Pathophysiology of Hemophilic Arthropathy.
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ABSTRACT:
SUBMITTER: Melchiorre D
PROVIDER: S-EPMC5532571 | biostudies-other | 2017 Jun
REPOSITORIES: biostudies-other
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Project description:Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of ?-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of ?-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.
| S-EPMC4618067 | biostudies-literature
Project description:Hemophilia A and B are rare X-linked inherited bleeding disorders caused by complete or partial deficiency in or the absence of coagulation factors VIII and IX. Recurrent joint bleeding (hemarthrosis) is the most frequent clinical manifestation of severe hemophilia. Unless appropriately managed, even subclinical hemarthrosis can lead to the development of hemophilic arthropathy, a disabling condition characterized by joint remodelling, chronic pain, and a reduced quality of life, and eventually requires joint replacement. Given the lack of specific treatments to reduce blood-induced synovitis, the prevention of bleeding is pivotal to the maintenance of joint health. Prophylactic coagulation factor replacement therapy using extended half-life recombinant drugs has significantly improved patients' quality of life by reducing the burden of intravenous injections, and the more recent introduction of nonreplacement therapies such as subcutaneous emicizumab injections has improved treatment adherence and led to the greater protection of patients with hemophilia A. However, despite these advances, chronic arthropathy is still a significant problem. The introduction of point-of-care ultrasound imaging has improved the diagnosis of acute hemarthrosis and early hemophilic arthropathy, and allowed the better monitoring of progressive joint damage, but further research into the underlying mechanisms of the disease is required to allow the development of more targeted treatment. In the meantime, patient management should be based on the risk factors for the onset and progression of arthropathy of each individual patient, and all patients should be collaboratively cared for by multidisciplinary teams of hematologists, rheumatologists, orthopedic surgeons, and physiotherapists at comprehensive hemophilia treatment centers.
| S-EPMC8456897 | biostudies-literature
Project description:Hemophilic arthropathy is a form of joint disease that develops secondary to joint bleeding and presents with synovial hypertrophy, cartilage and bony destruction. The arthropathy can develop despite clotting factor replacement and is especially disabling in the aging population. Pathobiological tissue changes are triggered by release of hemoglobin and iron deposition in the joint, but the sequence of events and the molecular mechanisms resulting in joint deterioration are incompletely understood. Treatment options other than clotting factor replacement are limited. Improvements in the treatment of hemophilia necessitate a better understanding of the processes that lead to this disabling condition and better diagnostic tools. Towards that end, studies of the molecular mechanisms leading to the arthropathy, as well as the development of sensitive imaging techniques and biomarkers are needed. These will pave the way to identify the cause of acute pain such as joint bleeding or synovitis, detect early, potentially reversible structural changes, and predict progression of disease. This review describes current imaging techniques and the development of high resolution musculoskeletal ultrasound with power Doppler to afford point-of-care diagnosis and management, the potential utility of diagnostic biomarkers, and summarizes our current knowledge of the pathobiology of hemophilic arthropathy.
| S-EPMC5034876 | biostudies-other
Project description:Hemophilia is a congenital coagulopathy characterized by a deficiency of one of the clotting factors. It is characterized by the development of hematomas and hemarthrosis, either spontaneously or after minor trauma. The recurrence of hemarthroses leads to progressive and degenerative joint damage from childhood (hemophilic arthropathy). This arthropathy is characterized by disabling physical effects that limit the functionality and quality of life of these patients. Medical progress achieved over the last decade in the drug treatment of hemophilia has improved the medium and long-term prospects of patients with more effective and long-lasting drugs. The universal use of safer, more effective and prolonged prophylactic treatments may promote the prevention of bleeding, and also therefore, of the development of hemarthrosis and joint damage. A number of imaging instruments have been developed for the assessment of hemarthrosis and hemophilic arthropathy, using ultrasound, magnetic resonance imaging and simple radiology. Different physical examination scores and questionnaires allow the assessment of joint health, self-perceived activity and functionality of patients with hemophilia. The approach to these patients should be interdisciplinary. Assessment of the processes that affect pain in these patients and the development of pain education models should be implemented. Expert advice and information to patients with hemophilia should be based on individual functional prevention diagnoses, advice on available therapies and sports practice, as well as health recommendations.
