Coactivation of platelets and the blood coagulation cascade contributes to the pathophysiology of arterial
thrombosis. Combination
therapy with antiplatelet and
anticoagulant drugs may be needed for maximizing the prevention and treatment of arterial
thrombosis. Few studies have thoroughly investigated the combined antithrombotic and
bleeding effects of these
antithrombotic agents. We, therefore, evaluated the antithrombotic and
bleeding profiles of dual and triple
therapy with
razaxaban, a
direct factor Xa inhibitor, plus
aspirin and/or
clopidogrel in rabbit models of electrolytic injury-induced
carotid artery thrombosis and cuticle bleeding time, respectively. Compounds were infused either IV or into the portal vein from 1 h before arterial injury or cuticle transection to the end of experiment. Carotid blood flow was used as a marker of antithrombotic effect. We first evaluated the antithrombotic potency of
razaxaban, and examined its ex vivo effects on coagulation parameters to confirm its selectivity. Antithrombotic ED(50) of
razaxaban averaged 0.22 +/- 0.05 mg/kg/h (n = 6).
Razaxaban at 3 mg/kg/h IV produced full antithrombotic efficacy, increased significantly ex vivo activated partial thromboplastin time and prothrombin time by 2.2 +/- 0.1- and 2.3 +/- 0.1-fold, respectively, and inhibited ex vivo
factor Xa activity significantly by 91 +/- 5% (n = 6, P < 0.05) without affecting ex vivo
thrombin activity.
Razaxaban at concentrations up to 10 muM did not alter in vitro platelet aggregation responses to
ADP,
gamma-thrombin or
collagen. To identify additive or synergistic antithrombotic effects of the various combination
therapies, we purposefully used marginally effective doses of
razaxaban at 0.1 mg/kg/h,
aspirin at 0.3 mg/kg/h and
clopidogrel at 1 mg/kg/h. Dual combination of threshold doses of
razaxaban and
aspirin or
clopidogrel produced an enhanced antithrombotic effect without further increases in bleeding time. When compared with dual
therapy with
aspirin and
clopidogrel (38 +/- 5% increase in blood flow), addition of
razaxaban increased blood flow to 75 +/- 5% without additional bleeding time effects (n = 6/group, P < 0.05). In summary,
razaxaban was an effective
antithrombotic agent in a rabbit model of arterial
thrombosis. Low-dose
razaxaban was useful in combination with sub-optimal doses of
aspirin and/or
clopidogrel for the prevention of occlusive arterial
thrombosis without excessive
bleeding.