Abstract
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.
Highlights
Oral anticoagulants, dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor Xa inhibitor represent novel therapeutic strategies for the prevention of deep vein thrombosis, and for the stroke prevention in atrial fibrillation [1]
We evaluated the antithrombotic efficacies of dabigatran and rivaroxaban alone or in combination with antiplatelet agents by analyzing in vitro thrombus formation patterns under arterial and venous shear conditions in a flowchamber system
Thrombus formation was accelerated in the control blood samples at a shear rate of 600 s21
Summary
Dabigatran, a direct thrombin inhibitor (anti-IIa), and rivaroxaban, a direct factor Xa inhibitor (anti-Xa) represent novel therapeutic strategies for the prevention of deep vein thrombosis, and for the stroke prevention in atrial fibrillation [1]. It has been suggested that the addition of anti-IIa or anti-Xa agent to antiplatelet therapy may improve clinical outcomes after ACS [6,7,8,9,10] These combination therapies are often associated with the increased risk of bleeding complications, implicating a relatively narrow therapeutic dose window [8,9,10]. It is, clinically important to individually assess residual hemostatic functions by testing anticoagulant and antiplatelet agents under the same conditions. Some of the latter limitations may be overcome by evaluating fibrin-rich platelet thrombus formation under flow conditions [12]
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