Comparative evaluation of direct thrombin and factor Xa inhibitors with antiplatelet agents under flow and static conditions: an in vitro flow chamber model.
Dabigatran and rivaroxaban are novel oral anticoagulants that specifically inhibit thrombin and factor Xa, respectively. The aim of this study is to elucidate antithrombotic properties of these anticoagulant agents under arterial and venous shear conditions. Whole blood samples treated with dabigatran or rivaroxaban at 250, 500, and 1000 nM, with/without aspirin and AR-C66096, a P2Y12 antagonist, were perfused over a microchip coated with collagen and tissue thromboplastin at shear rates of 240 and 600 s(-1). Fibrin-rich platelet thrombus formation was quantified by monitoring flow pressure changes. Dabigatran at higher concentrations (500 and 1000 nM) potently inhibited thrombus formation at both shear rates, whereas 1000 nM of rivaroxaban delayed, but did not completely inhibit, thrombus formation. Dual antiplatelet agents weakly suppressed thrombus formation at both shear rates, but intensified the anticoagulant effects of dabigatran and rivaroxaban. The anticoagulant effects of dabigatran and rivaroxaban were also evaluated under static conditions using thrombin generation (TG) assay. In platelet-poor plasma, dabigatran at 250 and 500 nM efficiently prolonged the lag time (LT) and moderately reduce peak height (PH) of TG, whereas rivaroxaban at 250 nM efficiently prolonged LT and reduced PH of TG. In platelet-rich plasma, however, both anticoagulants efficiently delayed LT and reduced PH of TG. Our results suggest that dabigatran and rivaroxaban may exert distinct antithrombotic effects under flow conditions, particularly in combination with dual antiplatelet therapy.
Research Institute, Fujimori Kogyo Co., Yokohama, Kanagawa, Japan ; Department of System Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Kazuya
K
Hosokawa
Research Institute, Fujimori Kogyo Co., Yokohama, Kanagawa, Japan.
Tomoko
T
Ohnishi
Research Institute, Fujimori Kogyo Co., Yokohama, Kanagawa, Japan.
Hisayo
H
Sameshima
Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan.
Naoki
N
Miura
Department of System Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Takehiko
T
Koide
Department of System Biology in Thromboregulation, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Ikuro
I
Maruyama
Department of Anesthesiology, Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America.
Kenichi A
KA
Tanaka
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D000069604:Dabigatran; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D056656:Lab-On-A-Chip Devices; D008297:Male; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D000069552:Rivaroxaban; D013876:Thiophenes / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
C092108:2-propylthio-D-beta,gamma-difluoromethylene ATP; D000925:Anticoagulants; D000991:Antithrombins; D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D009025:Morpholines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D013876:Thiophenes; D015091:beta-Alanine; D000255:Adenosine Triphosphate; D005337:Fibrin; D013925:Thromboplastin; D000069552:Rivaroxaban; D013917:Thrombin; D015951:Factor Xa; D000069604:Dabigatran; D001241:Aspirin