title: Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice: rationale, development and prophylactic intervention.
abstract: BACKGROUND
  Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available specifically investigating spontaneous muscle bleeds in a hemophilic setting.
  
  
  OBJECTIVE
  The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology.
  
  
  METHODS
  A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice after treadmill exercise; (ii) a study evaluating the pharmacokinetics of recombinant FIX (rFIX) in hemophilia B mice and based on these data; (iii) the treatment study, which tested therapeutic intervention with rFIX. At termination of the treadmill studies the presence of bleeds was evaluated.
  
  
  RESULTS
  Treadmill exercise resulted in a high incidence of muscle bleeds in F9-KO mice but not in C57BL/6NTac mice. Treating hemophilia B mice with rFIX before treadmill exercise prevented muscle bleeds.
  
  
  CONCLUSIONS
  A novel model of muscle bleeds in hemophilia B mice, responsive to rFIX, has been developed.
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Tranholm
authors.forename: A T
authors.initials: AT
authors.lastname: Kristensen
authors.forename: M L
authors.initials: ML
authors.lastname: Broberg
authors.forename: M P
authors.initials: MP
authors.lastname: Groth
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D003029:Coagulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005164:Factor IX / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006406:Hematoma / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D002836:Hemophilia B / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D006470:Hemorrhage / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009135:Muscular Diseases / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D005082:Physical Exertion; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D003029:Coagulants; D011994:Recombinant Proteins; D005164:Factor IX
keywords: animal model; hematoma; hemophilia B; muscles; treadmill test