A Compartment-Specific Histopathological Framework for Experimental Hemophilic Arthropathy

Background: Hemophilic arthropathy is a complex multi-compartmental joint disease. Synovial inflammation and hyperplasia, vascular remodeling, cartilage matrix depletion, and structural cartilage damage represent related but distinct components of the disease process. Experimental models are essential for investigating these processes and evaluating potential joint-directed interventions. Histopathological assessment therefore requires standardized approaches capable of evaluating individual joint compartments rather than relying exclusively on a single global histopathology outcome.,Objective: To test whether a standardized, compartment-specific framework could be applied to experimental hemophilic joint disease. .,Methods: Hemarthrosis was induced in hemophilia B mice by one or three joint capsule punctures 15 days apart (n=7/group), with non-injured hemophilic mice as controls. Knees were collected 15 days after the final bleed. Three examiners blinded to the experimental conditions assessed synovial pathology, cartilage proteoglycan loss, and cartilage erosion according to SMASH recommendations, with additional quantification of synovial vascularization.,Results: A single joint bleed resulted in marked synovial thickening and an increase in synovial pathology compared versus controls. Synovial abnormalities persisted after repeated bleeds, with pannus formation and cartilage invasion. Proteoglycan loss was significantly increased after both single and repeated bleeds, whereas increased synovial vascularization and cartilage erosion were observed after repeated bleeds. Thus, individual histopathological parameters captured distinct dimensions of blood-induced joint pathology rather than behaving as a single uniform outcome.,Conclusion: A standardized, compartment-specific approach combining SMASH criteria with synovial vascularization enables a more precise assessment of synovial and cartilage pathology and may provide relevant endpoints for preclinical studies of hemophilic arthropathy.