The effect of the oral direct activated factor X (factor Xa) inhibitor apixaban 
on tissue factor-induced thrombin generation in human plasma was investigated in 
vitro using the calibrated automated thrombogram (CAT) method and compared with 
the oral direct factor Xa inhibitor rivaroxaban and the direct thrombin 
inhibitor dabigatran. Pooled citrated, anticoagulated, platelet-poor human 
plasma was spiked with apixaban, rivaroxaban, or dabigatran at concentrations of 
0.01 to 10 μM. The inhibitory potencies of the compounds were quantified by 5 
CAT parameters: the control thrombin lag time (LT) and time to thrombin peak 
(TTP) for the doubling of inhibitor concentration (IC2x); and the control 
endogenous thrombin potential (ETP), thrombin peak, and maximum rate of thrombin 
generation (Vmax) for the inhibitor concentration, which inhibited 50% (IC50). 
The inhibitors modified CAT concentration dependently. Their inhibitory 
potencies, expressed as IC2x LT, IC2x TTP, IC50 ETP, IC50 peak thrombin, and 
IC50 Vmax, were as follows: 0.10 ± 0.01, 0.19 ± 0.02, 0.65 ± 0.11, 0.089 ± 
0.019, and 0.049 ± 0.007 μM for apixaban; 0.049 ± 0.007, 0.070 ± 0.009, 0.43 ± 
0.07, 0.048 ± 0.008, and 0.022 ± 0.005 μM for rivaroxaban; and 0.063 ± 0.019, 
0.18 ± 0.06, 0.50 ± 0.08, 0.55 ± 0.06, and 0.57 ± 0.27 μM for dabigatran. In 
summary, apixaban, rivaroxaban, and dabigatran have similar potencies in the 
prolongation of LT and TTP. The CAT parameters that are related to the rate of 
thrombin generation during the propagation phase (ie, peak thrombin and Vmax) 
are more sensitive to activities of apixaban and rivaroxaban than dabigatran. 
The ETP is the least sensitive parameter for measuring the activities of these 
inhibitors. Recombinant activated factor VII at 5 and 50 μg/mL reversed the 
anticoagulant effects of apixaban more at 0.2 μM than at 2 μM. Our study 
suggests that the CAT method is a sensitive assay to monitor the pharmacodynamic 
and pharmacokinetic properties of apixaban, rivaroxaban, and dabigatran, and may 
provide insight into the mechanism of action of these inhibitors. Recombinant 
activated factor VII may have some potential to reverse the anticoagulant 
effects of apixaban in vitro.