Impact of Joint Bleeding on Joint Function in a Murine Model of Hemophilia A.

Abstract

Hemophilia is a congenital bleeding disorder that commonly results in musculoskeletal complications due to recurrent bleeding into joints. After an acute joint bleed, there is pain, swelling and limited motion due to the increase in intra-articular pressure and inflammation. Blood in the joint space provokes a proliferative and inflammatory disorder known as hemophilic synovitis (HS), which causes mechanical dysfunction and eventually destruction of the articular surface and bone. Among persons in the USA with severe hemophilia, nearly half have some restriction in activity (Evatt 2004) and it is estimated that 73% of boys enter adolescence with arthropathy and between 13–16 years of age, two or more major joints are affected (Brackmann,1992). Detail examination of the earliest changes in joint function following 1–3 joint hemorrhages is difficult to perform in patients. In this project, a murine model of HS (Valentino,2004) was used to examine the impact of a minimum number of hemarthrosis on joint function. The hypothesis tested was that there is a relationship between hemarthrosis and joint dysfunction. It was expected that joint dysfunction would be observed following few bleeds. Also, it was expected that a single hemarthrosis will result in permanent joint dysfunction. To test these hypotheses, 25 mice deficient in factor VIII coagulant activity were injured, times three, at weekly intervals to induce hemarthrosis then their ability to ambulate monitored using a Rotorod: Economex apparatus, which is intended for testing coordination and impairment of locomotor agility of laboratory animals. Mice were trained to ambulate on the rotating rod then injured and retested 2, 4 and 7 days after each hemarthrosis. A 2nd group of 25 mice was not injured and served as controls. At the conclusion of the experiment, mice were sacrificed and the knee joints examined by gross and histological methods. Correlations were drawn between the ambulatory dysfunction and the pathological changes observed. Preliminary data showed:mice can be trained to ambulate on the Rotarod,acute hemarthrosis temporarily impairs their ability to ambulate, andafter mice recover from acute injury they regain their lost ability to ambulate to the point that their performance is better than previous.