Defective lymphangiogenesis and iron removal after hemarthrosis in factor VIII-deficient mice are rectified with therapeutic factor VIII administration-implications for joint health.

IF 5 2区医学 Q1 HEMATOLOGY

Journal of Thrombosis and Haemostasis Pub Date : 2025-09-02 DOI:10.1016/j.jtha.2025.08.016

Bilgimol Chumappumkal Joseph, Juan Andres De Pablo-Moreno, Nicca Falah, Mia Lora Cacho, Annette von Drygalski

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引用次数: 0

Abstract

Background: Maladaptive lymphangiogenesis after hemarthrosis in factor(F)VIII-deficient (knockout [KO]) mice facilitates synovial iron accumulation.

Objectives: To investigate the effect of FVIII treatment on lymphangiogenesis, iron clearance, and joint health after hemarthrosis.

Methods: Two days after knee injury/bleed (subpatellar needle puncture) FVIII-KO mice were separated into 3 groups receiving (1) intravenous saline, (2) recombinant human FVIII for 2 days, or (3) murine (m)FcFVIII for 14 days. FVIII activity levels were measured repeatedly (peak/trough) for 14 days. Joint tissues were processed at 2 and 4 weeks postbleed for Prussian blue staining (iron), CD68 (macrophage), αSMA (vascular remodeling), and LYVE1 (lymphangiogenesis) immunohistochemistry, and Safranin-O-Green staining (cartilage health).

Results: Joint injury caused profound hemarthrosis. Mice treated with mFcFVIII maintained stable FVIII activity levels for 14 days (troughs 29%-38%). Pronounced synovial iron accumulation colocalizing with macrophages, along with severely impaired lymphangiogenesis and joint health parameters, were present in saline-treated mice at 2 and 4 weeks when compared with baseline. Short-term recombinant human FVIII 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 with respect to cartilage health.

Conclusion: 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 postbleed management.

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治疗性给药FVIII纠正了FVIII缺陷小鼠关节血肿后淋巴生成缺陷和铁去除-对关节健康的影响。

背景：因子(F)VIII缺乏症（KO）小鼠关节血肿后的不适应淋巴管生成促进滑膜铁积聚。目的：探讨FVIII治疗对血肿后淋巴管生成、铁清除和关节健康的影响。方法：膝关节损伤/出血（髌骨下针穿刺）2 d后，将FVIII- ko小鼠分为3组，分别给予(1)静脉注射生理盐水，(2)重组人（rh）FVIII 2 d,(3)小鼠(m)FcFVIII 14 d。连续14天反复测定FVIII活性水平（峰/谷）。在出血后2周和4周对关节组织进行普鲁士蓝染色（铁）、CD68（巨噬细胞）、αSMA（血管重塑）、LYVE1（淋巴管生成）和红花素- o -绿（组织学、软骨健康）。结果：关节损伤引起深度关节积血。经mFcFVIII处理的小鼠在14天内保持稳定的FVIII活性水平（波幅为29-38%）。与基线相比，盐水处理小鼠在2周和4周时出现了明显的滑膜铁积累与巨噬细胞共定位，以及严重受损的淋巴管生成和关节健康参数。短期给药导致部分淋巴管生成和铁清除受损，关节健康参数恢复延迟。相比之下，用mFcFVIII治疗的小鼠在正常淋巴管生成的同时经历了快速的铁清除，与关节健康参数的快速有效正常化有关，特别是在软骨健康方面。结论：关节血肿后，延长FVIII在“轻度血友病范围”（+/- fc介导作用）的可用性似乎对淋巴管生成、快速铁清除和关节修复（包括糖胺聚糖依赖性软骨修复）至关重要。因此，患者强化FVIII治疗可能有利于出血后的处理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Thrombosis and Haemostasis 医学-外周血管病

CiteScore

24.30

自引率

3.80%

发文量

321

审稿时长

1 months

期刊介绍： The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.