Joint Bleeding Research Articles

Risk Factors for Joint Bleeding in Severe Hemophilia a and B: Analysis of the Community Counts Longitudinal Surveillance Cohort

Background: One of the most devastating complications of Hemophilia A or B (HemA, HemB) is end-stage joint damage characterized by chronic pain and functional disability. Joint bleeding is the best predictor of joint damage in hemophilia. A wide range of new therapeutics from extended half-life factor (EHL) concentrates to non-factor therapies such as factor VIII mimetics, hemostatic rebalancers and gene therapy have been recently approved or are in late-stage clinical trials that hold the promise of decreased joint disease in severe hemophilia. Specific Aim: Given the progressive improvements in the therapeutic armamentarium of hemophilia care, this study aimed to determine current predictors of joint bleeding in individuals with severe hemophilia on continuous prophylaxis in the context of a national surveillance project. Methods: Eligible participants were males with severe HemA or HemB, aged 2 to 44 years, on continuous prophylaxis therapy and participating in Community Counts (CC) during the period December 2013 to November 30, 2022. CC is a bleeding disorders surveillance project funded by the Centers for Disease Control and Prevention and administered through the American Thrombosis and Hemostasis Network in 141 federally funded Hemophilia Treatment Centers across the United States. CC collects data on sociodemographics, bleeding episodes, treatment products, and health outcomes during patients' annual comprehensive care visits. Data were analyzed using annualized joint bleeding rates (AJBR), calculated using the number and location of all joint bleeds occurring in 10 joints (shoulders, elbows, hips, knees, ankles) during the year since the last surveillance visit based on infusion logs and/or other patient records. Age and other demographic subgroups were compared via rate ratios (RR) and 95% confidence intervals (CI). Methods accounting for multiple measurements from the same individuals over time were used for multivariate analyses. AJBR differences according to demographic and clinical variables were assessed via p values comparing Beta coefficients from these models. Results: The HemA cohort included 2505 persons, 8542 observations years and 13,224 joint bleeds for an overall AJBR of 1.55. The HemB cohort included 439 persons, 1488 observation years and 1326 joint bleeds for an overall AJBR of 0.89. Joint bleeding increased with age. In comparison to those ages 2-9 years, RRs were significantly increased for ages 10-19 and 20-44 for both HemA (1.23 [CI 1.1-1.3]) and 3.17 [CI 3-3.4], respectively), and HemB (2.2 [1.8-2.7] and 5.8 [4.8-7], respectively). Uninsured persons had higher AJBR than insured (HemA, RR 1.8 [1.6-2.1] and HemB, RR 6.9 [5.2-9.]. Table 1 compares characteristics associated with AJBR in multivariate analysis. The use of the FVIII mimetic in persons with HemA was associated with fewer joint bleeds (-1.00 joint bleeds per year). Persons with HemA showed modest decreases in AJBR with EHL therapies (-0.26), a finding not observed in persons with HemB. Worse AJBR outcomes were associated with missed doses for persons with both HemA and HemB. Joint bleeding was significantly associated with unemployment with disability for persons with HemA but not HemB. Trends in AJBR were similar between HemA and HemB for the following: adults had more joint bleeding than children, including adolescents aged 10-19 who are often engaged in team sports; compared with the Northeast, AJBR were higher in all other geographic regions; persons on Government insurance had higher AJBR than persons on Commercial insurance. Discussion: In a multivariate analysis of data on a large longitudinal cohort of persons with severe hemophilia on prophylaxis, use of the FVIII mimetic, ≥90% treatment adherence and treatment in the Northeast United States were associated with significantly lower AJBR. The increased joint bleeding rate in adults compared with children and adolescents may be related to pre-existing joint disease, less intense prophylactic regimens or decreased activity and fitness. Additional studies can further inform optimal hemophilia therapy regimens.

The Effect of Concizumab Prophylaxis on Target Joints, Resolution and Joint Bleeds in Patients With Hemophilia A or B With or Without Inhibitors in Phase 3 Clinical Trials

Background: Concizumab is a recombinant anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody under development as a once-daily subcutaneous prophylactic treatment for hemophilia patients with and without inhibitors, and has the potential to be one of the first subcutaneous treatment options for hemophilia B. Recurring joint bleeds may cause hemophilic arthropathy and reduce the quality of life of patients with hemophilia (van Vulpen LFD et al. Haemophilia. 2018; 24 Suppl 6:44-49). Results on target joints, their resolution, and joint bleeds in patients with hemophilia (hemophilia A or B with inhibitors [HAwI or HBwI] or without inhibitors [HA or HB]) from the prospective, multicenter, open-label explorer7 (NCT04083781) and explorer8 (NCT04082429) phase 3 concizumab clinical trials at the 56-week cut-off are presented. Aims: To assess and communicate the effect of longer term (56 weeks) concizumab prophylaxis (PPX) on target joints, their resolution, and joint bleeds in patients with hemophilia A or B with or without inhibitors. Methods: After informed consent/ethics committee approval were obtained, patients in both explorer7 and explorer8 trials were exposed to no PPX (arm 1) or concizumab PPX (arms 2-4) based on their treatment regimen before the trial. After the main part of the trial, all patients (arms 1-4) could continue in the extension part of the trial receiving concizumab for up to 136 weeks. Upon treatment restart following a treatment pause due to thromboembolic events, patients received a 1.0 mg/kg concizumab loading dose on Day 1, followed by an initial 0.20 mg/kg daily dose starting on Day 2, with potential adjustment to 0.15 or 0.25 mg/kg based on measured plasma concizumab concentration after week 4. The data presented here are from the 56-week cut-off that was defined as when all patients had completed the visit after 56 weeks or permanently discontinued treatment. Annualized bleeding rate (ABR) of joint bleeds was evaluated for all patients. Target joints at baseline by age group and target joint resolutions during the trial were assessed separately for this abstract. Target joints were defined as 3 or more spontaneous bleeds into a single joint within a consecutive 6-month period, and target joints were deemed resolved when there have been ≤2 bleeding episodes in the joint during the previous 12 months of exposure (Blanchette VS et al. J Thromb Haemost. 2014;12(11):1935-1939). Results: A total of 144 patients with HA or HB and a total of 127 patients with HAwI or HBwI were exposed to concizumab PPX at the 56-week cut-off. Upon treatment restart, 144 patients with HA or HB and 112 patients with HAwI or HBwI were included in the studies and were allocated to the new concizumab PPX dosing regimen, of which the majority were adults (HA + HB: 105; HAwI + HBwI: 72), some were adolescents (12-17 years) (HA + HB: 36; HAwI + HBwI: 40), and a few were elderly/very elderly (65-84 years) (HA + HB: 3; HAwI + HBwI: 0). Patients who had at least one target joint at baseline (HA + HB: adults [45/108], adolescents [18/36]; HAwI + HBwI: adults [35/72], adolescents [20/40]) mostly reported target joints in the ankle, elbow, and knee, and a few in the hip and shoulder, as presented per age group in Table 1. Of these patients who were exposed to concizumab PPX for at least 12 months, 49 patients with HA or HB reported a total of 80 target joints at baseline, of which 69 (86.3%) were resolved at the 56-week cut-off, and 49 patients with HAwI or HBwI reported 85 target joints at baseline, of which 78 (91.8%) were resolved at the 56-week cut-off. Most target joints were resolved within 12 months after treatment start (median [25th; 75th percentile])( 12.0 months [12.0; 12.0]), both for patients with HA or HB and HAwI or HBwI. The median ABRs for treated spontaneous and traumatic target joint bleeding episodes were 0.0 for patients with HA or HB and HAwI or HBwI, and the median ABRs for treated spontaneous and traumatic joint bleeding episodes were 1.3 for patients with HA or HB and 0.0 for patients with HAwI or HBwI at the 56-week cut-off, as presented in Table 2. Conclusions: Once-daily, subcutaneous concizumab prophylaxis resolved 86.3% of target joints in patients with HA or HB, and 91.8% of target joints in patients with HAwI or HBwI, most patients within 12.0 months. The median ABRs for treated spontaneous and traumatic target joint bleeding episodes at 56 weeks for both patients with HA or HB and HAwI or HBwI were 0.0.

A Retrospective Analysis and Characterization of Female Patients with Bleeding Disorders Hemophilia B, Hemophilia B and Von Willebrand's Disease and Their Treatment Type at Banner MD Anderson Cancer Center

Introduction: Women with bleeding disorders experience bleeding in mucocutaneous tissues, uterine bleeding, and in muscles and joints. In men, bleeding of more than 1 or 2 bleeds per year is justification for starting prophylaxis with factor and non-factor replacement therapy. At Banner MD Anderson Cancer Center (BMDACC), women are offered prophylaxis according to the same standard. Uterine bleeding classified as excessive or disruptive to daily activity is considered bleeding requiring prophylaxis. Aim: Describe the number of women in the bleeding disorder database from June 2018 to December 2022 with Hemophilia A (HemA), Hemophilia B (HemB) and Von Willebrand Disease (VWD) with respect to number on prophylaxis to prevent bleeds. Specific factor levels and subtype of VWD were not gathered as part of this project. Rather, patients were offered prophylaxis based on symptoms of bleeding. Prophylaxis is defined as treatment to prevent bleeding associated with day-to-day activity, but not prior to planned procedures. The type of treatment was recorded, type of access if needed (peripheral intravenous access v. central venous access) and why treatment was started. Results: Among 101 female patients in the BMDACC bleeding disorder database, 64 had a diagnosis of HemA, HemB or VWD. Among HemA, 13 of 17 (76%) were on prophylaxis with factor replacement or emicizumab. Joint bleeding and pain were the most common reasons for starting prophylaxis in 6 of 13 patients and menorrhagia was the second most common in 3 patients. Among HemB, 2 of 4 (50%) were on factor replacement. Rectal bleeding and menorrhagia were reasons to start prophylaxis. Among VWD, 24 of 43 (56%) were on prophylaxis with one or more of the following treatments: factor replacement, desmopressin or antifibrinolytic replacement. Menorrhagia was the most common reason for starting prophylaxis in 13 of 24 patients and joint bleeding was the next most common in 4 patients. Additional reasons were trauma, mucocutaneous, urinary tract bleeding, and bleeding during pregnancy. Patients with VWD were much more likely to require central IV access in the form of a chest port-a-cath 14 of 43 (33%) than patients with HemA or HemB, of which no patients required central access. Patients with HemA or HemB were more likely to use factor replacement than VWD to prevent bleeding symptoms. Patients with VWD were more likely than patients with HemA or Hem B to have a diagnosis prior to age 18; VWD had 16 of 43 (37%), HemA had 3 of 17 (18%) and HemB had 0 of 4 (0%). Conclusions: Female patients with inherited bleeding disorders have bleeding symptoms that may require the initiation of routine treatment to prevent bleeding and should be offered treatment with hemostatic agents to prevent bleeding when bleeding frequency exceeds more than 1 or 2 bleeds per year. Heavy menstrual bleeding, joint bleeding, joint pain, gastrointestinal and genitourinary bleeding are reported in this patient population as reasons to start prophylaxis with hemostatic agents. Further study is underway to assess the efficacy of starting prophylaxis in these patients. In the Author's experience, once factor replacement is started, patients are pleased with the change in their health status after initiation of treatment and continue to be compliant with treatment recommendations although they may have difficulty in administering those treatments. Patients with VWD were much more likely than those with HemA or HemB to require placement of a central venous access device. Further study into this observation is needed to understand why this is so.

Earliest Possible Detection and Intervention for Synovitis in Hemophilia- Results from a Single Center Retrospective Cohort Study

Introduction There is scientific evidence to suggest that the most serious health problems for hemophilic patients arise from joint damage, which in turn results from joint bleeding, which is overlooked and therefore not treated. The ankle joint was affected the earliest in most hemophilic patients. Strategies for detecting and treating bleeding in hemophilic patients need to be further developed and made more widely known by clinicians. Aim of our study The aim of our retrospective, single-center cohort study was to compare the effects of reactive versus preventive joint ultrasound as guidance for adjustments of treatment regimens for patients with severe hemophilia at our Hemophilia Comprehensive Care Center (HCCC) in Duisburg, Germany. Methods Before 2020, we used ultrasound according to the German hemophilia-synovitis guidelines in 2018. This meant that we sonographed the ankle joints and knees of most of our patients when they reported discomfort in the joint or when a joint bleeding had occurred. In these cases, prophylactic hemophilia treatment was immediately adjusted to a level at which the bleeding and/or discomfort stopped. If the factor treatment was not sufficient to accomplish this goal, the joints were treated with radiosynoviorthesis (RSO). In 2020, we changed our diagnostic strategy from reactive to preventive measures. Thus, we used ultrasound on every ankle and knee joint of our severely hemophilic patients at least once a year. If we found so called “silent symptoms,” which means touch-sensitive joints, the joints were sonographed once every three months. In cases of signs of joint degradation, we adjusted the prophylactic factor treatment accordingly. Results From 2020 to 2022, we examined a total of 1193 joints of 688 patients with hemophilia A or B, as well as with vWD disease type 2 or 3 and other severe coagulation disorders (factor VII deficiency, factor XIII deficiency, afibrinogenemia, and Glanzman disease). Of these, 103 had severe hemophilia A or B. In this study, we examined 656 joints sonographically. Of these, we examined 281 ankle joints in 80 patients and 175 knees in 64 patients, and adjusted the therapy regimens accordingly in these patients if necessary. Seven RSOs of the ankle joints and three RSOs of the knees were performed in the cohort up to 2020. After 2020, only two RSOs of the ankle joints were performed in the cohort. Conclusions At least for patients at our HCCC in Duisburg, Germany, we were able to show for the period 2020-2022 that closer ultrasound monitoring of ankle joints and knees in patients with severe hemophilia A or B and appropriate adjustment of prophylactic factor therapy was associated with less severe and less frequent joint degradation.

Experience with Emicizumab Among People with Hemophilia A in the Canadian Hemophilia Bleeding Disorders Registry

Background: The use of emicizumab as prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes in congenital hemophilia A (HA) was approved by Health Canada for the treatment of people living with HA (PwHA) with FVIII inhibitors in 2018, and without inhibitors in 2019. Here we present the results of a non-interventional, cohort study, using data routinely collected by the Canadian Bleeding Disorders Registry (CBDR) to evaluate treatment patterns of emicizumab in Canada and the associated safety and effectiveness outcomes, including quality of life. Methods: De-identified data were extracted from the CBDR database for all registered PwHA who had received emicizumab at least once prior to December 31, 2022. Baseline demographic characteristics were stratified by disease severity (defined by the level of endogenous FVIII activity) and age. Effectiveness outcomes were measured by the proportion of patients with zero, traumatic, spontaneous, or joint bleeds as well as annualized bleeding rates (ABR) for any treated bleed. Intra-patient comparisons of bleeding were performed for all patients and for those with at least six months follow-up in both pre- and post-emicizumab periods as a sensitivity analysis. Effectiveness outcomes also included patients' Hemophilia Joint Health Score (HJHS), Patient Reported Outcomes, Burdens and Experiences (PROBE), and EQ-5D index and visual analog scale (VAS) scores. We performed a complete data analysis, without imputation. This study was approved by the research ethics board of McMaster University and other participating centers, and abides by the guiding principles of the Declaration of Helsinki. Results: In total, 533 PwHA received at least one dose of emicizumab (PwHA E) in the CBDR database. Overall, 498 (93.4%) PwHA E had severe disease, 28 (5.3%) had moderate disease, and 7 (1.3%) had mild disease. At start of emicizumab exposure, 220 (41.3%) PwHA E were <18 years old; 78 (14.6%) PwHA E had current FVIII inhibitors, 82 (15.4%) had a history of FVIII inhibitors, and 373 (70%) had no history of inhibitors ( Table 1). A total of 13 adverse events were reported in the entire observation period, including one event of thrombosis (occurring in one person with COVID-19), seven allergic reactions, two FVIII Inhibitor development, two neurological events (headache; and headache, nausea, and vomiting) and one case of large hematoma developed at operative site following removal of port-a-cath. Moreover, nine COVID-19 cases were reported as adverse events. Over a median (first quartile, third quartile) follow-up time of 249 (136, 395) days, 388 (72.8%) PwHA E had no recorded bleeds. Out of 145 PwHA E with recorded bleeds, 106 had joint bleeds, 87 had traumatic bleeds, 69 had spontaneous bleeds and 46 had other bleeds (Table 2). An intra-patient comparison in all PwHA E (n=533) showed a decrease in mean (95% confidence interval [CI]) annualized bleeding rate (ABR) from 1.22 (1.06, 1.42), pre-emicizumab (2018, prior to first dose) to 0.50 (0.41, 0.60) post-emicizumab (rate ratio (95% CI) 0.41 (0.33, 0.50), p-value <0.001). The Intra-patient comparison in PwHA E without current inhibitor (n=455) showed a decrease in mean ABR (95% CI) from 1.02 (0.87, 1.19) to 0.54 (0.44, 0.66) (rate ratio (95% CI) 0.53 (0.43, 0.65), p-value <0.001). The Intra-patient comparison in PwHA E with current inhibitor (n=78) showed a decrease in mean ABR (95% CI) from 5.03 (3.30, 7.66) to 0.41 (0.26, 0.65) (rate ratio (95% CI) 0.08 (0.04, 0.15), p-value <0.001). Conclusions: This analysis describes the baseline characteristics, safety and effectiveness outcomes of Canadian PwHA treated with emicizumab before December 31, 2022. A total of 387 new patients were included in this analysis compared to the previous one (data cut: December 31, 2021, n=146). The data shows that 72.8% PwHA E had no recorded bleeds since they started emicizumab and that there was a substantial decrease in bleeds post-emicizumab in both PwHA with and without current FVIII inhibitor. The safety profile of emicizumab was consistent with previous reports. The CBDR allows for a longitudinal follow-up of the Canadian hemophilia A population, which can inform healthcare practitioners and regulatory authorities of the safety and efficacy outcomes of treatments in routine clinical practice.

Bleeding Outcomes and Treatment Adherence in Patients with Hemophilia Receiving Standard and Extended Half-Life Factor Replacement Therapy: A Real-World Multinational Survey

Introduction Hemophilia A (HA) and B (HB) are heritable X-linked disorders characterized by recurrent and extended bleeding episodes resulting from a deficiency of factor VIII and IX, respectively. Management of hemophilia often relies on standard half-life (SHL) and extended half-life (EHL) factor replacement therapy. Effectiveness of these regimens can be affected by level of patient adherence. There are limited data describing the bleeding outcomes and treatment adherence of HA and HB patients receiving SHL or EHL therapy. Here, we aim to describe clinical outcomes, such as bleeding rates and types of bleeds, in a real-world setting among patients receiving either EHL or SHL prophylactic therapy, while also considering perceived treatment adherence. Methods Data were drawn from the Adelphi Hemophilia Disease Specific Programme™, a real-world cross-sectional survey of male HA and HB patients conducted in France, Germany, Italy, Spain, the United Kingdom, and the United States of America from February 2020 - May 2021. Hematologists and hematologist-oncologists reported data on consecutively consulting male HA and HB patients, including demographics, treatment history, perceived treatment adherence and bleed history. Patients received treatment prophylactically and had been receiving current treatment for ≥12 months prior to data collection. Patients were grouped by treatment type (SHL or EHL therapy). Analyses were descriptive. Results Overall, physicians provided data for 367 patients. Mean (standard deviation; SD) age was 26.9 (14.8) years, 286 patients had HA (66% were receiving SHL and 34% were receiving EHL) and 81 patients had HB (42% were receiving SHL and 58% were receiving EHL). Of the patients with baseline clotting factor data, 58% (n=209) had a baseline activity level of <1%. Table 1 shows treatment data split by hemophilia severity. Mean (SD) annualized bleed rates (ABR) for HA patients receiving SHL or EHL were 1.2 (1.8) and 1.6 (3.6), respectively. Mean (SD) treatment duration was 7.5 (6.7) years for SHL and 3.0 (2.3) years for EHL. In the 12 months prior to data collection the most common bleed types for SHL (n=96) and EHL (n=49) were joint bleeds (59% and 51%), nosebleeds (26% and 33%) and small cuts (25% and 31%), respectively. Physicians reported the most recent bleed as ‘spontaneous cause’ in 42% and 43% of patients receiving SHL (n=96) and EHL (n=49) treatment, respectively. Physicians perceived that 42% of SHL and 29% of EHL patients were 100% adherent to their prophylaxis regimen and took their treatment on time. Mean (SD) ABR for those with 100% adherence vs <100% adherence in SHL patients was 1.0 (1.3) and 1.3 (2.1), respectively. This was 0.3 (0.7) and 2.1 (4.1) in EHL patients. Mean (SD) ABR for HB patients receiving SHL or EHL were 1.4 (1.3) and 0.9 (1.1), respectively. Mean (SD) treatment duration was 9.7 (7.7) years for SHL and 3.4 (4.5) years for EHL. In the 12 months prior to data collection the most common bleed types for SHL (n=25) and EHL (n=23) were joint bleeds (52% and 65%) and bruising/skin bleeds (28% and 26%), respectively, and nosebleeds (36% SHL) or microbleeds (22% EHL). Physicians reported the most recent bleed as ‘spontaneous cause’ in 36% and 43% of patients receiving SHL (n=25) and EHL (n=23) treatment, respectively. Physicians perceived that 12% of SHL and 51% of EHL patients were 100% adherent to their prophylaxis regimen and took their treatment on time. Mean (SD) ABR for those with 100% adherence vs <100% adherence in SHL patients was 0.5 (1.0) and 1.5 (1.3), respectively. This was 0.9 (1.1) and 1.0 (1.2) in EHL patients. Conclusion We described the bleeding rates of HA and HB patients receiving prophylactic SHL and EHL therapy. Most patients were reported to have more than one bleed a year, and spontaneous bleeds were prevalent despite the use of EHL treatment in HA and HB patients. Physicians perceived that a high proportion of HA and HB patients were not 100% adherent to either SHL or EHL treatment. Patients who were <100% adherent had numerically higher mean ABRs than those who were 100% adherent. This indicates a need for treatments that maximize adherence and improve upon the current standard of care.

Characterization of Joint Disease in Women with Hemophilia: The Carriers Ultrasound Project (CUP) Study

Introduction: Women with hemophilia (WWH) are at risk for bleeding despite normal or mildly reduced plasma factor VIII (FVIII) or IX (FIX) activity levels. Subclinical joint bleeds can contribute to longstanding and irreversible joint damage. Although joint health has been well-studied among men with hemophilia, there is currently a gap in knowledge on the prevalence, clinical characteristics, and natural history of joint health in women with hemophilia. No prior studies have utilized point-of-care musculoskeletal ultrasound (POC-MSKUS) to assess the presence and characteristics of joint changes in carrier women. Aim: This multi-institutional, cross-sectional study primarily aimed to evaluate and compare the prevalence and extent of joint-related symptoms and joint changes in WWH compared to age-matched controls utilizing validated clinical tools including the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol. We also aimed to examine the relationship between innate FVIII and FIX levels and presence of joint disease changes in this population. Methods: Between 2017-2023, women aged 18 to 40 years were enrolled and divided in 2 cohorts. The “carrier cohort” included women with a confirmed hemophilia A or B diagnosis, regardless of factor activity level. The “control cohort” included women without personal or family history of a bleeding disorder. Individuals were excluded if they had history of joint trauma or surgery within 12 months prior to enrollment or any history of joint replacement. Collected clinical information included presence of bleeding symptoms, joint-related symptoms, and historical use of hemostatic medications. Participants underwent clinical and radiological assessment of bilateral elbows, knees, and ankles using the Hemophilia Joint Health Score (HJHS) and HEAD-US protocol. Factor activity levels were measured in the carrier cohort. Descriptive and interferential statistics were performed using SPSS software with p<0.05 considered statistically significant. Results: Fifty-eight women, including 30 controls (51.7%) and 28 carriers (48.3%) were enrolled. The mean age at enrollment was 30.7 years (range: 19-39 years). Most women were White (79.3%) and Hispanic (51.7%). Of the 28 carriers, 85.6% (n=24) were hemophilia A carriers and 14.3% (n=4) hemophilia B carriers, respectively ( TABLE 1). Among carriers, the mean and median factor activity levels were 56% and 54% (range 20-120%) respectively. Carriers reported significantly higher prevalence of bleeding symptoms when compared to controls, including heavy menstrual bleeding (64.3% vs. 10%, p<0.001), epistaxis (25% vs. 3.3%, p=0.017), gingival bleeding (25% vs. 3.3%, p=0.017), and easy bruising (50% vs. 3.3%, p<0.001). The majority (53.5%, n=15) of carriers reported presence of joint-related symptoms when compared to controls, including joint pain (50% vs. 3.3%, p<0.001) and joint swelling (28.6% vs. 0%, p=0.02). Three (10.7%) carriers reported history of overt joint bleeds. Carriers had significantly higher mean HJHS scores (4.7 vs. 1.5, p<0.001) than did controls, however no significant changes in HEAD-US scores were found. A high body mass index (BMI) (>25kg/m2) was significantly associated with an increased prevalence of joint bleeding (25% vs. 0%, p=0.03) among carriers. When dividing carriers in 2 groups based on their baseline factor activity level (>40% versus <40%), the prevalence of bleeding manifestations and joint-related symptoms were similar ( TABLE 2). Carriers with factor levels <40% were more likely to require factor replacement on-demand (60% vs. 17.4%, p=0.046) and anti-fibrinolytics (60% vs. 17.4%, p=0.046) than carriers with factor levels >40%. There were no changes in mean HJHS or mean HEAD-US scores among the two groups. Conclusions: Women with hemophilia are at increased risk of bleeding manifestations and joint-related symptoms, regardless of factor activity levels. This population also seems to have poorer joint health than do non-carrier women as assessed by HJHS. Dedicated follow-up to help prevent and treat joint-related complications among WWH seems imperative. Our study did not detect significant ultrasonographic joint changes in the carrier cohort. However, joint findings may become more evident later in life or when assessed with magnetic resonance imaging. Further long-term studies are needed to support our hypothesis.

Design of an Observational Study (PROVE) to Assess the Long-Term Effects of Prophylaxis with Simoctocog Alfa or Emicizumab on Joint and Bone Health in Hemophilia a Patients

Background: Arthropathy caused by repeated joint bleeding is a major complication in patients with severe hemophilia A and is associated with long-term morbidity. Factor VIII (FVIII) prophylaxis has proven benefits for prevention of bleeding, including joint bleeding, in these patients. Alongside preservation of joint health, FVIII prophylaxis may preserve bone mineral density (BMD) and reduce the risk of fractures. Emicizumab is a bi-specific monoclonal antibody with no structural homology to FVIII and is approved for prophylaxis in hemophilia A patients. However, data on the long-term impact of emicizumab on joint and bone health are limited. Aims: To assess the impact of long-term prophylaxis with simoctocog alfa (Nuwiq ®; a fourth generation recombinant FVIII) versus emicizumab on joint and bone health in people with hemophilia A. Methods: PROVE is a multinational, prospective, two-arm, low-interventional study that will collect clinical data on joint and bone health in patients receiving prophylaxis with simoctocog alfa or emicizumab in routine clinical practice. Approximately 200 male participants (100 in each treatment arm) at least 12 years of age with severe hemophilia A (FVIII activity [FVIII:C] <1%) will be enrolled. Written, informed consent will be obtained from each patient or their legal representative. The primary objective of the study is to evaluate the long-term effect of simoctocog alfa versus emicizumab on joint health as measured by magnetic resonance imaging (MRI). The primary endpoint will be a between-group comparison of the change in total score on the extended MRI (eMRI) scale (Table 1). Secondary and exploratory endpoints include the impact of simoctocog alfa vs emicizumab on bleeding rates, joint and bone health, physical activity, quality of life and safety (Table 1). Study treatments will be defined by the treating physician prior to inclusion of a patient into the study. Patients will not be randomized to the treatment groups but will continue with their current prophylactic regimen (simoctocog alfa or emicizumab). Patients will be provided with an electronic diary (eDiary) in which to record study related data, including treatment-related data, bleeding event details, fracture details, concomitant medications and adverse drug reactions. Each patient will be followed for up to 4 years. An interim analysis is planned after 2 years. Conclusion: ThePROVE study aims to generate real-world data on the long-term effects of prophylaxis with simoctocog alfa or emicizumab on joint and bone health in hemophilia A.

Extravascular Factor IX Pool Fed By Prophylaxis Is a True Hemostatic Barrier Against Bleeding

Factor IX (FIX) can bind to type-IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX. However, the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds have not been demonstrated. The capacity of 4 different FIX molecules (plasma derived [pd] and recombinants) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knock-out (KO) mice. A specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50-100 IU/kg, while pdFIX generated a FIX signal at all doses including 50 IU/kg. After five 100 IU/kg daily infusions of rFIX, a clear accumulation of FIX was seen in the liver and joints of animals having received 5-day daily FIX infusions with all FIX molecules, with a higher FIX labelling intensity compared to that observed after a single infusion of FIX 100 IU/kg or a single infusion of FIX 500 IU/kg. The extravascular procoagulant activity of FIX was assessed in saphenous vein bleeding assays performed 7 days after a single infusion of FIX 100 IU/kg. An additional group of FIX KO mice received intravenously for 5 days a single daily dose of 100 IU/Kg of one the four types of FIX concentrate in order to mimic prophylaxis. The number of clots formed in 15 minutes was significantly greater in mice having received prophylaxis during 5 days with 100 IU/kg FIX compared to untreated FIX KO mice (p=0.009) and to mice having received a single infusion of FIX 100 IU/kg (p<0.0001) (Figure 1). Taken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection towards bleeding.

Neutrophil-Dependent Immune Response Promotes Joint Damage in Hemophilia

Background: Hemophilic arthropathy (HA) is the predominant pathophysiology resulting from recurrent joint bleeding in individuals with hemophilia and leads to permanent joint damage, chronic pain and reduced quality of life. Although FVIII replacement therapy or FVIII mimetics like HEMLIBRA have significantly improved the disease outcome, joint bleeding continues to occur in severely hemophilic patients (FVIII<1%). HA starts at an early age and develops progressively over time, warranting the need for a therapy that can intervene the progression of HA. Unfortunately, such therapy does not exist and the etiological mechanism of HA remains poorly understood. Aim: To determine whether neutrophil Gasdermin-D (GSDMD)-dependent generation of neutrophil extracellular traps (NETs) in in the joint promotes HA. Methods: Knee joints in FVIII-total knockout (F8 TKO) or littermate WT male mice were injured using a needle . Scoring of the bleeding severity and histology of injured joints were conducted to assess the joint injury in mice.Imaging-flow-cytometry and ELISA assays were used to evaluate the number of circulating NETs in the blood samples of patients diagnosed with HA and mice with following knee injury. Neutrophils from HA patients, F8 TKO mice and matched controls were isolated, activation of GSDMD-pathway components was evaluated in neutrophils using qRT-PCR (gene expression) and western blotting (protein levels and cleavage). Results: F8 TKO but not control mice manifested unresolved joint injury and severe bleeding 5-days post knee injury. Circulating NETs (cNETs) and cNETs markers llike neutrophil elastase or citrulinated histones were significantly elevated in the plasma of hemophilia patients diagnosed with HA and injured F8 TKO mice but not plasma of control humans or injured WT mice or uninjured F8 TKO mice. Major genes (mRNA levels) associated with GSDMD-mediated NETs generation were significantly elevated in neutrophils of HA patients and injured F8 TKO mice compared to matched controls. Finally, western blot analysis revealed activation of GSDMD pathway in neutrophils isolated from HA patients and F8 TKO mice but not matched controls. Conclusions: These findings are the first to suggest that GSDMD-dependent generation of NETs contributes to the pathogenesis of HA

Adherence to Clotting Factor Treatment and Association with Bleeding and Health-Related Quality of Life in Persons with Hemophilia

Introduction: Measuring patient adherence to prophylactic treatment with clotting factor in persons with hemophilia includes both subjective and objective measurements. There are limited studies conducted in adherence research using objective measures and a few studies revealed lack of correlation between subjective and objective adherence measurement. The study objectives are 1) to develop an objective adherent measurement; and 2) to assess it's association with bleeding and health-related quality of life (HRQoL) using the data collected from the Hemophilia Utilization Group Study Part VI (HUGS VI), which was an observational, non-interventional study investigating adherence to factor replacement therapy among persons with hemophilia A or B. Methods: HUGS VI enrolled participants from eight U.S. federally-supported hemophilia treatment centers in seven states (California, Colorado, Georgia, Indiana, Pennsylvania, Texas, and Washington) from 2015 to 2017. We enrolled eligible participants who either used standard half-life (SHL) products or used extended half-life (EHL) products for less than six weeks. We collected data on socio-demographics, bleeds, joint problems, and pain via surveys, as well as HRQoL, as measured by SF-12 at enrollment and at each three-month follow-up. We collected monthly factor prescription data from the clinical chart, and monthly factor dispensing records from the participants' pharmacy. We calculated factor treatment for the proportion of days covered (PDC) as the sum of the days of treatment available based on dispensing records, divided by the sum of the days of treatment prescribed based on prescription records for nine months post-enrollment. PDC ≥0.8 was considered an objective measure of adherence to factor treatment. The number of bleeds was summed from each of three quarterly follow-up surveys. We defined EHL users as participants who started an EHL product during the study period, either six weeks prior to enrollment or anytime during the nine months follow up. Association of PDC with nine months bleeds, ratings of chronic pain, and SF-12 scores in the nine-month follow-up were analyzed using Pearson correlation and Student T-Tests. Results: We analyzed a sample of 69 adults (age ≥18 years) with moderate or severe hemophilia using prophylactic treatment who completed at least baseline and nine-month follow-up surveys and had both prescription and dispensing records. Mean age was 28.9±10.3 (standard deviation) years, 91.3% were hemophilia A, and 65.2% were adherent to clotting factor treatment with PDC ≥0.8. EHL users were less likely to be adherent to the treatment than non-EHL users (adherence rate was 47.4% vs. 72.0%, p=0.06). PDC was significantly and negatively correlated with nine months of joint bleeds (correlation coefficient r=-0.30, p=0.01), and total bleeds (r=-0.33, p=0.026), but positively correlated with SF-12 physical composite score (r=0.32, p=0.009). PDC was not correlated with chronic pain (r=0.08, p=0.51) or SF-12 mental composite score (r=0.03, p=0.79). The participants who were adherent to factor treatment had fewer mean joint and total bleeds (2.6±4.1 vs. 1.3±2.1, p=0.08, and 4.9±5.6 vs. 2.9±3.8, p=0.07, respectively) than those non-adherent to treatment, although the differences did not reach statistical significance. Compared to participants who were adherent to treatment, non-adherent participants had a lower SF-12 physical composite score, with an approximately 5-point difference (43.4±10.6 vs. 48.0±9.1, p=0.07). Conclusions: As the data collection period occurred when EHL products became commercially available, treatment adherence may have led to treatment selection as participants switched from SHL to EHL products. Our data showed that participants who were non-adherent to treatment were more likely to be EHL users. Better adherence with higher PDC was moderately correlated with fewer bleeds, but higher HRQoL physical health composite score. The objective adherence measurement developed in this study should be further studied to investigate whether switching from SHL to EHL improves treatment adherence and its association with clinical outcomes.

Understanding Natural History of Common Inherited Platelet Function Disorder (IPFD) Patients: An Indian Study

Background : Inherited platelet function disorders (IPFDs) are less well studied in a resource poor country in comparison to hemophilia and other bleeding disorders.With high rates of consanguinous marriages in some of the communities in India, Glanzmanns thrombasthenia (GT) and Bernard soulier syndrome (BSS) are the two platelet function disorders that are commonly diagnosed. There is no data on the nature of bleeding, mode of treatment, mortality as well as quality of life (QoL) in these conditions. Aim : To understand clinical manifestations, treatment, quality-of-life (QoL), mortality and other details in GT and BSS patients. Methods : This is a retrospective, non-interventional, observational single center data collection study.Subjects were eligible to participate, if they had confirmed reports of laboratory diagnosis of GT or BSS by both platelet aggregometry and flow cytometry studies. Data collected were demographics, medical history, co-morbidities (HIV, HCV, HBV), detailed treatment/product(s) usage, bleeding events, surgical procedures, and other adverse events. It also included patient-reported outcome questionnaires regarding health-related quality of life (HRQoL) using SF-36 and EQ-5D instruments. All data were entered into electronic case report forms by the laboratory personnel. Results : Sixty one ( GT 50, BSS 11) patients participated in the present study; 31 were males and 30 females. 43 were pediatric patients and 18 adults. Seventeen patients were diagnosed at birth and 10 patients were diagnosed beyond the age of 10 years. Forty four patients (72%) had parental consanguinity. Thirteen patients ( BSS 8, GT 5) did not have any major bleeding manifestations which required treatment. In the remaining patients, the median ABR was 10 ( range 2.5 - >75). The median ISTH BAT score was 10 (range 1-26.)The bleeding manifestations included epistaxis (61%), ecchymosis (58%) , gum bleed (48%), gastrointestinal bleed (28%), soft tissue bleed (23%), hematuria (8%), joint bleed (3%) and intracranial bleed ( 3%). Heavy menstrual bleed (HMB) was the primary bleeding manifestation in all females in the reproductive age group. Four patients were diagnosed following circumcision. Treatment strategies for bleeding events included antifibrinolytic agents alone (26%), platelet transfusion (43%), or whole blood and fresh frozen plasma (39%). Antifibrinolytic agents were also used as adjunct agents with platelet transfusion in majority of the patients. None of the patients were on recombinant activated FVIIa. Overall 8 deaths were reported due to bleeding in these 61 families during the last 10 years, the cause of death mainly being non-availability of treatment products. The self- reported median EQ-5D health score was 82.5 ( range 40-100) Figure 1 shows the detailed EQ-5D analysis in these 61 patients Conclusion : Present study provides detailed information of GT and BSS and its impact throughout life. A wide variation in clinical manifestations and disease outcomes was observed, the major attributing factor may possibly be socioeconomic factor which includes access to clinical resources and treatment products for bleed management. Unlike hemophilia, GT and BSS patients do not have the privilege of prophylactic treatment in our country, but there is a need for optimal disease management to normalize both physical and psychosocial outcomes. More such studies will add to an increased understanding of critical issues in these

Hemophilic Pseudotumor of Paranasal Sinuses in a Child with Severe Hemophilia a Receiving Emicizumab: A Case Report

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in individuals with hemophilia A (PwHA). Prophylaxis with subcutaneous emicizumab promotes adequate hemostasis in PwHA. Emicizumab prophylaxis in children with hemophilia A has been approved in the United States for use in PwHA ages newborn and older, with or without FVIII inhibitors. We report a 2-year-old boy with severe congenital hemophilia A who initially received prophylaxis with standard half-life factor VIII but later switched to subcutaneous emicizumab at 6 mg/kg every four weeks due to difficult IV access and parental preference. Shortly after starting emicizumab, the patient presented to the hospital with severe episodic epistaxis from the left nostril, requiring ICU admission and ENT consultation. Despite treatment, the condition did not improve, prompting the need for imaging studies. Subsequently, the patient developed ipsilateral eye proptosis and a mass protruding from the left nostril. CT and MRI imaging of the orbit revealed an expansible soft tissue mass measuring 2 x 2.5 x 4 cm occupying the right sphenoid sinus, extending to the nasal cavity. The mass had caused erosion of the clivus and the anterior cranial fossa floor, extending to the middle cranial fossa (Figures 1 & 2). He underwent endoscopic nasal debulking of the left nostril mass, and the pathological examination revealed a cystic mass with a thick capsule and intra-cystic blood clots, consistent with the characteristics of a hemophilic pseudotumor (HP). The fibrous stroma contained hemosiderin-laden macrophages with no evidence of malignancy. Emicizumab was discontinued before the operation, and the patient received several doses of recombinant FVIII to maintain hemostasis. Despite the debulking procedure, the patient continued to experience episodic epistaxis and joint bleeding. An inhibitor assay was performed at that time and showed high levels, leading to a switch to on-demand FVIII treatment for hemophilia A with an inhibitor. Managing the bleeding episodes with bypassing agents proved challenging, and the family expressed dissatisfaction. A decision was made to resume emicizumab treatment, and the patient eventually stabilized, experiencing no bleeding for nearly six months. Additionally, he regularly follows up with ENT specialty, with no further intervention or progression of the tumor. Notably, he did not receive any bypassing agents concomitantly with emicizumab. HP is characterized by encapsulated blood clots accumulating in extravascular tissues, especially the musculoskeletal system, in patients with bleeding tendencies, particularly hemophiliacs. It is a benign, expansible, soft tissue-like mass that exerts pressure on surrounding structures, mimicking a locally invasive malignancy. HP is a hematoma that grows and causes bone erosion through repeated bleeding episodes. A literature review revealed that HP is a rare hemorrhagic complication that develops in 1-2% of patients with severe hemophilia (Magallón et al. Am J Hematol. 1994). Its occurrence in patients receiving emicizumab prophylaxis is extremely rare. The first reported case involved a Japanese child with hemophilia who presented with a pseudotumor occupying the left maxillary sinus after repeated episodes of epistaxis. The mass caused a downward deviation of the ipsilateral eye and bulged into the buccal cavity. The patient received monthly prophylaxis with emicizumab at 6 mg/kg (Kawahara et al. Int J Hematol. 2022), but unlike our patient, he received bypassing agents concomitantly. Our reported case is unique because HP developed independently of bypassing agent therapies, as the patient did not receive any bypassing agents before the tumor's development. The likely explanation is related to repeated bleeding insults to the same anatomical location, leading to the cumulative development of hematoma and HPs. Another possibility could be attributed to the known adverse thrombotic effects of emicizumab treatment. Physicians treating hemophilia should remain vigilant for abnormal clinical signs, such as new masses in patients receiving emicizumab, which could indicate HP.

Understanding the Disease Burden of Severe Von Willebrand Disease in a Resource Poor Country: An Indian Cohort Study

Background : The national economic status impacts identification of rare diseases which also reflects access to standard healthcare infrastructure.Though VWD is the commonest bleeding disorder, the disease remains under-recognized and underdiagnosed in India due to its phenotypic and clinical heterogeneity and the need for multiple and complex diagnostic tests. The hospital based data shows a contrasting prevalence to that of the west, in that type 3 is the commonest subtype followed by type 1 and type 2 subtype. The treatment patterns of VWD too differs between countries and geographical regions. Unlike hemophilia, the bleed patterns and treatment details are not very well defined. There is a need to identify the unmet needs in the area of diagnosis and management. Aim : The study is aimed to increase understanding of clinical manifestations, treatment practices along with Quality of life (qoL) in severe VWD patients from India Methods : This is a cross-sectional, patient reported retrospective analysis of severe VWD patients from India. The eligibility criteria is confirmed diagnosis of VWD with documented laboratory reports. An informed consent was taken from each patient before participation in the study and the study was initiated after obtaining approval from Institute Ethics Committee. The EQ-5D instrumentswere used to measure patient reported health related QoL. Results : A total of sixty two severe VWD patients were included in the present study. Mean age of the patients was 23.8 years (SD + 13.2 years); median 22 years (range 5-56 years) and the mean age of diagnosis was 4.9 years (SD + 6.9 years). The mean ABR was 12.6 (SD + 8.9). Twenty five patients (40%) had a positive family history and 37 (60%) of the patients reported parental consanguinity. Common bleeding symptoms were of mucocutaneous nature like epistaxis, ecchymoses and gingival bleed .Prolonged bleed from cuts was reported by 46 (74%) of patients and 14 out of 27 women (52%) in the reproductive age group complained of severe menorrhagia ( Table 1). In approximately 76% of the patients, the major treatment product was intermediate purity FVIII whereas 3 patients were still being treated with either cryprecipitate or fresh frozen plasma. The EQ-5D data reported a worse health state in the EQ-5D-5L dimensions of pain/discomfort (34% moderate and 8% moderate to severe problems),usual activities (21% moderate problems and 3% moderate to severe problems), self-care (21% moderate problems) and anxiety (moderate 21% and 2% moderate to severe).There were two deaths due to bleeding in the previous 10 years . Conclusion : In a resource limited country like India, type 3 is the predominant subtype presenting in the treatment centers. All patients had mucocutaneous bleeding with epistaxis being the predominant manifestation, but joint bleeding is also not uncommon. The study also reveals much lower than optimal QoL in all patients, mobility being the least affected parameter. Despite India being the pharmacy of the world, these conditions are neglected by stakeholders.

