Exploring the biological basis of haemophilic joint disease: experimental studies

Abstract

Haemophilia has been recognized as the most severe among the inherited disorders of blood coagulation since the beginning of the first millennium. Joint damage is the hallmark of the disease. Despite its frequency and severity, the pathobiology of blood-induced joint disease remains obscure. Although bleeding into the joint is the ultimate provocation, the stimulus within the blood inciting the process and the mechanisms by which bleeding into a joint results in synovial inflammation (synovitis) and cartilage and bone destruction (arthropathy) is unknown. Clues from careful observation of patient material, supplemented with data from animal models of joint disease provide some clues as to the pathogenesis of the process. Among the questions that remain to be answered are the following: (i) What underlies the phenotypic variability in bleeding patterns of patients with severe disease and the development of arthropathy in some but not all patients with joint bleeding? (ii) What is the molecular basis underlying the variability? (iii) Are there strategies that can be developed to counter the deleterious effects of joint bleeding and prevent blood-induced joint disease? Understanding the key elements, genetic and/or environmental, that are necessary for the development of synovitis and arthropathy may lead to rational design of therapy for the targeted prevention and treatment of blood-induced joint disease.

Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis

“…In hemophilia bleeding is very common, especially into joints, where an inflammatory, proliferative synovitis develops. This results in hemophilic arthropathy, a multifactorial event in which the deposition of iron in the joints appears to exert a central role [32]. PDT induced hemorrhagic events followed by hemosiderin formation and iron deposition in the synovial membrane may contribute to the sustained inflammation after the treatment in our CIA mice.…”

Components in Plasma-Derived Factor VIII, But Not in Recombinant Factor VIII Downregulate Anti-Inflammatory Surface Marker CD163 in Human Macrophages through Release of CXCL4 (Platelet Factor 4)

“…In accordance with this, local synovial iron deposits are associated with increased catabolic activities in hemophilia [4]. Careful observation of patient material supplemented with data from animal models of joint disease clearly showed that the major mechanism of hemoglobin-induced joint injury is the deposition of iron in superficial and subsynovial layers of the joint, which is a hallmark of hemophilic synovitis [5]. Iron increases proliferation of synovial cells in a concentration-dependent manner and induces upregulation of mouse double minute 2 homolog (Mdm2) gene [6].…”

“…In normal cells, the Mdm2 binds to the tumor suppressor protein p53 and prevents its function [7,8]. Therefore, Mdm2 overexpression was proposed to be a suitable target in treating the underlying cell proliferation that leads to synovitis and arthropathy in hemophilia [5]. …”

An uncommon cause of elbow synovitis in an adult haemophilia patient

“…Such a hypertrophic synovium is then called haemophilic synovitis. The problem is that the hypertrophic synovium is very richly vascularized, and very prone to recurrent bleeding [1,2]. We present a very uncommon cause of unresponsive elbow synovitis in an adult haemophilia patient.…”