title: Recombinant human prothrombin (MEDI8111) prevents bleeding in haemophilia A and B mice.
abstract: 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 (MEDI8111) or plasma-derived human FII (pdhFII) was given as single doses to anaesthetized haemophilia A and B mice 3 min before tail transection and rhFVIII or rhFIX 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 rhFVIII or rhFIX. The concentrations that decreased BL and BT for rhFVIII by 50% (EC50) were 0.06 and 0.01 IU mL(-1) and for rhFIX 0.07 and 0.07 IU mL(-1) , respectively. Administration of rhFVIII and rhFIX dose-dependently increased thrombin generation potential but did not affect TAT. MEDI8111 and pdhFII dose-dependently decreased BL and BT in haemophilia A mice, EC50 37 and 87 and 100 and 155 mg L(-1) respectively. In haemophilia B mice given MEDI8111 EC50 was for BL 56 mg L(-1) and for BT 67 mg L(-1) . TAT and thrombin generation increased dose-dependently for MEDI8111 and pdhFII.
  
  
  CONCLUSIONS
  MEDI8111 dose-dependently decreased bleeding and increased procoagulant activity in haemophilia A and B mice and suggest that MEDI8111 may be useful for preventing bleeding in patients with haemophilia A and B.
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMED, Mölndal, Sweden.
authors.forename: K M
authors.initials: KM
authors.lastname: Hansson
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMED, Mölndal, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMED, Mölndal, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Elg
authors.affiliation: Department of Bioscience, AstraZeneca R&D, CVMD iMED, Mölndal, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Lövgren
mesh_terms: D000818:Animals; D003029:Coagulants / Q000627:therapeutic use; D004195:Disease Models, Animal; D005164:Factor IX / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D005169:Factor VIII / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy*; D002836:Hemophilia B / Q000188:drug therapy*; D006470:Hemorrhage / Q000517:prevention & control; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011516:Prothrombin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D003029:Coagulants; D011994:Recombinant Proteins; D011516:Prothrombin; D005169:Factor VIII; D005164:Factor IX
keywords: bleeding; coagulation; haemophilia; prothrombin