Initiation of degenerative joint damage by experimental bleeding combined with loading of the joint: A possible mechanism of hemophilic arthropathy

Abstract

Objective. To investigate the effect of a limited number of experimental joint bleedings, combined with loading of the affected joint, on the development of progressive degenerative joint damage.Methods. The right knee of 8 mature beagle dogs was injected with freshly collected autologous blood 3 times per week for 4 weeks, to mimic a limited number of joint hemorrhages occurring over a short period. To ensure loading of the experimental joint, the contralateral control knee of the animals was fixed to the trunk 4 hours per day, 3 days per week. Ten weeks after the last injection, cartilage tissue and synovium were collected from both knees to analyze features of joint degeneration. Cartilage was prepared for analysis of proteoglycan turnover (synthesis, retention, release, and content) and histologic features. Synovium was prepared for histologic analysis.Results. The rate of proteoglycan synthesis was significantly increased, characteristic of degenerative cartilage damage as seen in osteoarthritis. Release of newly formed proteoglycans (as a measure of retention) and total loss of proteoglycans from the cartilage matrix were increased. Cartilage matrix integrity was adversely altered, as shown by histologic damage. Histologic analysis also revealed signs of synovial inflammation. These effects were not observed 10 weeks after the experimental bleedings in joints that did not undergo forced loading.

Exposure of human cartilage tissue to low concentrations of blood for a short period of time leads to prolonged cartilage damage: An in vitro study

“…These in vitro findings were confirmed by in vivo animal studies (11,15,16). Although the effects revealed in the in vivo experiments in animals were less dramatic than has been observed in human joints, they clearly resulted in compromised joint cartilage, which is predictive of cartilage degenerative changes in the long term (11,15,16).…”

“…A 4-day period of exposure is assumed to be the natural time span of evacuation of blood from a joint (13,14), and at least 50% (v/v) blood in a synovial joint is the blood load expected to be present shortly after bleeding takes place (4). These in vitro findings were confirmed by in vivo animal studies (11,15,16). Although the effects revealed in the in vivo experiments in animals were less dramatic than has been observed in human joints, they clearly resulted in compromised joint cartilage, which is predictive of cartilage degenerative changes in the long term (11,15,16).…”

“…Moreover, physicians are reluctant to perform joint aspiration because of the potential for infection and, in the case of hemophilia, because of additional sites of bleeding. Since there is circumstantial evidence to support the view that aspiration of a joint is indicated to prevent joint damage later in life (3)(4)(5)(6)(9)(10)(11)15,16), the present study was initiated to determine the thresholds of blood exposure time and blood load that lead to long-lasting cartilage damage. A possible difference between coagulating and noncoagulating blood was taken into account, because it is not known whether blood coagulates in a joint, and if so, to what extent.…”

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations

“…Angiogenesis caused by VEGF release may also exacerbate synovitis [2,4]. Additionally, physical factors such as joint loading may act synergistically to cause long-term joint damage after joint bleeds [7]. In vitro studies demonstrate that these changes occur in a doseand time-dependent manner, and that a duration of joint exposure to blood as short as 2 days may be sufficient to initiate long-term changes [5].…”

Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX

“…Confirmation of efficacy of the IA approaches in large animals will be valuable, nonetheless; the progression of hemarthropathy may depend on weight-loading of the bleeding-damaged joint, with the effect increased in heavier animals. 63 In addition, gene expression using AAV serotypes has not always translated directly from mouse to large animals. 64 These investigations, documenting the capacity of IA FIX protein or gene therapy to protect the joint from bleeding-induced synovitis, suggest that joint-directed therapies may be useful adjuncts in hemophilia care, in addition to the intravascular replacement of deficient factor activity.…”