Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.

Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important.

Predictive parameters for spontaneous joint bleeding during emicizumab prophylaxis.

ABSTRACT: Emicizumab is approved for prophylaxis of patients with hemophilia A (HA). Despite its efficacy in reducing bleeding, some patients on emicizumab still experience hemarthrosis, but no tool is yet available to identify those at a higher risk of spontaneous joint bleeding. This study aimed to evaluate whether laboratory measurements (global coagulation assays and emicizumab concentration) and/or arthropathy scores can distinguish patients at higher risk of spontaneous joint bleeding while on emicizumab prophylaxis. A thrombin generation assay was performed upon the addition of tissue factor and synthetic phospholipids. Nonactivated thromboelastography was performed on citrated whole blood. Emicizumab concentrations were measured using a modified 1-stage factor VIII assay. The degree of hemophilic arthropathy was assessed using the Hemophilia Joint Health Score and Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score. A Cox proportional hazards model was used to evaluate the association between variables and bleeding. The predictive power of these variables was investigated using receiver operating characteristic (ROC) analysis. Forty patients with severe HA, with or without inhibitors, on emicizumab prophylaxis were enrolled in an observational cohort study. Ten of 40 developed spontaneous joint bleeding. None of the laboratory parameters were able to distinguish patients with a higher risk of spontaneous joint bleeding. ROC analysis showed that during emicizumab prophylaxis, only the presence of synovitis and a higher HEAD-US score were associated with spontaneous joint bleeding (area under the curve, 0.84). A greater degree of arthropathy and the presence of synovitis could help predict the risk of spontaneous joint bleeding in patients with HA on emicizumab prophylaxis.

Hemarthrosis in a Pediatric Patient With Immune Thrombocytopenia and Lyme Arthritis.

The presentation of immune thrombocytopenia is dependent on the degree of thrombocytopenia, with no to mild bleeding symptoms, primarily mucocutaneous bleeding. Severe bleeding in other organ systems is a rare complication. Spontaneous hemarthrosis is rare in patients without hemophilia. We report a child presenting with oral and cutaneous petechial lesions and left knee hemarthrosis without trauma. Laboratory findings showed severe thrombocytopenia consistent with immune thrombocytopenia. Serologic tests were consistent with Lyme disease. Hemarthrosis was presumed secondary to Lyme disease monoarticular joint inflammation with bleeding exacerbated by severe thrombocytopenia. Hemarthrosis resolved and platelet counts normalized following immunoglobulin infusion, steroid course, and antibiotics.

Predicting the development of hemophilic arthropathy in patients with hemophilia based on patient age: a retrospective single-center database study.

BACKGROUND: Patients with hemophilia (PWH) develop hemophilic arthropathy of the major joints due to recurrent hemarthrosis. This study retrospectively estimated the age at which PWH may expect to develop hemophilic arthropathy and undergo joint replacement surgery. RESEARCH DESIGN AND METHODS: Using retrospective data from PWH at a Czech orthopedic center, Kaplan Meier analyses were used to estimate the cumulative proportions of patients with hemophilic arthropathy and undergoing joint replacement surgery as a function of age. RESULTS: Based on 1028 joint examinations in 167 PWH, hemophilic arthropathy of the knees, elbows, ankles and hips was estimated to develop by a median age of 48, 51, 52 and 61 years, respectively, with ≈80% of patients having such damage by ≈70 years of age. Hemophilic arthropathy of the shoulder occurred much later (median >80 years). In patients undergoing knee or hip replacement surgery, hemophilic arthropathy of the knee and hip occurred at a median age of ≈50 and ≈60 years, respectively, with replacement surgery occurring at a median of ≈70 and >75 years. CONCLUSIONS: In PWH, the risk of developing hemophilic arthropathy accumulates continuously over the patient's lifetime, allowing predictions about the ages at which such damage and joint replacement surgery may occur.

Skeletal complications in patients with hemophilia: a single-center experience.

