Prevention of haemarthrosis in a murine model of acute joint bleeding.
Preservation of normal joint function in patients with haemophilia is a goal of modern therapy. Regular injections of anti-haemophilic factor concentrate reduce the risk of joint bleeding, the optimal regimen for which remains under investigation. The goals of the experiment described here are: (i) to assess the capacity of a murine model of severe haemophilic arthropathy to predict the likelihood of success of a test product to prevent joint bleeding and the complications that follow and (ii) to compare the effectiveness of recombinant human activated factor VII (rFVIIa) to recombinant human factor VIII (rFVIII) to prevent acute joint bleeding in the mouse model of haemarthrosis. Mice lacking expression of FVIII received a single intravenous injection of human rFVIII (280 U kg(-1)), rFVIIa (10 mg kg(-1)) or vehicle prior to blunt trauma injury to the knee joint. Mice receiving rFVIII and rFVIIa developed less injury-induced joint bleeding, swelling and loss of range of motion compared to mice pretreated with vehicle. Despite the reduction in clinical symptoms, synovial hyperplasia was evident in all groups after 7 days although less pronounced in mice receiving rFVIII and rFVIIa. The data under these experimental conditions demonstrate: (i) that this model can be used to evaluate novel therapies designed to prevent joint bleeding (prophylaxis) and (ii) both rFVIII and rFVIIa reduced acute haemarthrosis but did not completely prevent synovitis, the sequelae of blood induced joint injury.
Valentino
L A
LA
The RUSH Hemophilia and Thrombophilia Center, Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA. lvalentino@rush.edu
Hakobyan
N
N
Kazarian
T
T
Sorensen
B B
BB
Tranholm
M
M
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004341:Drug Evaluation / Q000379:methods; D005169:Factor VIII / Q000627:therapeutic use; D015942:Factor VIIa / Q000627:therapeutic use; D006395:Hemarthrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D007718:Knee Injuries / Q000150:complications / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000627:therapeutic use; D013583:Synovial Membrane / Q000473:pathology; D013585:Synovitis / Q000473:pathology / Q000517:prevention & control; D014949:Wounds, Nonpenetrating / Q000150:complications / Q000473:pathology
D011994:Recombinant Proteins; D005169:Factor VIII; C103587:recombinant FVIIa; D015942:Factor VIIa