Chumappumkal Joseph Bilgimol, De Pablo-Moreno Juan Andres, Falah Nicca, Lora Cacho Mia, von Drygalski Annette
University of California San Diego, Department of Medicine, Division of Hematology/Oncology, La Jolla, CA, USA.
Department of Genetic, Physiology and Microbiology, Biology School, Complutense University of Madrid, Madrid, Spain.
J Thromb Haemost. 2025 Sep 2. doi: 10.1016/j.jtha.2025.08.016.
Maladaptive lymphangiogenesis after hemarthrosis in Factor(F)VIII deficient (KO) mice facilitates synovial iron accumulation.
To investigate the impact of FVIII treatment on lymphangiogenesis, iron clearance, and joint health after hemarthrosis.
Two days after knee injury/bleed (sub-patellar needle puncture) FVIII-KO mice were separated into three groups receiving (1) intravenous saline, (2) recombinant human (rh)FVIII for 2 days, or (3) murine (m)FcFVIII for 14 days. FVIII activity levels were performed repeatedly (peak/trough) for 14 days. Joint tissues were processed at 2 and 4 weeks post-bleed for Prussian blue staining (iron), CD68 (macrophage), αSMA (vascular remodeling), LYVE1 (lymphangiogenesis), and Safranin-O-Green (histology, cartilage health).
Joint injury caused profound hemarthrosis. Mice treated with mFcFVIII maintained stable FVIII activity levels for 14 days (troughs 29-38%). Pronounced synovial iron accumulation co-localizing with macrophages, along with severely impaired lymphangiogenesis and joint health parameters, were present in saline-treated mice at 2 and 4 weeks when compared to baseline. Short-term rhFVIII administration resulted in partially impaired lymphangiogenesis and iron clearance with delayed recovery of joint health parameters. In contrast, mice treated with mFcFVIII experienced rapid iron clearance alongside normal lymphangiogenesis, associated with fast and effective normalization of joint health parameters, particularly in respect to cartilage health.
Prolonged FVIII availability in the "mild hemophilia range" (+/- Fc-mediated effects) after hemarthrosis seem critical for lymphangiogenesis, rapid iron removal and joint repair, including glycosaminoglycan-dependent cartilage restoration. Intensified courses of FVIII treatment in patients may therefore be beneficial for post-bleed management.
因子（F）VIII 缺乏（KO）小鼠关节积血后适应性淋巴管生成异常促进滑膜铁蓄积。
研究 FVIII 治疗对关节积血后淋巴管生成、铁清除及关节健康的影响。
膝关节损伤/出血（髌下针刺）2 天后，将 FVIII-KO 小鼠分为三组，分别接受（1）静脉注射生理盐水，（2）重组人（rh）FVIII 治疗 2 天，或（3）鼠源（m）FcFVIII 治疗 14 天。连续 14 天反复检测 FVIII 活性水平（峰值/谷值）。出血后 2 周和 4 周对关节组织进行处理，用于普鲁士蓝染色（检测铁）、CD68（巨噬细胞）、αSMA（血管重塑）、LYVE1（淋巴管生成）和番红 O-固绿染色（组织学、软骨健康）。
关节损伤导致严重关节积血。接受 mFcFVIII 治疗的小鼠 14 天内 FVIII 活性水平保持稳定（谷值为 29%-38%）。与基线相比，生理盐水治疗组小鼠在 2 周和 4 周时出现明显的滑膜铁蓄积，且与巨噬细胞共定位，同时淋巴管生成和关节健康参数严重受损。短期给予 rhFVIII 导致淋巴管生成和铁清除部分受损，关节健康参数恢复延迟。相比之下，接受 mFcFVIII 治疗的小鼠铁清除迅速，淋巴管生成正常，关节健康参数快速有效恢复正常，尤其是软骨健康方面。
关节积血后“轻度血友病范围”内（±Fc 介导效应）FVIII 的持续存在似乎对淋巴管生成、快速铁清除和关节修复至关重要，包括依赖糖胺聚糖的软骨修复。因此，强化 FVIII 治疗疗程可能对患者出血后管理有益。