BACKGROUND: Arthropathy is a common complication in patients with hemophilia. We examined the prevalence of this skeletal complication in patients with hemophilia who were registered at a Comprehensive Hemophilia Center in Shiraz, Southern Iran. MATERIALS AND METHODS: In this cross-sectional study, an orthopedic specialist visited 448 patients and conducted screenings for skeletal complications. The assessment included evaluating the type of hemophilia, disease severity, treatment modality, the presence of inhibitors, and the identification of skeletal complications. RESULTS: Ninety patients with hemophilia A, with a mean age (SD) of 31.6 (14.4) years, and 10 patients with hemophilia B, with a mean age of 30.5 (20.6) years, were assessed. The most frequently affected joints were the knee and ankle joints. In the univariate analysis, patients with severe disease were more likely to exhibit synovitis, a target joint, and bone disease compared to patients with non-severe disease. Additionally, a history of treated or active hepatitis and an annual bleeding rate showed significant associations with the target joint. In the multivariable logistic regression analysis, disease severity (OR 14.43, 95% CI 1.6-129.6) and a higher age at diagnosis (OR 1.06, 95% CI 1.00-1.13) increased the likelihood of developing osteoporosis. A history of hepatitis (OR 3.67, 95% CI 1.28-10.48) was identified as an independent risk factor for the target joint. CONCLUSION: Skeletal complications are a common occurrence in hemophilia. Regular consultations with orthopedic specialists, focusing on bleeding control and hepatitis prevention, are essential for reducing the impact of this debilitating complication.

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers.

AIM: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. METHODS: This cross-sectional study included patients with severe haemophilia A born 1970-2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM-1, Coll2-1, COMP, CS846, TIMP, and urinary CTX-II) were compared individually and as combined indexes between patients with and without active synovial proliferation. RESULTS: This cohort consisted of 79 patients with a median age of 31 years (range 16.5-50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was .6 (.2-1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. CONCLUSION: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation.

Hemophilic arthropathy: how to diagnose subclinical bleeding early and how to orthopedically treat a damaged joint.

INTRODUCTION: It is important to know the current status of hemophilic arthropathy diagnoses, treatments, complications, and outcomes in developed countries. AREAS COVERED: A bibliographic search in PubMed for articles published from 1 January 2019 through 12 June 2023 was performed. EXPERT OPINION: In developed countries with specialized hemophilia treatment centers, primary hematological prophylaxis (started before the age of 2 years and after no more than one joint bleed) has almost completely eliminated the joint-related problems of the disease. The ideal goal of zero hemarthroses can be achieved only with intense and well-dosed prophylaxis: intravenous infusion of coagulation factor - standard half-life or extended half-life; periodic or subcutaneous injections of nonfactor products (emicizumab or fitusiran). However, hemophilic arthropathy continues to occur due to subclinical joint hemorrhages. In one study, 16% of the joints without reported hemarthroses showed signs of previous subclinical bleeding (hemosiderin deposits with/without synovial hypertrophy on magnetic resonance imaging were deemed signs of previous subclinical bleeding), rendering evidence for subclinical bleeding in people with severe hemophilia with lifelong prophylaxis treatment. Subclinical joint hemorrhages can be averted only by employing accurate and tailored prophylaxis.

Synovitis in hemophilia: preventing, detecting, and treating joint bleeds.

