Department of Medicine, University of California San Diego, La Jolla, California, USA.
Department of Radiology, University of California San Diego, La Jolla, California, USA.
J Thromb Haemost. 2021 May;19(5):1200-1211. doi: 10.1111/jth.15268. Epub 2021 Mar 22.
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.
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.
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.
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.
间质、软骨和骨胶原蛋白已被提议作为血友病性关节炎关节恶化的生物标志物。基底膜（IV 型和 VIII 型）胶原蛋白作为与急性关节出血相关的内皮细胞更替的生物标志物的作用尚不清楚。
31 名成年血友病患者前瞻性研究 3 年，在无痛间期和疼痛事件期间进行肌肉骨骼超声/功率多普勒（MSKUS/PD），以确定关节出血状态、滑膜血管血流和 10 种血浆胶原蛋白转换标志物。使用血友病关节健康评分和 Pettersson 评分确定关节健康状况。在动物研究中，通过膝关节损伤诱导 VIII 因子缺乏症小鼠出血。使用 MSKUS/PD 和组织学评估滑膜血管重塑。分析小鼠血浆样本中 IV 型胶原蛋白转换标志物。
共汇编了 91 次患者就诊。25 次是由于急性疼痛发作，其中 16 次确诊为关节积血。IV 型胶原蛋白转换标志物（PRO-C4 和 C4M）和 VIII 型胶原蛋白合成标志物（PRO-C8）在急性关节积血时短暂升高。关节积血伴有滑膜微血管血流增加（MSKUS/PD），IV 型胶原蛋白标志物水平与关节 PD 信号相关。在 VIII 因子缺乏症小鼠中，血浆 IV 型胶原蛋白转换标志物水平与滑膜 αSMA 染色呈负相关，表明 IV 型胶原蛋白转换减少与血管增厚有关。
我们的研究结果表明，与滑膜血管重塑密切相关的基底膜转换标志物可能是急性关节积血的系统性生物标志物。新生血管过程中的血管不稳定可能参与关节积血的动态变化。