| S-EPMC9586168 | biostudies-literature
Project description:Hemophilic arthropathy is the result of repetitive intra-articular bleeding and synovial inflammation. In people with hemophilic arthropathy (PWHA), very little is known about the neural control of individual muscles during movement. The aim of the present study was to assess if the neural control of individual muscles and coordination between antagonistic muscle pairs and joint kinematics during gait are affected in PWHA. Thirteen control subjects (CG) walked overground at their preferred and slow velocity (1 m/s), and 14 PWHA walked overground at the preferred velocity (1 m/s). Joint kinematics and temporal gait parameters were assessed using four inertial sensors. Surface electromyography (EMG) was collected from gluteus maximus (GMAX), gluteus medius (GMED), vastus medialis (VM), vastus lateralis (VL), rectus femoris (RF), medial gastrocnemius (MG), lateral gastrocnemius (LG), soleus (SOL), tibialis anterior (TA), semitendinosus (ST), and biceps femoris (BF). Waveforms were compared using the time-series analysis through statistical parametric mapping. In PWHA compared to CG, EMG amplitude during the stance phase was higher for LG (for both velocities of the CG), BF (slow velocity only), and ST (preferred velocity only) (p < 0.05). Co-contraction during the stance phase was higher for MG-TA, LG-TA, VL-BF, VM-ST, LG-VL, and MG-VM (both velocities) (p < 0.05). MG and LG were excited earlier (preferred velocity only) (p < 0.05). A later offset during the stance phase was found for VL, BF, and ST (both velocities), and BF and GMAX (preferred velocity only) (p < 0.05). In addition, the range of motion in knee and ankle joints was lower in PWHA (both velocities) and hip joint (preferred velocity only) (p < 0.05). In conclusion, the neural control of individual muscles and coordination between antagonistic muscles during gait in PWHA differs substantially from control subjects.
| S-EPMC7006441 | biostudies-literature
Project description:BACKGROUND:The pathophysiology of hemophilic arthropathy is complex and not completely understood. In this study, we aimed to identify biomarkers that can affect the hemophilic arthropathy severity. METHODS:Fifty patients were analyzed for biomarker frequencies; in 37 patients, articular symptoms were evaluated based on the physical joint examination score, and in 18, it was based on magnetic resonance imaging. Eight polymorphisms, namely FV 1691G>A, FII 20210G>A, MTHFR 677C>T and 1298A>C, TNF?-308G>A and -238G>A, ACAN VNTR, and IL1RN*2-VNTR were identified. RESULTS:Patients with the MTHFR 677TT genotype showed a higher number of affected joints (1.83 ± 0.9 vs. 0.55 ± 0.7 for CC; p = .023), whereas those with the MTHFR 1298AC genotype exhibited higher effusion according to two radiologists (0.90 ± 0.31/1.20 ± 0.63 vs. 0.38 ± 0.52/0.50 ± 0.53 for AA genotype; p = .043/0.036, respectively). In addition, patients with the TNF?-308GA genotype had more subchondral cysts (0.75 ± 0.95 vs. 0.07 ± 0.26 for GG genotype; p = .041). CONCLUSIONS:The distribution of risk genotypes for MTHFR and TNF?-308GA suggests their association with clinical parameters of hemophilic arthropathy. Cohort studies are essential to verify these associations.
| S-EPMC6825867 | biostudies-literature
Project description:Repeated intra-articular hemorrhages lead to hemophilic arthropathy in severe hemophilia. Inflammation and pro-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNFα)) might be involved in this pathogenesis. We hypothesized that anti-TNFα may provide adjuvant protection for hemophilic arthropathy management. We measured TNFα in synovial lavage from hemophilia mice subjected to hemarthrosis induction and synovial fluid from patients with hemophilic arthropathy (n = 5). In hemophilia mice, recurrent hemarthroses were induced, anti-TNFα was initiated either from day (D)7 after one hemarthrosis episode or D21 after three hemarthroses episodes (n ≥ 7/treatment group). In patients with hemophilic arthropathy (16 patients with 17 affected joints), a single dose of anti-TNFα was administered intra-articularly. Efficacy, characterized by synovial membrane thickness and vascularity, was determined. Elevated TNFα in synovial lavage was found in the hemophilia mice and patients with hemophilic arthropathy. Hemophilia mice subjected to three hemarthroses developed severe synovitis (Synovitis score of 6.0 ± 1.6). Factor IX (FIX) replacement alone partially improved the pathological changes (Synovitis score of 4.2 ± 0.8). However, anti-TNFα treatment initiated at D7, not D21, significantly provided protection (Synovitis score of 1.8 ± 0.9 vs. 3.9 ± 0.3). In patients with hemophilic arthropathy, intra-articular anti-TNFα significantly decreased synovial thickness and vascularity during the observed period from D7 to D30. Collectively, this preliminary study seems to indicate that TNFα may be associated with the pathogenicity of hemophilic arthropathy and anti-TNFα could provide adjuvant protection against hemophilic arthropathy. Further studies are required to confirm the preliminary results shown in this study.