INTRODUCTION: Most bleeding events in individuals with hemophilia occur within the ankle, knee, and elbow joints. Should the bleeding persist, the synovial membrane starts to hypertrophy and a vicious cycle of chronic hemophilic synovitis (CHS) occurs, leading to joint destruction. AREAS COVERED: This article covers the prompt diagnosis of CHS by point-of-care ultrasonography (POC-US) and its treatment by means of several types of synovectomy. EXPERT OPINION: It is essential to prevent, detect and treat hemophilic synovitis, because it indicates that the joint has bled and is at risk of bleeding further. Prophylaxis with standard half life (SHL) factor VIII (FVIII) concentrate is the standard of care for individuals with severe hemophilia A and can also be considered for selected patients with moderate disease. Several years of real-world experience with extended half life (EHL) FVIII, emicizumab, and other drugs in development will be needed to ascertain their final effect on bleeding and its complications. We must look for synovitis in individuals declaring joint pain and in asymptomatic patients, and POC-US is the most reasonable imaging instrument with which to carry out periodic joint screening. Radiosynovectomy, chemical synovectomy, and arthroscopic synovectomy markedly reduce bleeding events.

Monitoring recovery of joints after bleeding: Physical examination and ultrasound are complementary.

AIM: Traditionally, recovery after a joint bleed in people with bleeding disorders is evaluated by clinical symptoms. Following a bleed, however, asymptomatic joints may still show synovial hypertrophy and effusion on ultrasound. We evaluated the duration of full recovery from a joint bleed. Additionally, we determined how recovery differed when assessed by physical examination and ultrasound. METHODS: In this retrospective cohort study, we investigated joint bleeds in elbows, knees and ankles of people with haemophilia or Von Willebrand disease who attended the Van Creveldkliniek between 2016 and 2021. Physical examination (warmth, swelling, range of motion and gait) and ultrasound (effusion and synovial hypertrophy) were performed within 7 days after the onset of the bleed, 1 week after the first examination and monthly thereafter until patients had recovered fully. Joint bleeds were treated in line with the current international treatment guidelines. RESULTS: We evaluated 30 joint bleeds in 26 patients. The median recovery time was 1 month (range 0.3-5 months). In 47% of the joint bleeds, the recovery took longer than 1 month. The moment of recovery based on physical examination and ultrasound differed in 27% of bleeds. Both persistent abnormalities at physical examination in joints with normalized ultrasounds and persistent ultrasound findings in clinically recovered joints occurred. CONCLUSION: Joint bleed recovery can take long and recovery times differed per bleed. Recovery differed when assessed by physical examination or ultrasound. Therefore, both should be used to closely monitor recovery of joint bleeds and offer personalized care.

Magnetic resonance imaging evidence for subclinical joint bleeding in a Dutch population of people with severe hemophilia on prophylaxis.

BACKGROUND: Previous studies suggest that subclinical bleeding occurs in persons with hemophilia. OBJECTIVES: The aim of this study was to investigate whether patients with lifelong access to prophylaxis showed signs of previous subclinical bleeding on magnetic resonance imaging (MRI) in joints without a history of joint bleeding. METHODS: This single-center cross-sectional study included persons with severe hemophilia A on prophylaxis, aged 16 to 33 years, with lifetime bleeding records available. Per participant, 1 index joint without a history of joint bleeding was evaluated with 3-Tesla MRI, including hemosiderin sensitive sequences. MRI scans were reviewed according to the International Prophylaxis Study Group (IPSG) additive MRI scale (range, 0-17/joint). Hemosiderin deposits with/without synovial hypertrophy were considered signs of previous subclinical bleeding. Additionally, physical examination was performed, followed by ultrasound examination according to the Hemophilia Early Arthropathy Detection with Ultrasound protocol. RESULTS: In 43 patients with a median age of 23.5 years, 43 joints (16 elbows, 13 knees, 14 ankles) without reported bleeds were evaluated with MRI. The median IPSG MRI score was 1 (range, 0-9). Signs of previous subclinical bleeding were observed in 7 of 43 joints (16%; 95% CI, 7-30): 7 of 7 joints showed hemosiderin deposits, with concomitant synovial hypertrophy in 2 of 7 joints. MRI changes were accompanied by swelling and ultrasound-detected synovial hypertrophy in 1 ankle only. None of the other joints showed abnormalities at physical examination and ultrasound. CONCLUSION: In this study, 16% of the joints without reported bleeds showed signs of previous subclinical bleeding, providing evidence for subclinical bleeding in people with severe hemophilia with lifelong access to prophylaxis.

