Persistent Vascular Remodeling and Leakiness are Important Components of the Pathobiology of Re‐bleeding in Hemophilic Joints: Two Informative Cases

Kidder, Wesley; Chang, Eric Y.; Moran, Colleen; Rose, Steven C.; Drygalski, Annette von

doi:10.1111/micc.12273

Cited by 22 publications

(36 citation statements)

References 21 publications

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“…Hemarthrosis in FVIII‐deficient mice leads to synovial neovascularization and associated vascular permeability, followed by formation of large, irregular vessels with increased α‐smooth muscle actin (αSMA) expression . The findings in mice align with patient case studies . Synovial vascular changes may be fueled by upregulation of pro‐angiogenic factors, such as vascular endothelial growth factor, matrix metalloproteinase (MMP)‐9, and stromal‐derived factor‐1, and inflammatory responses to hemarthrosis, including macrophage infiltration and upregulation of proinflammatory cytokines (interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐α) .…”

Section: Introductionmentioning

confidence: 68%

“…Accumulating evidence suggests that vascular remodeling and instability in association with hemarthrosis may perpetuate joint bleeding events in hemophilia, promoting target joint formation and arthropathic progression . Previously, we have shown that joint bleeding in FVIII‐deficient mice induces temporary inflammation, neovascularization, and vessel permeability, succeeded by vascular remodeling and tissue repair processes .…”

Section: Discussionmentioning

confidence: 89%

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Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII‐deficient mice

Cooke

Wyseure

Zhou

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Vascular remodeling associated with hemophilic arthropathy (HA) may contribute to bleed propagation, but the mechanisms remain poorly understood. Objectives To explore molecular mechanisms of HA and the effects of hemostasis correction on synovial vascular remodeling after joint injury in hypocoagulable mice. Methods Factor VIII (FVIII)‐deficient mice +/− FVIII treatment and hypocoagulable wild‐type mice (HypoBALB/c) were subjected to subpatellar puncture. HypoBALB/c mice were treated with warfarin and anti‐FVIII before injury, after which warfarin was continued for 2 weeks or reversed +/− continuous anti‐FVIII until harvest. Synovial vascularity was analyzed at baseline and 2 to 4 weeks post injury by histology, musculoskeletal ultrasound with power Doppler (microvascular flow), and Evans blue extravasation (vascular permeability). Synovial gene expression and systemic markers of vascular collagen turnover were studied in FVIII‐deficient mice by RNA sequencing and enzyme‐linked immunosorbent assay. Results Vascular changes occurred in FVIII‐deficient and HypoBALB/c mice after injury with minimal effect of hemostasis correction. Increased vascular permeability was only significant in FVIII‐deficient mice, who exhibited more pronounced vascular remodeling than HypoBALB/c mice despite similar bleed volumes. FVIII‐deficient mice exhibited a strong transcriptional response in synovium that was only partially affected by FVIII treatment and involved genes relating to angiogenesis and extracellular matrix remodeling, with vascular collagen turnover markers detected systemically. Conclusions Intact hemostasis at the time of hemarthrosis and during healing are both critical to prevent vascular remodeling, which appears worse with severe and prolonged FVIII deficiency. Unbiased RNA sequencing revealed potential targets for intervention and biomarker development to improve management of HA.

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 89%

Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII‐deficient mice

Cooke

Wyseure

Zhou

et al. 2019

Journal of Thrombosis and Haemostasis

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“…10 Hence, individual prophylactic therapy with ultrasound monitoring may benefit medical resources allocation, particularly in developing countries such as China. As is known to many, subclinical joint bleeding could not be ruled out in the absence of baseline joint examination with MSKUS, due to aberrant neoangiogenesis and vascular remodelling of the affected joint.…”

