Introduction: Interstitial, cartilage, and bone collagens have been proposed as biomarkers of joint deterioration in hemophilic arthropathy. The role of basement membrane (type IV and VIII) collagens as biomarkers of endothelial turnover in relation to acute joint bleeding is not understood.

Methods: Thirty-one adult patients with hemophilia were studied prospectively for 3 years with musculoskeletal ultrasound/power Doppler (MSKUS/PD) during pain-free intervals and painful events for joint bleed status, synovial vascular flow, and 10 plasma markers of collagen turnover. Joint health was determined using Hemophilia Joint Health Scores and Pettersson scores. In animal studies, bleeding was induced in factor VIII-/- mice by knee joint injury. Synovial vascular remodeling was assessed using MSKUS/PD and histology. Murine plasma samples were analyzed for type IV collagen turnover markers.

Results: Ninety-one patient visits were compiled. Twenty-five were due to acute painful episodes, with 16 confirmed hemarthroses. Type IV collagen turnover markers (PRO-C4 and C4M), and a type VIII collagen synthesis marker (PRO-C8), were transiently elevated during acute hemarthrosis. Hemarthrosis was accompanied by increased synovial microvascular flow (MSKUS/PD), and levels of type IV collagen markers correlated with PD signals in the joint. In factor VIII-deficient mice, plasma levels of type IV collagen turnover markers correlated negatively with synovial αSMA staining, indicating that reduced type IV collagen turnover was associated with thicker vessels.

Conclusions: Our findings suggest that basement membrane turnover markers, closely linked to synovial vascular remodeling, may be systemic biomarkers of acute hemarthrosis. Vascular instability during neovascularization may be involved in the dynamics of hemarthrosis.

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