Teleguidance for Patient Self-Imaging of Hemophilic Joints Using Mobile Ultrasound Devices: A Pilot Study.

BACKGROUND: Teleguidance on portable devices opens the possibility of joint self-imaging in persons with hemophilia (PWH). AIMS: Determine the feasibility of patient self-imaging with/without teleguidance. METHODS: Adult PWH received ultrasound teaching including 11 views for hemarthrosis detection in ankles, elbows, and knees. The patients acquired five randomly selected views with the Butterfly/IQ probe without assistance at 2, 6-8 weeks, and 3-4 months later, followed by teleguidance. Image acquisition was timed, patients identified anatomic landmarks, and image quality was graded. Questionnaires assessed the imaging experience. Hemophilia Joint Health Score (HJHS) indicated arthropathy status. RESULTS: Of 132 PWH, 10 (median age 52 years) opted for study inclusion. Most had severe Hemophilia A, were white/non-Hispanic, with at least a high school degree and, overall, similar to the other 122 PWH. At 2 and 6 weeks after training, ~80% images were acquired correctly compared with 53% at 12 weeks. Accuracy of landmark recognition was ~55%. With teleguidance, all images were acquired correctly, with near-perfect image quality (P ≤ .01 compared with the 3-4 month time point). Median HJHS of scanned joints was 11.5 at each time point, demonstrating a similar spectrum of arthropathic changes. Median time of image acquisition was fast, and similar with or without teleguidance (median 01:04 [mm:ss] vs median 01:02), but differed slightly between arthropathic and non-arthropathic joints. Study participants and the imaging facilitator rated that it was easy to navigate mobile technology and acquire images with teleguidance. CONCLUSION: Mobile ultrasound with teleguidance for joint self-imaging is feasible and warrants further exploration.

Safety and effectiveness of fascial therapy in the treatment of adult patients with hemophilic elbow arthropathy: a pilot study.

Background: Hemophilic arthropathy is characterized by loss of function and chronic pain. Fascial therapy mobilizes the connective tissue and is thus involved in the condition of the injured fascial complex and the surrounding tissues.Objective: To evaluate the safety of a physiotherapy program using fascial therapy in patients with hemophilic elbow arthropathy.Methods: Fourteen adult patients with hemophilia were randomly assigned to a control group and an intervention group. The intervention consisted of three 45-min sessions of fascial therapy over a 3-week period. Assessment was carried out at baseline, after treatment, and at follow-up. The study variables were bleeding frequency using a self-registration of bleeding; joint pain using the visual analog scale; range of motion with a universal goniometer; and joint status assessed with Hemophilia Joint Health Score.Results: None of the patients developed joint bleeding during the experimental period. Joint pain in the experimental group decreased by 1.43 out of 2.43 (95% CI 0.52 to 2.33) and 2.14 out of 2.57 (95% CI 0.18 to 4.10) in right and left elbow, respectively, more than the control group by 3 weeks. Flexion increased by 3.57 degrees out of 129.14 (95% CI 5.48 to 1.65) in right elbow and joint condition improved by 1.14 points out of 6.0 (95% CI 0.01 to 2.26) more than the control group by 3 weeks.Conclusion: Fascial therapy does not appear to produce elbow hemarthrosis in patients with hemophilia. This treatment can improve joint pain, range of motion, and elbow status in patients with hemophilia.

Hemophilic arthropathy: Current knowledge and future perspectives.

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.

Effects of myofascial release on frequency of joint bleedings, joint status, and joint pain in patients with hemophilic elbow arthropathy: A randomized, single-blind clinical trial.