Section: Discussionmentioning

confidence: 99%

Age‐related severity and distribution of haemophilic arthropathy of the knee, ankle and elbow among Chinese patients with haemophilia

et al. 2019

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Introduction and aims Age‐related severity and distribution of haemophilic arthropathy (HA) among Chinese patients with haemophilia using the Haemophilia Early Detection with Ultrasound (HEAD‐US) system have not been extensively studied. Methods In our study, 89 patients with moderate and severe haemophilia were recruited. A total of 534 joints (knees, ankles and elbows on both sides included) were evaluated using musculoskeletal ultrasound (MSKUS) and scored using the HEAD‐US system. Results Prevalence and average number of HA were 39.1% and 0.7, 90.6% and 3.2, 94.1% and 4.5, and 100% and 4.3 for ages ≤10, 11‐20, 21‐30 and 31‐40 years, respectively. Prevalence and mean number of knee, ankle and elbow arthropathies also increased with age, although joint damages progressed in unparallel patterns. A significant difference in synovium subscores was observed between patients aged <10 and >10 years. An increasing tendency was observed in cartilage and subchondral bone subscores along with age before 30 years. No significant difference in mean joint scores was found between patients receiving on‐demand therapy and those receiving on‐demand to low‐dose prophylactic therapy. Conclusions Haemophilic arthropathy developed in early childhood and progressed mainly before 30 years of age among Chinese patients with haemophilia, although in different ways among the knee, ankle and elbow.

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“…The presence of power Doppler signals reveals abnormal synovial or soft tissue microperfusion, which is a hallmark of synovial inflammation in rheumatoid arthritis . Unique to hemophilic arthropathy, positive power Doppler signals also indicate vascular remodeling associated with leaky vessels and bleeding tendencies . Therefore, it is important to capture the extent of power Doppler signal abnormalities during musculoskeletal US examinations of hemophilic joints.…”

Section: Discussionmentioning

confidence: 99%

Development and Reliability of the Joint Tissue Activity and Damage Examination for Quantitation of Structural Abnormalities by Musculoskeletal Ultrasound in Hemophilic Joints

Volland

Zhou

Barnes

et al. 2018

J of Ultrasound Medicine

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Objectives Musculoskeletal ultrasound (US) is used increasingly to examine hemophilic arthropathy. However, quantitative algorithms to document findings are lacking. We developed and sought to validate a protocol quantifying hemophilic joint abnormalities. Methods Thirty‐one patients with hemophilia were examined serially for 2 years with musculoskeletal US (≈600 joint examinations and ≈6000 images). Based on the spectrum of pathologies, a quantitative algorithm, named Joint Tissue Activity and Damage Examination (JADE), was developed for soft tissue and osteochondral measurements, including power Doppler, using nominal group techniques. To study intra‐ and inter‐rater reliability, 8 musculoskeletal US–experienced hemophilia providers performed anatomic landmark recognition and tissue measurements on 86 images with arthropathic changes, with repetition 1 month later. Twenty‐three musculoskeletal US–inexperienced providers performed similar assessments. Inter‐operator reliability was established by 6 musculoskeletal US–experienced hemophilia providers, each acquiring images and JADE assessments of 3 hemophilic arthropathic joints. A radiologist and musculoskeletal sonographer functioned as adjudicators. The statistical analysis was performed with the intraclass correlation coefficient (ICC), Fleiss κ, and Cohen κ where appropriate. Results The musculoskeletal US–experienced providers showed excellent intra‐and inter‐rater reliability for tissue measurements (ICCs, 0.94–0.96). Agreement was good to excellent for landmark recognition (Fleiss κ, 0.87‐0.94). Inter‐operator reliability was excellent for measurements and landmark recognition (ICC, 0.90; Fleiss κ, 1.0). Agreement with adjudicators was mostly good to excellent. Musculoskeletal US–inexperienced providers showed excellent inter‐rater reliability for measurements (ICC, 0.96) and moderate agreement for landmark recognition (Fleiss κ, 0.58). Conclusions The JADE protocol appears feasible for quantifying hemophilic intra‐articular abnormalities. Musculoskeletal US–trained hemophilia providers showed high intra‐rater, inter‐rater, and inter‐operator reliability, supporting JADE as a protocol for clinical management and research.

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Persistent Vascular Remodeling and Leakiness are Important Components of the Pathobiology of Re‐bleeding in Hemophilic Joints: Two Informative Cases

Cited by 22 publications

References 21 publications

Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII‐deficient mice

Mechanisms of vascular permeability and remodeling associated with hemarthrosis in factor VIII‐deficient mice

Age‐related severity and distribution of haemophilic arthropathy of the knee, ankle and elbow among Chinese patients with haemophilia

Development and Reliability of the Joint Tissue Activity and Damage Examination for Quantitation of Structural Abnormalities by Musculoskeletal Ultrasound in Hemophilic Joints

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