DX-9065a, an orally active factor Xa inhibitor, does not facilitate haemorrhage induced by tail transection or gastric ulcer at the effective doses in rat thrombosis model

DX-9065a is an ancithrombin III (AT III)-independent and selective inhibito r of activated blood coagulation factor X (FXa). We evaluated the effects o f DX-9065a and warfarin on bleeding time and blood loss in rat tail transec tion model and on blood loss in hydrochloride (HCl)-induced rat gastrointes tinal haemorrhage model. The blood loss was determined by measuring the hae moglobin content in saline immersed with transected tail or hematin chlorid e content in the gaster after HCl administration. DX-9065a or warfarin was administered orally at 1 h or 15-21 h before the haemorrhagic stimuli, resp ectively. The dose required for 50% inhibition of thrombus formation (ID50) was 21 mg/kg for DX-9065a and 0.75 mg/kg for warfarin in a copper wire-ins erted arteriovenous (AV) shuns model. In contrast to DX-9065a (10 or 30 mg/ kg), warfarin (0.75 mg/kg) significantly prolonged the bleeding time. In ra t tail transection model, the blood loss for the control group was 102 +/- 41 mu l at 20 min after the transection. While warfarin (0.75 mg/kg) facili tated the blood loss about 5 times as much as the control, DX-9065a (10 or 30 mg/kg) did not. In rat gastrointestinal model, the blood loss for the co ntrol group was 15.9 +/- 5.6 mu l at 15 min after HCl administration. In co ntrast to DX-9065a (10 or 30 mg/kg), warfarin (0.75 mg/kg) increased the bl ood loss about twice as much as the control. Thus, compared with warfarin, DX-9065a only increased bleeding time or blood loss to a minor extent in th e doses tested. These observations suggest that direct inhibition of FXa co uld be preferable to warfarin in the suppression of thrombosis without haem orrhagic complications.