BACKGROUND: Chronic joint injury of the elbow joint is common in patients with hemophilia. Myofascial release is used for the management of pain and functionality in patients with chronic restrictions. OBJECTIVE: To evaluate the effectiveness of myofascial release in patients with hemophilic elbow arthropathy. METHODS: Sixty-nine patients with hemophilia took part in this randomized controlled trial. They were recruited from 10 hemophilia patient Associations. They were randomly allocated to experimental (n = 35) or control group (n = 34). The intervention consisted of three 50-min sessions of fascial therapy over a 3-week period. The intervention included 11 bilaterally administered maneuvers in both upper limbs (from shoulder girdle to forearm). The study variables were frequency of elbow bleeding (self-report), joint status (Hemophilia Joint Health Score), and joint pain (visual analog scale) at baseline, after the intervention, and at the 3-month follow-up. RESULTS: There were significant changes (P < .001) in the repeated measures factor in the frequency of hemarthrosis (F = 20.64), joint status (F = 31.45), and perceived joint pain (F = 30.08). We found group interaction with the (P < .001) in the frequency of hemarthrosis (F = 21.57), joint status (F = 99.98), and perceived joint pain (F = 44.26). There were changes (P < .01) in the pairwise comparison analysis between the pretreatment assessment and the posttreatment and follow-up assessments. CONCLUSIONS: Myofascial release decreases frequency of elbow bleedings, and improved joint status and perception of elbow pain in patients with hemophilic elbow arthropathy. Myofascial release may be recommended to improve joint status and joint pain in patients with hemophilic elbow arthropathy.

Prevention of Unplanned Surgery Due to Delayed Diagnosis of Occult Ipsilateral Femoral Neck Fractures Associated with Femoral Shaft Fractures: A Study of the CT Capsular Sign with Lipohemarthrosis.

BACKGROUND: The purpose of the present study was to investigate the effectiveness of using the computed tomography (CT) capsular sign with lipohemarthrosis of the hip joint as a selective indicator for preoperative magnetic resonance imaging (MRI) of the hip or prophylactic fixation of the ipsilateral femoral neck for the prevention of unplanned surgery due to delayed diagnosis of occult ipsilateral femoral neck fractures in patients with high-energy femoral shaft fractures. METHODS: We evaluated the CT capsular sign with lipohemarthrosis in patients with a high-energy femoral shaft fracture without a preoperative diagnosis of an ipsilateral femoral neck fracture. The CT capsular sign with lipohemarthrosis was considered positive when the side-to-side difference in anterior capsular distension was >1 mm and lipohemarthrosis was seen on soft-tissue-window CT images. A positive CT capsular sign with lipohemarthrosis prompts preoperative hip MRI or prophylactic femoral neck fixation with a reconstruction nail. RESULTS: One hundred and fifty-six consecutive patients were included. Eight patients were preoperatively diagnosed with a displaced or hairline ipsilateral femoral neck fracture, whereas the remaining 148 patients showed no ipsilateral femoral neck fracture on radiographs and bone-window CT images. On soft-tissue-window CT images, 29 (19.6%) of the 148 patients had a positive CT capsular sign with lipohemarthrosis. We performed preoperative MRI for 3 patients; in the remaining 26 patients, prophylactic femoral neck fixation was performed with a reconstruction nail. We identified 5 occult ipsilateral femoral neck fractures among the 29 patients with a positive sign: 2 on preoperative MRI scans, 2 on immediate postoperative radiographs, and 1 on radiographs made 6 weeks postoperatively. In 119 patients with a negative sign, no occult ipsilateral femoral neck fracture was identified. All occult ipsilateral femoral neck fractures healed without further displacement of the femoral neck. Consequently, additional unplanned surgery for delayed diagnosis of occult ipsilateral femoral neck fracture was not required. CONCLUSIONS: The use of the CT capsular sign with lipohemarthrosis as a selective indicator for preoperative hip MRI or prophylactic femoral neck fixation with a reconstruction nail in patients with high-energy femoral shaft fractures is effective for preventing unplanned surgery due to delayed diagnosis of occult ipsilateral femoral neck fractures. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence.