Experimental haemophilic synovitis: rationale and development of a murine model of human factor VIII deficiency

Abstract

Haemophilia is a genetic disease as a result of the deficiency of blood coagulation factor VIII or IX. Bleeding is common, especially into joints where an inflammatory, proliferative synovitis develops resulting in a debilitating arthritis, haemophilic arthropathy. The pathogenesis of blood-induced haemophilic synovitis (HS) is poorly understood. The gross, microscopic and ultrastructural changes that occur in the synovial membrane following human and experimental hemarthrosis have been described. Repeated episodes of bleeding induce synoviocyte hypertrophy and hyperplasia, an intense neovascular response and inflammation of the synovial membrane. The component(s) in blood that initiates these changes is(are) not known, although iron is often proposed as one possibility. Here, we describe a novel murine model of human haemophilia A, which facilitates the examination of large number of animals and tissue specimens. The effects of hemarthrosis on the physical, gross and microscopic changes evoked following joint bleeding are described. Controlled, blunt trauma to the knee joint consistently resulted in joint swelling because of a combination of bleeding and inflammation. Hemosiderin was found in the synovial membrane. Similar to hemarthrosis in human haemophilia, joint bleeding resulted in acute morbidity evidenced by inactivity, weight loss and immobility. With time the animals recovered. The model of experimental murine HS described here has utility in the study of the pathogenesis of HS. This is the first of a series of articles, which will discuss the pathophysiology and characterize the model, with comparison of his model to others which have been published previously. It should provide a useful model to test potential therapeutic interventions.

Buprenorphine does not impact the inflammatory response in haemophilia A mice with experimentally-induced haemarthrosis

“…The analgesic dosing regimen was decided as recommended by Hau et al 45 At termination the knee joints were opened, inspected macroscopically, and bleeding was scored according to the visual bleeding score (VBS). 46 Body weight and joint diameter were measured before the induction of the joint bleed and again at termination. Blood was sampled from the retro-orbital plexus, and synovial fluid was sampled from both knee joints.…”

“…The joint cavity was assessed and the presence of blood was noted. The joint was scored according to the VBS 46 based on the presence of blood and the degree of distension of the joint cavity.…”

State‐of‐the‐art imaging techniques for the evaluation of haemophilic arthropathy: present and future

“…Some authors [6][7][8][9] suggest that intra-articular blood has a precursor direct effect on cartilage, as a result of the iron-catalysed formation of destructive oxygen metabolites, subsequently affecting the synovium. Other authors [10,11] suggest that there is a hemosiderin-induced synovial triggering process. Nevertheless, most likely both processes occur in parallel, and while they influence each other, they probably do not depend on each other.…”

“…Nevertheless, most likely both processes occur in parallel, and while they influence each other, they probably do not depend on each other. It is well known, however, that synovial changes precede cartilage changes over the course of haemophilic arthropathy [10].…”

Previously undiagnosed hemophilia patient with intracerebral hemorrhage

“…In 90% of the patients aged 25 or younger a severe bleeding to major joint happens. [9][10][11][12][13][14] In our patient, recurrent bleeding into the knee joint caused secondary arthropathy. In patients with hereditary factor deficiency fresh frozen plasma (10-15 mL/kg) may be administered until hemophilia A or B diagnosis is reached.…”