Systemic vascular basement membrane markers linked to synovial vascular remodeling are biomarkers of hemarthrosis in patients with hemophilia

Abstract

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 painfree 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.

How to assess, detect, and manage joint involvement in the era of transformational therapies: Role of point‐of‐care ultrasound

“…56 Basement membrane types IV and VIII collagens are potentially useful systemic biomarkers of endothelial turnover, which is closely associated with synovial vascular remodelling in haemophilic joint bleeding. 61 However, further study is needed to support its use as a diagnostic marker of acute haemarthrosis in haemophilia.…”

“…In particular, urinary CTX‐II, serum COMP and serum chondroitin sulphate 846 were found to have good correlation with radiographic joint damage and joint space narrowing 56 . Basement membrane types IV and VIII collagens are potentially useful systemic biomarkers of endothelial turnover, which is closely associated with synovial vascular remodelling in haemophilic joint bleeding 61 . However, further study is needed to support its use as a diagnostic marker of acute haemarthrosis in haemophilia.…”

Pain in Hemophilia: Unexplored Role of Oxidative Stress

“…A recent study detected a positive neuropathic pain component when PWH completed pDq, a questionnaire that identifies neuropathic components in an individual´s pain profile [ 30 ]. Moreover, non-bony ankylosed knees from hemophilia patients with greater pain showed increased protein gene product (PGP) 9.5 positive sensory nerve fiber sprouting and NGF concentrations when compared to bony-ankylosed knee of end-stage hemophilic arthropathy with milder pain [ 136 ]. Impaired conditioned pain modulation response in PWH is suggestive of the involvement of the descending inhibitory pain pathway [ 137 ].…”