What is the rationale for mesenchymal stromal cells based therapies in the management of hemophilic arthropathies?

Hemophilia A and B are rare X-linked genetic bleeding disorders due to a complete or partial deficiency in the coagulation factors VIII or IX, respectively. The main treatment for hemophilia is prophylactic and based on coagulation factor replacement therapies. These treatments have significantly reduced bleeding and improved the patients' quality of life. Nevertheless, repeated joint bleedings (hemarthroses), even subclinical hemarthroses, can lead to hemophilic arthropathy (HA). This disabling condition is characterized by chronic pain due to synovial inflammation, cartilage and bone destruction requiring ultimately joint replacement. HA resembles to rheumatoid arthritis because of synovitis but HA is considered as having similarities with osteoarthritis as illustrated by the migration of immune cells, production of inflammatory cytokines, synovial hypertrophy and cartilage damage. Various drugs have been evaluated for the management of HA with limited success. The objective of the review is to discuss new therapeutic approaches with a special focus on the studies that have investigated the potential of using mesenchymal stromal cells (MSCs) in the management of HA. A systematic review of the literature has been made. Most of the studies have focused on the interest of MSCs for the delivery of missing factors VIII or IX but in some studies, more insight on the effect of MSC injection on synovial inflammation or cartilage structure were provided and put in perspective for possible clinical applications.

Selective inhibition of activated protein C anticoagulant activity protects against hemophilic arthropathy in mice.

Recurrent spontaneous or trauma-related bleeding into joints in hemophilia leads to hemophilic arthropathy (HA), a debilitating joint disease. Treatment of HA consists of preventing joint bleeding by clotting factor replacement, and in extreme cases, orthopedic surgery. We recently showed that administration of endothelial cell protein C receptor (EPCR) blocking monoclonal antibodies (mAb) markedly reduced the severity of HA in factor VIII (FVIII)-/- mice. EPCR blocking inhibits activated protein C (APC) generation and EPCR-dependent APC signaling. The present study was aimed to define the role of inhibition of APC anticoagulant activity, APC signaling, or both in suppressing HA. FVIII-/- mice were treated with a single dose of isotype control mAb, MPC1609 mAb, that inhibits anticoagulant, and signaling properties of APC, or MAPC1591 mAb that only blocks the anticoagulant activity of APC. Joint bleeding was induced by needle puncture injury. HA was evaluated by monitoring joint bleeding, change in joint diameter, and histopathological analysis of joint tissue sections for synovial hypertrophy, macrophage infiltration, neoangiogenesis, cartilage degeneration, and chondrocyte apoptosis. No significant differences were observed between MPC1609 and MAPC1591 in inhibiting APC anticoagulant activity in vitro and equally effective in correcting acute bleeding induced by the saphenous vein incision in FVIII-/- mice. Administration of MAPC1591, and not MPC1609, markedly reduced the severity of HA. MAPC1591 inhibited joint bleed-induced inflammatory cytokine interleukin-6 expression and vascular leakage in joints, whereas MPC1609 had no significant effect. Our data show that an mAb that selectively inhibits APC's anticoagulant activity without compromising its cytoprotective signaling offers a therapeutic potential alternative to treat HA.

Predicting joint involvement through tailored prophylaxis in severe haemophilia A, is it possible?

INTRODUCTION: Tailored prophylaxis is the current treatment regimen for patients with severe haemophilia A. Recently, published guidelines describe two possible approaches, based on clinical characteristics or estimation of pharmacokinetic parameters. However, both have strengths and weaknesses, and their characteristics need to be integrated to optimize treatment appropriately. In this paper, we present a model that considers together the characteristics of prophylaxis and the relevance of each. METHODS: The age at initiation of prophylaxis, number of bleeding events, treatment regimen, therapeutic adherence, FVIII trough levels, and joint status were analyzed in 59 patients followed at La Paz University Hospital between January 2000 and December 2019. RESULTS: The mean duration of primary prophylaxis of 113.37 ± 57.79 months. Eighty-three percent (n = 49) had no joint status involvement at the end of follow-up (HJHS and HEAD-US = 0). The median ABR was 0.7 (IQR 0.2 -1.0) and 54.2% presented trough levels of FVIII during follow-up >1 IU/dL. 72,9% engaged in some type of physical activity and overall adherence was over 85% in all patients evaluated. The regression analysis performed, considering all these factors, showed that the initiation of prophylaxis before 21 months of age was the most relevant protective factor against the appearance of joint involvement (OR 88.33 p.031 CI 95% 1.49-5224.40) CONCLUSION: Early initiation of prophylaxis was the most relevant factor in the protection of joint status. More comprehensive analysis models adapted to the characteristics of each population, are needed to adequately individualize treatment.

The frequency of sarcopenia in haemophilia patients: Effects on musculoskeletal health and functional performance.

INTRODUCTION: In patients with haemophilia A, chronic arthropathy develops over time as a result of recurrent joint bleeds, which leads to restricted mobility and disability in the affected joints. There are limited studies in the literature evaluating sarcopenia in patients with haemophilia. The present study aims to determine the prevalence of sarcopenia in severe haemophilia-A patients and to evaluate musculoskeletal health and functional performance. METHODS: Thirty haemophilia-A patients and 26 adult male volunteers were enrolled in the study. For detection of sarcopenia, the appendicular skeletal muscle mass (ASM) obtained by bioelectrical impedance analysis (BIA) was divided by height squared (m2 ) to obtain the appendicular skeletal muscle mass index (ASMI) value. The thighs of both lower extremities were measured using the Modified Sonographic Tight Adjustment Ratio (STAR) method, which was obtained by adding the bilateral rectus femoris and vastus intermedius muscle thicknesses measured by ultrasound. Hand and quadriceps muscle strength (MS) were measured with a dynamometer. Physical performance was determined using the walking speed (WS), timed up-and-go test (TUGT), 5-repetition sit-to-stand test (5RSTS), and 6-min walk test (6MWT). Haemophilia Joint Health Score (HJHS) and Haemophilia Early Arthropathy Detection-Ultrasonography (HEAD-US) were also used to assess the musculoskeletal system. RESULTS: According to the modified STAR values calculated based on body mass index, sarcopenia was present in 15 (50%) of 30 patients. However, based on the ASMI-BIA values, sarcopenia was present in only two (6.6%) patients. A weak correlation was found between ASMI and HJHS, HEAD-US, WS, TUGT, and hand MS (left), while a moderate correlation was found with knee MS (right), knee MS (left), and 5RSTS. A strong correlation was found between the modified STAR score and HEAD-US, HJHS, knee MS (left), 5RSTS, TUGT, and WS, while a moderate correlation was found with hand MS (left), hand MS (right), and knee MS (right). CONCLUSION: This study showed muscle loss, joint mobility restrictions, and decreased functional capacity in haemophilia patients and demonstrated the presence of sarcopenia in these patients. The STAR measurement method showed stronger relationships with MS and functional performance values than ASMI measurements in terms of evaluating sarcopenia.

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.

30-sit-to-stand power is a better tool than isometric knee extensor strength to detect motor impairment in people with haemophilic arthropathy.

INTRODUCTION: Regular assessment of motor impairments is crucial in people with haemophilic arthropathy (PwHA). This study aimed to determine if there are differences in 30-seconds sit-to-stand (30-STS) power and maximal voluntary isometric contraction (MVIC) of the knee extensors between PwHA and healthy control group (CG). The secondary aims were to investigate the correlation between 30-STS power and MVIC of knee extensors with clinical characteristics and to assess their effectiveness in identifying motor impairment in PwHA. METHODS: A cross-sectional study was conducted by collecting data from PwHA (n = 17) and a sedentary CG (n = 15). MVIC (torque) and 30-STS power were normalised to body mass. Correlation analysis and simple linear regression adjusted for age were used to assess the association between tests and clinical variables. Using z-scores derived from the mean and standard deviation of the CG, we compared the MVIC and the 30-STS power in PwHA. RESULTS: PwHA showed lower MVIC and 30-STS power compared to CG (p < .001; large effect size d > .8). Lower 30-STS power was associated with greater joint impairment and greater fear of movement, whereas MVIC showed no association with clinical variables. 30-STS power showed a lower z-score compared to MVIC (p < .001). In addition, 30-STS power detected 47% of PwHA with motor impairment compared to 0% for MVIC (p = .002). CONCLUSIONS: Our results suggest that 30-STS power may be more effective than knee extensors MVIC in detecting motor impairment in PwHA. Consequently, lower limb skeletal muscle power, rather than maximum knee extensor strength, appears to be more affected in PwHA.

Defining success in haemophilia care - Are we doing it right?

INTRODUCTION: Transformational advances have occurred in the management of haemophilia in the last decade leading to much better outcomes. However, a detailed and critical examination of its assessment and reporting show gaps in many aspects. These are discussed in this review. METHODS: The relevant literature related to different aspects of management of haemophilia was reviewed to identify gaps which need to be addressed. These include detection and diagnosis of haemophilia, documentation and reporting of joint bleeding, its management and methods of reporting in clinical trials and practice, aspects of personalizing care as well as access to therapeutic products and the need for and organization of comprehensive care. RESULTS: Current diagnostic approaches have more than doubled the identified number of persons with haemophilia (PWH) over the last 25 years but still constitute only ∼30% of the expected number. Joint bleeding is the primary indicator of disease severity and treatment efficacy, but there is lack of consistency and standardization in the way it is recorded and reported. Its continued use as an efficacy measure of modern treatments which maintain steady state factor levels or equivalence of >5% will lack sensitivity. The treatment of acute haemarthrosis has focussed on haemostasis and pain control, ignoring the role of inflammation in joint damage. Phenotypic heterogeneity of severe haemophilia has recognized clinical and laboratory variations based on haemostasis but not differences in local response to blood in the joint. At the organizational level, IU/capita provides a relevant measure of access to therapeutic products when the detection rate is ∼100% but is fallaciously low when detection rates are very low. With highly effective modern therapies for haemophilia and nearly no bleeding, the concept of comprehensive care team will need modifications. CONCLUSION: As haemophilia care advances, a deeper dive is needed into the details of various aspects its management to ensure consistency and contemporary relevance.

Expert United Kingdom consensus on the preservation of joint health in people with moderate and severe haemophilia A: A modified Delphi panel.

AIM: For people with haemophilia A (PwHA), bleeding in the joints leads to joint damage and haemophilia-related arthropathy, impacting range of motion and life expectancy. Existing guidelines for managing haemophilia A support healthcare professionals (HCPs) and PwHA in their efforts to preserve joint health. However, such guidance should be reviewed, considering emerging evidence and consensus as presented in this manuscript. METHODS: Fifteen HCPs experienced in the management of PwHA in the UK participated in a three-round Delphi panel. Consensus was defined at ≥70% of panellists agreeing or disagreeing for Likert-scale questions, and ≥70% selecting the same option for multiple- or single-choice questions. Questions not reaching consensus were revised for the next round. RESULTS: 26.8% (11/41), 44.8% (13/29) and 93.3% (14/15) of statements reached consensus in Rounds 1, 2 and 3, respectively. HCPs agreed that prophylaxis should be offered to patients with a baseline factor VIII (FVIII) level of ≤5 IU/dL and that, where there is no treatment burden, the aim of prophylaxis should be to achieve a trough FVIII level ≥15 IU/dL and maintain a longer period with FVIII levels of ≥20-30 IU/dL to provide better bleed protection. The aspirational goal for PwHA is to prevent all joint bleeds, which may be achieved by maintaining normalised (50-150 IU/dL) FVIII levels. CONCLUSION: The panel of experts were largely aligned on approaches to preserving joint health in PwHA, and this consensus may help guide HCPs.

Primary prophylaxis implementation and long-term joint outcomes in Swedish haemophilia A patients.

INTRODUCTION: Primary prophylaxis is the gold standard in severe haemophilia A (SHA) but time to escalate the prophylaxis regimen varies. AIM: Assess prophylaxis implementation and long-term joint health outcomes in SHA with primary prophylaxis. METHODS: Adult male patients born after 1980, with SHA on primary prophylaxis, started before the age of 3 years and second joint bleed, and no history of FVIII inhibitors, were enrolled. Repeated joint-health examinations were performed with HJHS or HEAD-US; VERITAS-PRO assessed adherence. RESULTS: Thirty patients were enrolled with, at inclusion, median age 33.5 years, annualized bleed rate and joint bleed rate 0, and FVIII consumption 4232 IU/kg/year, respectively. The median age was 1.2 years, at prophylaxis start once weekly with a median FVIII dose of 47.7 IU/kg, and 1.7 years, by the time escalation to a final regimen had occurred, with a median infusion frequency of thrice weekly and FVIII dose 41.7 IU/kg, respectively. Older age correlated with later transition to escalated prophylaxis (p < .001). Longer time to escalated prophylaxis correlated to more bleeds (p < .001). Median HJHS increased slowly, reaching 4 at 35-40 years. HJHS at 15-20 years correlated with higher HJHS afterwards. Median total HEAD-US score was 1 and correlated with HJHS (p < .001). Median VERITAS-PRO score was 36, indicating good treatment adherence. CONCLUSION: Primary prophylaxis is effective but does not completely prevent the gradual development of arthropathy in SHA. Joint assessments with HJHS should start at an early age, as they correlate with arthropathy in later life. Prophylaxis escalation should proceed expeditiously to prevent bleeds.

Assessing joint health in haemophilia patients: The combined value of physical examination and ultrasound imaging.

INTRODUCTION: Early diagnosis of joint damage is pivotal in haemophilia to prevent the occurrence and progression of haemophilic arthropathy thus providing optimal personalised management. The haemophilia joint health score version 2.1 (HJHS) is based on a physical examination of the mainly affected joints. Musculoskeletal ultrasound has demonstrated the capability to detect early changes in terms of synovitis and osteochondral damage. The haemophilia early detection with ultrasound (HEAD-US) score has been proposed as a simple and reliable evaluation tool. AIM: This study aims to investigate the correlation between the HJHS and the HEAD-US scores performed by two independent operators (physical therapist and musculoskeletal ultrasound expert) for the evaluation of the joint health status of patients with haemophilia. METHODS: Consecutive adult patients independent of the severity degree were included. Elbows, knees and ankles were evaluated by a physical therapist by HJHS and by a musculoskeletal ultrasound expert following the HEAD-US protocol. RESULTS: We observed a good positive correlation between HJHS and HEAD-US (Spearman's rho 0.72). The main discrepancy in conceptually similar domains was found between the HJHS swelling and the HEAD-US synovitis (rho 0.17), as ultrasound was able to detect even mild synovitis when HJHS swelling was scored 0 in up to 40% of cases. CONCLUSIONS: The HJHS and HEAD-US correlate well even when performed by two independent operators. Musculoskeletal ultrasound is particularly useful for the early detection of synovitis. The routine assessment of both scores helps clinicians define the stage and extension of joint involvement and set up a personalised treatment.

A qualitative study on the perioperative experiences and demands of haemophilic arthropathy patients undergoing total joint replacement.

INTRODUCTION: Total joint replacement is the optimal treatment option for patients with severe haemophilic arthritis. Current research emphasizes patient-reported outcomes as a vital measure for evaluating surgical outcomes and patient satisfaction. Nevertheless, very limited information about the subjective experience of perioperative haemophiliacs in the literature, highlighting the need for exploration in this area. AIM: To investigate the psychological experiences and health demands of haemophilic arthropathy patients during the perioperative period of total joint replacement. DESIGN: Qualitative descriptive research with semistructured individual interviews. METHODS: From June to September 2023, nine patients with severe haemophilic arthropathy who underwent total joint replacement at a Haemophilia Diagnosis and Treatment Centre in China were interviewed for average 37 min per person. Data were analysed using the traditional content analysis method and reported following the consolidated criteria for reporting qualitative research. The study is reported according to the COREQ checklist. RESULTS: Interviews described two main themes: (1) emotional decline which involves preoperative overoptimism, early postoperative anxiety and disease uncertainty during the early independent rehabilitation. (2) wellness aspiration which includes rehabilitation support and spiritual healing. CONCLUSION: This study reveals the patients' significant psychological changes and their well-being aspiration, particularly out-of-hospital rehabilitation needs. Strengthening communication between multidisciplinary teams and patients, enhancing the involvement of nurses, broadening the scope of functions at primary Haemophilia Treatment Centres, and developing telerehabilitation, these concerted efforts may improve the overall treatment experience for patients.