| S-EPMC7019955 | biostudies-literature
Project description:BACKGROUND:Elbow arthropathy is characteristic in patients with hemophilia. Arthropathy is manifested by decreased range of motion, pain, loss of strength and muscular atrophy, and axial changes. The objective is to evaluate the safety of two physiotherapy programs combining manual therapy and home exercises with educational sessions in patients with hemophilic elbow arthropathy. METHODS:This is a randomized study with 27 patients with elbow hemophilic arthropathy with a mean age of 34.48 (SD: 12.99) years, were randomised to Manual Therapy group, educational group and control group. The physiotherapy programmes were: manual therapy through joint traction, passive muscles stretching and proprioceptive neuromuscular facilitation; and educational sessions and daily home exercises. The study lasted for twelve weeks, with two sessions a week in manual therapy group and one session every two weeks with daily home exercises in educational group. The variables measured were range of motion of elbow, biceps strength, circumference of arm, and elbow pain. RESULTS:The treatment with manual therapy improved the circumference of arm, flexion elbow and elbow pain. Six months later, MT group still enjoyed improved. In the educational group there were improvements, but not significant, in the measured variables. CONCLUSION:Neither of the two physiotherapy interventions caused elbow hemarthrosis. The treatment with manual therapy improved the range of movement and circumference of arm, and lessened pain in hemophilic patients with chronic elbow arthropathy. No hemarthrosis was recorded during treatment or during the follow-up period. Larger randomized clinical trials are required to confirm the results of this study. TRIAL REGISTRATION:( NCT02198040 ). Registered 22 July 2014, retrospectively registered.
| S-EPMC6122620 | biostudies-literature
Project description:BackgroundHemophilic ankle arthropathy is manifested by degenerative functional alterations and chronic pain. Myofascial release techniques are used to treat soft tissue adhesions, relieve pain, and reduce tissue sensitivity.ObjectiveThis study aims to evaluate the safety and efficacy of a protocol using self-myofascial release with a foam roller to be applied in patients with hemophilic ankle arthropathy.MethodsPatients with ankle arthropathy (N=70) will be recruited, enrolled, and assigned to one of two groups-experimental or control-in a 1:1 allocation ratio. Patients will be recruited from 5 centers in different regions of Spain. Patient data will be collected at baseline, posttreatment, and follow-up. The primary outcome will be frequency of ankle joint bleeding (self-reported). The secondary outcomes will be ankle range of motion (measured with a digital goniometer); joint pain (measured with a visual analog scale and an algometer); joint status (measured using the Hemophilia Joint Health Score); muscle strength (measured with a dynamometer); functionality of lower limbs (measured using the 6-minute walking test); activity (self-reported); and muscle flexibility (measured using the fingertip-to-floor test). The treatment program includes 11 exercises that must be administered bilaterally. A mobile app will be developed where each patient will be able to observe the exercises to be carried out. Each session will last 15 minutes with 5 physiotherapy sessions per week for a period of 3 months. It is expected that patients with hemophilia who receive the foam roller intervention will show improvement in mobility, pain, and status of the ankle joint; muscle strength; and function in the lower extremities.ResultsThe study has been approved by the institutional review board of the University of Murcia. Patient recruitment will begin in September 2020, and the intervention period will last until June 2021. Data collection will take place between September 2020 and October 2021.ConclusionsThis protocol describes a randomized clinical trial to examine the safety and efficacy of a self-myofascial release intervention using a foam roller in patients with hemophilic ankle arthropathy.Trial registrationClinicalTrials.gov NCT03914287; http://clinicaltrials.gov/ct2/show/NCT03914287.International registered report identifier (irrid)PRR1-10.2196/15612.
| S-EPMC7428933 | biostudies-literature
Project description:Comparison between hemophilia (HA) patients and non-hemophilic (no HA) patients on different cell culture passages. This allows to see if there are epigenetic changes in fibroblasts like synoviocytes when there is blood in the joint. We compared five patients: two no-HA and three HA patients. The replicates were made on different cell culture passages. The cells were activated by LPS to make an inflammatory reaction.
2019-02-10 | E-MTAB-7442 | biostudies-arrayexpress