Biomarkers as Diagnostic and Prognostic Tools for Hemophilic Arthropathy.

Repeated joint bleeds cause hemophilic arthropathy, which can develop despite regular prophylaxis with clotting factors. Therefore, recognizing ongoing or subclinical bleeds is an important element of assessing the therapeutic needs of patients with hemophilia. Joint bleeds lead to the remodeling of the synovia and subsequent osteochondral damage if bleeding persists or recurs. These processes can be demonstrated by biomarkers in the synovial fluid, blood, or urine, in addition to conventional imaging. Biomarkers that are upregulated in patients with hemophilia in the context of joint bleeds and synovitis are markers of fibrinolysis, inflammation and angiogenesis while markers of extracellular matrix degradation indicate osteochondral damage. Blood-induced inflammation and cartilage damage of the joint correlates with the release of iron-generated reactive oxygen species, IL-1β, and tumor necrosis factor α, which in turn induce the expression of IL-6 and C-reactive protein. Joint bleeds can also cause the release of the endothelial basement membrane markers C4M and Pro-C4 into the blood circulation. Upregulation of biomarkers of osteochondral damage, such as CTX-II, cartilage oligomeric matrix protein, and CS846, results from the dissolution of collagen type 2 and associated proteoglycans in the extracellular matrix of the cartilage. These biomarkers have been shown to indicate blood-induced inflammation, angiogenesis, and cartilage dysfunction but their capacity to predict critical milestones such as the transition to synovia hypertrophy or osteochondral damage needs to be assessed. Further research is necessary to resolve the natural history of hemophilic arthropathy and to provide patients with hemophilia with novel tools to predict disease and treatment outcomes.