Joint bleeds in mild hemophilia: Prevalence and clinical characteristics.

INTRODUCTION: Joint bleeds are a common and frequent complication associated with hemophilia, increasing the risk of hemophilic arthropathy. It is important to define and characterize the presence of joint complications in mild hemophilia to develop strategies to mitigate disease burden. AIMS: To characterize the prevalence, clinical characteristics of joint bleeds, and risk factors that may lead to hemarthrosis in people with mild hemophilia. METHODS: Following Institutional Review Board approval, a retrospective chart review was conducted for patients with mild hemophilia seen at the Yale Hemophilia Treatment Center or Classical Hematology Program. RESULTS: The medical records of 70 patients were reviewed. Eighty one percent were male and 19 percent were female. Twenty individuals with mild hemophilia had a history of joint bleeding, 13 were traumatic bleeds, 7 were spontaneous. The age of first joint bleed ranged from 4 to 58 years old, with an average age of 20.8-years old. Ten patients developed joint bleeds between the ages of 10 and 20 years old. The most common locations of joint bleeding were the knee (n = 11) and ankle (n = 7). Eight of 70 patients had hepatitis C (HCV), 6 experienced joint bleeding. CONCLUSIONS: In this study, almost one third of patients with mild hemophilia experienced joint bleeding, often without history of trauma. Joint range of motion was abnormal in more than a third of the patients with mild hemophilia regardless. These data highlight the need for ongoing evaluation and characterization of joint health in individuals with mild hemophilia. HIGHLIGHTS: Twenty-nine percent of individuals with mild hemophilia had history of joint bleed. PwH and mild diseases with previous or current hepatitis C had higher likelihood of joint bleeding. Approximately 15% of PwH and mild diseases had abnormal joint examinations without a confirmed history of joint bleeding.

A post hoc comparative real-world analysis of HEAD-US score for joint health assessment of patients with severe haemophilia A and B in Spain.

AIM: Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed. METHODS: The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators. RESULTS: Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2 ± 11.8 and 32.7 ± 14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p < .01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients. CONCLUSION: This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted.

Arthroscopic ankle surgery in people with haemophilia.

INTRODUCTION: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. AIM: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. METHODS: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. RESULTS: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). CONCLUSION: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

The utility of standing knee radiographs for detection of lipohemarthrosis: comparison with supine horizontal beam radiographs.

OBJECTIVES: Lipohemarthrosis is a key finding in acute trauma patients and indicates an intra-articular fracture. The horizontal beam lateral radiography with supine position is known to be the best technique to demonstrate knee lipohemarthrosis. Our main purpose was to compare the sensitivity of supine and standing lateral knee radiographs to detect lipohemarthrosis. METHODS: In our retrospective study, consecutive patients with lipohemarthrosis on computed tomography of the knee between October 2019 and September 2021 were included. Fractured bone, the presence of lipohemarthrosis, and image quality in both standing and supine anteroposterior and lateral knee radiographs were evaluated. Interobserver reliability of the three observers was calculated. Fisher exact chi-square and z-proportion tests were used to compare lateral and anteroposterior knee radiographs. Krippendorff's Alpha and Kappa coefficients were used for inter-observer agreement. RESULTS: A total of 61 patients (38 men [62.3%], 23 women [37.7%]; mean age, 43 years ± 17 [standard deviation]) were included. The most common type of fracture was isolated tibial fractures (n = 32; 52.5%). The sensitivity of showing lipohemarthrosis of standing lateral knee radiographs (95.5%) was higher than supine lateral radiographs (38.5%) (p < 0.001). While non-optimal image quality did not affect lipohemarthrosis detection on lateral radiographs (p > 0.99), it caused a significant decrease in the diagnosis of lipohemarthrosis on anteroposterior radiographs (p = 0.036). We found a good-excellent interobserver agreement in lipohemarthrosis detection. CONCLUSIONS: Standing lateral radiographs have higher sensitivity than supine lateral radiographs in detecting lipohemarthrosis and are beneficial for detecting lipohemarthrosis which indicates the presence of occult-evident intraarticular fracture in patients with knee trauma. CLINICAL RELEVANCE STATEMENT: Standing lateral knee radiographs offer a useful method for reducing the misdiagnosis of the occult intra-articular fractures by showing the fat-fluid leveling more clearly. Its advantages may be more prominent when the advanced imaging modalities are limited. KEY POINTS: • Fat-fluid level (lipohemarthrosis) is an important radiographic sign to assess patients with acute trauma. It almost always indicates an intra-articular fracture. • Our retrospective study results support that lipohemarthrosis sign could be observed more frequently in standing lateral knee radiographs than in supine lateral radiographs. • Knee trauma patients, when available, should be evaluated with standing lateral radiographs for the diagnosis of lipohemarthrosis.

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.

Non-clotting factor therapies for preventing bleeds in people with congenital hemophilia A or B.

BACKGROUND: Management of congenital hemophilia A and B is by prophylactic or on-demand replacement therapy with clotting factor concentrates. The effects of newer non-clotting factor therapies such as emicizumab, concizumab, marstacimab, and fitusiran compared with existing standards of care are yet to be systematically reviewed. OBJECTIVES: To assess the effects (clinical, economic, patient-reported, and adverse outcomes) of non-clotting factor therapies for preventing bleeding and bleeding-related complications in people with congenital hemophilia A or B compared with prophylaxis with clotting factor therapies, bypassing agents, placebo, or no prophylaxis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, electronic databases, conference proceedings, and reference lists of relevant articles and reviews. The date of the last search was 16 August 2023. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating people with congenital hemophilia A or B with and without inhibitors, who were treated with non-clotting factor therapies to prevent bleeds. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed studies for eligibility, assessed risk of bias, and extracted data for the primary outcomes (bleeding rates, health-related quality of life (HRQoL), adverse events) and secondary outcomes (joint health, pain scores, and economic outcomes). We assessed the mean difference (MD), risk ratio (RR), 95% confidence interval (CI) of effect estimates, and evaluated the certainty of the evidence using GRADE. MAIN RESULTS: Six RCTs (including 397 males aged 12 to 75 years) were eligible for inclusion. Prophylaxis versus on-demand therapy in people with inhibitors Four trials (189 participants) compared emicizumab, fitusiran, and concizumab with on-demand therapy in people with inhibitors. Prophylaxis using emicizumab likely reduced annualized bleeding rates (ABR) for all bleeds (MD -22.80, 95% CI -37.39 to -8.21), treated bleeds (MD -20.40, 95% CI -35.19 to -5.61), and annualized spontaneous bleeds (MD -15.50, 95% CI -24.06 to -6.94), but did not significantly reduce annualized joint and target joint bleeding rates (AjBR and AtjBR) (1 trial; 53 participants; moderate-certainty evidence). Fitusiran also likely reduced ABR for all bleeds (MD -28.80, 95% CI -40.07 to -17.53), treated bleeds (MD -16.80, 95% CI -25.80 to -7.80), joint bleeds (MD -12.50, 95% CI -19.91 to -5.09), and spontaneous bleeds (MD -14.80, 95% CI -24.90 to -4.71; 1 trial; 57 participants; moderate-certainty evidence). No evidence was available on the effect of bleed prophylaxis using fitusiran versus on-demand therapy on AtjBR. Concizumab may reduce ABR for all bleeds (MD -12.31, 95% CI -19.17 to -5.45), treated bleeds (MD -10.10, 95% CI -17.74 to -2.46), joint bleeds (MD -9.55, 95% CI -13.55 to -5.55), and spontaneous bleeds (MD -11.96, 95% CI -19.89 to -4.03; 2 trials; 78 participants; very low-certainty evidence), but not target joint bleeds (MD -1.00, 95% CI -3.26 to 1.26). Emicizumab prophylaxis resulted in an 11.31-fold increase, fitusiran in a 12.5-fold increase, and concizumab in a 1.59-fold increase in the proportion of participants with no bleeds. HRQoL measured using the Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) physical and total health scores was improved with emicizumab, fitusiran, and concizumab prophylaxis (low-certainty evidence). Non-serious adverse events were higher with non-clotting factor therapies versus on-demand therapy, with injection site reactions being the most frequently reported adverse events. Transient antidrug antibodies were reported for fitusiran and concizumab. Prophylaxis versus on-demand therapy in people without inhibitors Two trials (208 participants) compared emicizumab and fitusiran with on-demand therapy in people without inhibitors. One trial assessed two doses of emicizumab (1.5 mg/kg weekly and 3.0 mg/kg bi-weekly). Fitusiran 80 mg monthly, emicizumab 1.5 mg/kg/week, and emicizumab 3.0 mg/kg bi-weekly all likely resulted in a large reduction in ABR for all bleeds, all treated bleeds, and joint bleeds. AtjBR was not reduced with either of the emicizumab dosing regimens. The effect of fitusiran prophylaxis on target joint bleeds was not assessed. Spontaneous bleeds were likely reduced with fitusiran (MD -20.21, 95% CI -32.12 to -8.30) and emicizumab 3.0 mg/kg bi-weekly (MD -15.30, 95% CI -30.46 to -0.14), but not with emicizumab 1.5 mg/kg/week (MD -14.60, 95% CI -29.78 to 0.58). The percentage of participants with zero bleeds was higher following emicizumab 1.5 mg/kg/week (50% versus 0%), emicizumab 3.0 mg/kg bi-weekly (40% versus 0%), and fitusiran prophylaxis (40% versus 5%) compared with on-demand therapy. Emicizumab 1.5 mg/kg/week did not improve Haem-A-QoL physical and total health scores, EQ-5D-5L VAS, or utility index scores (low-certainty evidence) when compared with on-demand therapy at 25 weeks. Emicizumab 3.0 mg/kg bi-weekly may improve HRQoL measured by the Haem-A-QoL physical health score (MD -15.97, 95% CI -29.14 to -2.80) and EQ-5D-5L VAS (MD 9.15, 95% CI 2.05 to 16.25; 1 trial; 43 participants; low-certainty evidence). Fitusiran may result in improved HRQoL shown as a reduction in Haem-A-QoL total score (MD -7.06, 95% CI -11.50 to -2.62) and physical health score (MD -19.75, 95% CI -25.76 to -11.94; 1 trial; 103 participants; low-certainty evidence). The risk of serious adverse events in participants without inhibitors also likely did not differ following prophylaxis with either emicizumab or fitusiran versus on-demand therapy (moderate-certainty evidence). Transient antidrug antibodies were reported in 4% (3/80) participants to fitusiran, with no observed effect on antithrombin lowering. A comparison of the different dosing regimens of emicizumab identified no differences in bleeding, safety, or patient-reported outcomes. No case of treatment-related cancer or mortality was reported in any study group. None of the included studies assessed our secondary outcomes of joint health, clinical joint function, and economic outcomes. None of the included studies evaluated marstacimab. AUTHORS' CONCLUSIONS: Evidence from RCTs shows that prophylaxis using non-clotting factor therapies compared with on-demand treatment may reduce bleeding events, increase the percentage of individuals with zero bleeds, increase the incidence of non-serious adverse events, and improve HRQoL. Comparative assessments with other prophylaxis regimens, assessment of long-term joint outcomes, and assessment of economic outcomes will improve evidence-based decision-making for the use of these therapies in bleed prevention.

Crohn's disease in hemophilic arthropathy patient: a case report.

Crohn's disease (CD) is an inflammatory bowel disease affecting the digestive tract, the incidence of which is on the rise worldwide. The most common clinical manifestation of hemophilia is arthropathy secondary to recurrent joint effusions and chronic synovitis. This article reports on a rare 25-year-old male patient with both hemophilic arthropathy and Crohn's disease who was at risk for pathogenic gastrointestinal bleeding. After undergoing endoscopic pathologic testing and genetic testing, a multidisciplinary expert work-up of a treatment and nutritional plan was performed. The patient improved clinically and adhered to conservative treatment. This case report is the first report of this rare co-morbidity, demonstrating the highly pathogenic mutation locus and summarizing the clinical experience of early diagnosis and treatment.

Quantitative MRI assessment of joint effusion using T2-relaxometry at 3 Tesla: a feasibility and reproducibility study.

OBJECTIVE: T2-relaxometry could differentiate between physiological and haemorrhagic joint effusion (≥ 5% blood) in vitro. Are quantitative T2-relaxation time measurements of synovial fluid feasible and reproducible in vivo in clinically bleed-free joints of men with haemophilia? MATERIALS AND METHODS: In this cross-sectional study, we measured T2-relaxation times of synovial fluid in clinically bleed-free ankles, knees or elbows of men with severe haemophilia A using a T2-mapping sequence (duration ≤ 7 min) at 3 Tesla MRI. Manual and circular regions of interest (ROI) were drawn in the synovial fluid of each joint by two independent observers to measure T2-relaxation times. Measurement feasibility was expressed as the success rate of the measurements by both observers. The interobserver and intraobserver reproducibility of the measurements were evaluated by the intraclass correlation coefficient of absolute agreement (ICC) and the limits of agreement (LoA) from Bland Altman analysis. RESULTS: We evaluated 39 clinically bleed-free joints (11 ankles, 12 knees, 16 elbows) of 39 men (median age, 24 years; range 17-33) with severe haemophilia A. The success rate of the T2-measurements was ≥ 90%. Interobserver reliability was good to excellent (manual ROI: ICC = 0.92, 95% CI 0.76-0.97; circular ROI: ICC = 0.82, 95% CI 0.66-0.91) and interobserver agreement was adequate (manual ROI: LoA = 71 ms; circular ROI: LoA = 146 ms). Intraobserver reliability was good to excellent (manual ROI: ICC = 0.78, 95% CI - 0.06-0.94; circular RO: ICC = 0.99, 95% CI 0.98-0.99) and intraobserver agreement was good (manual ROI: LoA = 63 ms; circular ROI: LoA = 41 ms). CONCLUSION: T2-relaxometry of synovial fluid in haemophilia patients is feasible with good interobserver and intraobserver reproducibility.

Biomarkers Involved in the Pathogenesis of Hemophilic Arthropathy.

Hemophilia, which is a rare disease, results from congenital deficiencies of coagulation factors VIII and IX, respectively, leading to spontaneous bleeding into joints, resulting in hemophilic arthropathy (HA). HA involves complex processes, including synovial proliferation, angiogenesis, and tissue remodeling. Despite ongoing research, factors contributing to HA progression, especially in adults with severe HA experiencing joint pain, remain unclear. Blood markers, particularly collagen-related ones, have been explored to assess joint health in hemophilia. For example, markers like CTX-I and CTX-II reflect bone and cartilage turnover, respectively. Studies indicate elevated levels of certain markers post-bleeding episodes, suggesting joint health changes. However, longitudinal studies on collagen turnover and basement membrane or endothelial cell markers in relation to joint outcomes, particularly during painful episodes, are scarce. Given the role of the CX3CL1/CX3XR1 axis in arthritis, other studies investigate its involvement in HA. The importance of different inflammatory and bone damage biomarkers should be assessed, alongside articular cartilage and synovial membrane morphology, aiming to enhance understanding of hemophilic arthropathy progression.