Recombinant human prothrombin (MEDI8111) prevents bleeding in haemophilia A and B mice

Background Haemophilia A and B are treated with FVIII and FIX replacement therapy. Treatment may be complicated by inhibitory antibodies that require bypass therapy such as FEIBA ® in which prothrombin ( FII ) is suggested to be the main active component. Methods To evaluate the effect of FII on haemophilia recombinant human (rh) FII ( MEDI 8111) or plasma‐derived human FII (pdh FII ) was given as single doses to anaesthetized haemophilia A and B mice 3 min before tail transection and rh FVIII or rh FIX was used for comparison. After tail transection, automatic bleeding registration was used to continuously measure blood loss ( BL ) and bleeding time ( BT ). Thrombin generation and plasma concentrations of human FVIII , FIX , FII and thrombin–antithrombin complex ( TAT ) were measured. Results Blood loss and BT were dose‐dependently decreased by rh FVIII or rh FIX . The concentrations that decreased BL and BT for rh FVIII by 50% ( EC 50) were 0.06 and 0.01 IU mL −1 and for rh FIX 0.07 and 0.07 IU mL −1 , respectively. Administration of rh FVIII and rh FIX dose‐dependently increased thrombin generation potential but did not affect TAT . MEDI 8111 and pdh FII dose‐dependently decreased BL and BT in haemophilia A mice, EC 50 37 and 87 and 100 and 155 mg L −1 respectively. In haemophilia B mice given MEDI 8111 EC 50 was for BL 56 mg L −1 and for BT 67 mg L −1 . TAT and thrombin generation increased dose‐dependently for MEDI 8111 and pdhFII. Conclusion MEDI 8111 dose‐dependently decreased bleeding and increased procoagulant activity in haemophilia A and B mice and suggest that MEDI 8111 may be useful for preventing bleeding in patients with haemophilia A and B.