyo.co.jp.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D019007:P-Selectin / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D019007:P-Selectin; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000068799:Prasugrel Hydrochloride
keywords: Adenine nucleotide; P2Y(12) antagonist; Platelet; Prasugrel; Sickle cell disease