Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in 
late-stage clinical development. This study evaluated the in vitro effect of 
apixaban on human platelet aggregation induced by thrombin derived via the 
extrinsic pathway. Direct inhibitors of FXa (rivaroxaban), FVIIa (BMS-593214), 
thrombin (dabigatran, argatroban) and FXIa (BMS-262084) were included for 
comparison. Citrated human platelets-rich plasma (PRP) was treated with 50 mg/ml 
corn trypsin inhibitor (to block the contact factor pathway) and 3 mM 
H-Gly-Pro-Arg-Pro-OH-AcOH (to prevent fibrin polymerisation). Human tissue 
factor (TF) (Innovin; dilution 1:1,000 to 1:1,500) plus 7.5 mM CaCl2 was added 
to PRP pre-incubated with vehicle or increasing concentrations of inhibitors. 
The TF-induced platelet aggregation was measured by optical aggregometry. TF 
produced 85 +/- 3% aggregation of human platelets in the vehicle-treated group 
(n=10). Apixaban and other factor inhibitors, except the FXIa inhibitor, 
inhibited TF-induced platelet aggregation with IC50 (nM) values as follows: 4 
+/- 1 (apixaban), 8 +/- 2 (rivaroxaban), 13 +/- 1 (BMS-593214), 46 +/- 1 
(dabigatran) and 79 +/- 1 (argatroban). BMS-262084 (IC50 = 2.8 nM vs. human 
FXIa) had no effect on TF-induced platelet aggregation at 10 microM. These 
inhibitors at 10 microM had no effect on platelet aggregation induced by ADP and 
collagen, as expected from their mechanism of action. This study demonstrates 
that inhibition of thrombin generation by blocking upstream proteases (FVIIa and 
FXa) in the blood coagulation cascade is as effective as direct thrombin 
inhibition in preventing TF-induced platelet aggregation. Under these 
experimental conditions, a FXIa inhibitor did not prevent TF-induced platelet 
aggregation.