Potential role of proteases in HA. During hemarthroses, blood comes into contact with joint structures. The introduction of blood causes an influx of iron (Fe), interacting with hydrogen peroxide (H₂O₂) produced by chondrocytes, resulting in hydroxyl radicals (OH), causing chondrocyte apoptosis. Type A synoviocytes incorporate hemosiderin and produce proinflammatory cytokines IL-1α, IL-6, and TNF-α, leading to an intraarticular cytokine storm that worsens cartilage and bone damage. These cytokines promote the recruitment and activation of monocytes and macrophages, prompting of production of MMPs and plasminogen activators (uPA and tPA). Synovial tissue proliferation occurs under inflammatory conditions to produce pro-MMPs and upregulate uPA, while angiogenesis occurs under the influence of VEGF, leading to the formation of synovial pannus. There is a hemostatic imbalance in the synovial fluid of patients with hemophilia. It is characterized by high levels of thrombomodulin and impaired TAFI activation due to low TF levels. Lack of TAFI activation, in turn, enhances uPA-mediated fibrinolysis and consequent clot instability leading to premature clot lysis. The influx of plasminogen occurs with blood and is converted to plasmin by uPA. Plasmin activates MMPs to degrade cartilage and bone. ADAMTS, a disintegrin and metalloprotease with thrombospondin type 1 motifs; MMP: matrix metalloprotease; TF, tissue factor; TFPI, thrombin activatable fibrinolysis inhibitor; TM, thrombomodulin. Created with Biorender.com.