Characterizing early blood-induced joint damage: towards new treatment modalities of hemophilic arthropathy

Musculoskeletal bleeding is the hallmark of hemophilia and cannot be completely prevented despite clotting factor prophylaxis. Blood in the joint results in synovial inflammation, cartilage degeneration and bone remodelling. Recurrent joint bleeding leads to the disabling condition called hemophilic arthropathy. To date, there is no treatment that directly intervenes in this process.

This thesis focuses on the early disease process of blood-induced joint damage. This involves the timely identification of hemophilia patients who are at risk of hemophilic arthropathy. We demonstrated in a retrospective study that the combination of the biomarkers uCTX-II and sCS-846, measured in urine and serum, differentiates between hemophiliacs with rapidly and slowly progressive hemophilic arthropathy. A prospective study is needed to establish its prognostic value.

Moreover, this thesis contributes to the understanding of animal models to study early pathological changes in the joint. Optimizing these preclinical models is critical for animal welfare and relevance to clinical practice. Based on the pathophysiology targets for therapy of blood-induced joint damage can be derived. The role of iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration are promising in this respect. Iron plays a pivotal role in the process of blood-induced athropathy, causing both inflammation and oxidative stress. We demonstrated that treatment with the iron chelator deferasirox at the time of bleeding does not prevent joint damage in hemophilic mice. Therefore, the application of systemic iron chelation as a therapeutic solution does not seem feasible, but in vitro research suggests that deferasirox may have a chondroprotective effect via inhibition of the NF-ĸB signaling. However, deferasirox is harmful to chondrocytes in the absence of blood, complicating its use in clinical practice.

In conclusion this thesis further increased our understanding of the pathophysiology of early blood-induced arthropathy by identifying patients at increased risk, optimizing preclinical models and studying iron chelation as a treatment, providing a basis for the development of new treatment strategies to prevent hemophilic arthropathy.