Abstract Number: PB0245
Meeting: ISTH 2020 Congress
Background: Current anticoagulants can reduce risks of venous thromboembolism and ischemic stroke, however, they have a certain risk of critical bleeding. Activated blood coagulation factor XI (FXIa) is a serine protease involved in the amplification of thrombin production. Elevated levels of plasma factor XI are associated with venous thromboembolism and ischemic stroke, while subjects with congenital FXI deficiency have less bleeding tendency.
Aims: To evaluate the effect of ONO-1600586, an oral direct FXIa inhibitor, in a rabbit model of venous thrombosis and skin bleeding.
Methods: Rabbits with fasting condition were orally administered a solvent as a control, a FXIa inhibitor (ONO-1600586, 50mg/kg), or a factor Xa inhibitor (rivaroxaban, 15 mg/kg) 90 minute before thrombus formation. The venous thrombus was induced by a balloon injury and stenosis in rabbit jugular vein, and was weighted 3 hours after the thrombus formation. The bleeding time and volume were evaluated with 3 cm length of skin incision on thigh. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured before, 75 minutes and 4.5 hours after the drug administration.
Results: ONO-1600586 prolonged aPTT 2.7 times but not PT at 4.5 hours. Rivaroxaban prolonged PT 1.5 times and aPTT 1.5 times at 4.5 hours. ONO-1600586 (81 +/- 65 mg, n=11, p< 0.01) and rivaroxaban (64 +/- 51 mg, n=9, p< 0.01) similarly reduced venous thrombus weight, compared with that of control (207 +/- 91 mg, n=9). Rivaroxaban prolonged the bleeding time (20 +/- 8 minutes, n=9, p< 0.05) and increased the bleeding volume (185 +/- 86 µL, n=9, p< 0.05), compared with that of control (7.8 +/- 4.7 minutes, 83 +/- 30 µL, n=9) and ONO-1600586 (8.3 +/- 4.2 minutes, 94 +/- 46 µL, n=11).
Conclusions: ONO-1600586 may be a safer anticoagulant targeting FXIa for venous thromboembolism.
To cite this abstract in AMA style:Oguri N, Yamashita A, Okawa H, Kouyama S, Asada Y. ONO-1600586, an Oral Direct Factor XIa Inhibitor, Suppresses Thrombus Formation in Rabbit Jugular Vein without Bleeding Tendency [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/ono-1600586-an-oral-direct-factor-xia-inhibitor-suppresses-thrombus-formation-in-rabbit-jugular-vein-without-bleeding-tendency/. Accessed May 6, 2021.
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