Effect of the Direct Factor Xa Inhibitor Apixaban in Rat Models of Thrombosis and Hemostasis

Abstract

Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. Apixaban was evaluated in rat thrombosis and hemostasis models. Thrombosis was produced in the carotid artery by FeCl2 application, in the vena cava by either FeCl2 application or tissue factor injection, and in an arterial-venous shunt. Hemostasis was assessed using cuticle, renal cortex, and mesenteric artery bleeding times. Intravenous apixaban infusions of 0.1, 0.3, 1, and 3 mg/kg per hour increased the ex vivo prothrombin time to 1.24, 1.93, 2.75, and 3.98 times control, respectively. The 0.3, 1, and 3-mg/kg per hour doses inhibited thrombosis in all models. Concentrations for 50% thrombus reduction ranged from 1.84 to 7.57 microM. The 3-mg/kg per hour dose increased cuticle, renal, and mesenteric bleeding times to 1.92, 2.13, and 2.98 times control, respectively. Lower doses had variable (1 mg/kg per hour) or no effect (0.1, 0.3 mg/kg per hour) on hemostasis. Heparin's prolongation of renal and cuticle bleeding time was twice that of apixaban when administered at a dose that approximated apixaban (3 mg/kg per hour) efficacy in arterial thrombosis. In summary, apixaban was effective in a broad range of thrombosis models at doses producing modest increases in multiple bleeding time models.

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

“…On the basis of the calculation from concentrations reported in literature, we found that >50% inhibition of thrombosis was observed at >97% fXa EO in a venous and arterial FeCl 2 thrombosis model and at >99% fXa EO in stasis and AVS thrombosis models in the rat, thus validating the choice of the model and animal species (Schumacher et al. 2010). These levels were consistent with the 99.2% calculated EO achieved at apixaban median C min (107 ng/mL) at the 5 mg BID SPAF dose.…”

“…2009; Schumacher et al. 2010). It should be noted, however, that the apixaban doses, their pharmacodynamic effects (e.g., PT), and their antithrombotic activities were directly in agreement with published literature (Schumacher et al.…”

“…It should be noted, however, that the apixaban doses, their pharmacodynamic effects (e.g., PT), and their antithrombotic activities were directly in agreement with published literature (Schumacher et al. 2010). While it is possible that small differences in CBT assay techniques may have accounted for bleeding effects at intermediate levels of inhibition of thrombosis, it seems unlikely that our assay techniques were solely responsible for this discrepancy as the bleeding associated with modulation of fIX and fIXa were in line with the phenotype of hemophilia B patients and the extended bleeding observed in animal models of hemophilia B (Gui et al.…”

“…Rat protocols of AVS and CBT were based on previously published procedures (Schumacher et al. 2010; Metzger et al. 2015) and performed in the same animal.…”

Risk of long-term anticoagulation under sustained severe arterial hypertension: A translational study comparing warfarin and the new oral anticoagulant apixaban

“…Regarding the translational relevance, it has to be mentioned that both similarities and differences exist between human and rodent coagulation systems. 31 Unfortunately, due to its long-term design, important pathophysiological measures could not be determined in this study. In particular, brain water content measurements are frequently performed in the context of experimental ICH.…”