Reduced Vitamin C Levels in Patients with Bleeding of Unknown Cause and Generalized Joint Hypermobility

Introduction Vitamin C is essential for the synthesis of collagen. Ehler-Danlos syndrome (EDS) is a group of collagen disorders associated with generalized joint hypermobility (HM), bleeding and bruising. The genetic cause of the HM EDS subtype (hEDS) is unknown. Referral to haematology clinics may result in the diagnosis: bleeding of unknown cause (BUC), where no specific haemostatic treatment is available. However, it is a clinical experience, published in many textbooks, that bleeding, and bruising associated with EDS improve by oral intake of vitamin C. No previous studies examined vitamin C levels in patients with BUC. The aim of the study is to investigate the association of vitamin C levels with HM and vascular fragility in patients with BUC. Methods Patients with bleeding tendency are referred to our Haemophilia Center. Following ISTH-BAT score, normal coagulation test (INR, APTT, fibrinogen, F8, F9, F11, F13, VWFAg, VWFRist) and inconclusive results of flow cytometry analysis of platelet function, patients are diagnosed with BUC. Patients with a high ISTH-BAT score > 10 were included in this study. We performed clinical examinations by a tourniquet test for capillary fragility and a Beighton score for generalized HM. A skin extensibility test was performed by pulling on the skin off the forearm and the lateral side of the throat until resistance was met. The test was considered positive (abnormal) if the skin extended more than 2 cm in both sites when pulled. Germline DNA was analyzed by whole genome sequencing (WGS) analysis and an in silico panel of 170 genes associated with bleeding and generalized HM was examined. Additionally, homozygous polymorphism in vitamin C genes ( GULOP, SLC23A1, SLC23A2, SVCT1, HP, GST and SOD2) known to cause reduced vitamin C levels, were assessed Vitamin C analysis: The participants received oral and written guidelines regarding intake of vitamin C in relation to the blood sample. The guidelines included no vitamin C supplements for 3 days before the blood sampling and no intake of vitamin C rich food on the day of the appointment. Plasma samples were immediately acidified by addition of 10% meta-phosphoric acid to ensure the stability of ascorbic acid, and subsequently analyzed by high-performance liquid chromatography. Severe vitamin C deficiency was defined as <11µM, deficiency as < 23 µM, suboptimal status as 23-49 µM and adequate status as >49 µM. Results Sixty probands and 20 healthy age- and gender-matched controls (HC) were included. Most patients were women (56/60, 93%), median age 48 (range 21- 75) and median BAT score 13 (range 10-21). By WGS a 67-year woman with Beighton score 7 was diagnosed with Noonan syndrome due to a pathogenic variant in PTPN11 (c.922A>G). Also, a 62-year woman without HM was diagnosed with mild FV deficiency due to a heterozygous variant in F5 (c.449A>G). No other causal variants were identified. In a patient with a homozygous variant in SLC23A1, vitamin C level was suboptimal 42µM.Suboptimal vitamin C levels were found in 19/60 patients and 2/20 HC. One patient was severely vitamin C deficient (7µM). Vitamin C levels were significantly lower in patients compared to HC (median 56 µM vs 76 µM; p = 0.012). Beighton score was positive in 29/60 patients and 1/20 HC (p<0.001). In 18/60 patients versus 0/20 HC the skin extensibility test was abnormal (p = 0.01). In 12/29 patients with a positive Beighton score the test for skin extensibility was also positive indicating a diagnosis of hEDS. Tourniquet test was positive (> 10 petechiae) in 18/60 patients and 4/20 HC (p>0.5). Patients with positive Beighton scores had significantly higher BAT scores than patients without HM (P= 0.014). No significant associations were found between vitamin C levels, a positive Beighton score, a positive Tourniquet test or a high BAT score respectively. Conclusions We found that a high proportion of patients with BUC have generalized HM, abnormal skin extensibility and positive tourniquet test. Indeed, patients with HM had increased ISTH-BAT scores compared to patients with negative Beighton scores. Our data support that hEDS may be an underlying cause of BUC. Further studies are needed to determine the genetic background of hEDS. Levels of vitamin C were reduced in patients with BUC compared to age and sex matched control. Our results could pave the way for a randomized study of vitamin C supplements versus placebo for bleeding and bruising in patients with generalized HM and BUC.

The Correlation of Muscle Mass and Walking Distance with Joint Health and Functional Status in Hemophilic Arthropathy Among People with Hemophilia a (PwHA)

Introduction: Hemophilic arthropathy resulting from repeat joint bleeding is a common complication for people with hemophilia (PWH), despite the current prophylaxis therapy. Monitoring the status of musculoskeletal health for PWH is necessary. Muscle plays a critical role in maintaining and promoting the joint health. Muscle atrophy is one of the key features of haemophilic arthropathy. Up to date, there are more studies focusing on joint health of PWH but few having attention on the impact of limbs muscles on joint status of PWH. Clinical assessments such as muscle circumference and manual muscle strength tests fail to detect subtle muscle changes. The study aimed to evaluate the ultrasound measurement of muscle thickness in people with hemophilia A (PwHA) and its correlation to joint health and functional impairments. Methods and Materials: In the observational cross-sectional study, 29 PwHA (median age 35 years; range 13-63) were enrolled, including 27 severe-type diseases on prophylaxis therapy and 2 moderate-type diseases on episodic treatment. Muscle thickness of quadriceps and medial gastrocnemius were measured by ultrasound. Joint health and functional capacity were assessed using Haemophilia Joint Health Score (HJHS), Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US), Haemophilia Quality of Life Questionnaire for Adults (Haemo-A-QoL), and Haemophilia Activities List (HAL). 6-Minute Walking Test (6MWT) for global functional evaluation. Results: At the time when the 29 patients receiving this survey of joint health, there were 28 on rFVIIIFc treatment for an average of 31.2 months (mean: 33.5, range 19.5－43), among whom 26 severe-type patients had rFVIIIFc prophylaxis and 2 moderate-type patients had on-demand therapy with rFVIIIFc. Only one severe-type patient had received non-rFVIIFc product prophylaxis for > 3 years. Totally 174 joints were examined. By correlation analysis, a significant correlation was found between both quadriceps and calf muscle thickness and the HJHS knee and ankle scores, respectively, with a negative correlation ( r= -0.45, p=0.015*, right quadriceps; r= -0.60, p<0.001***, left quadriceps; r= -0.39, p=0.039*, right calf; r= -0.58, p<0.001***, left calf). A significant correlation between muscle thickness and HEAD-US was observed between quadriceps muscle and knee score, with a negative correlation ( r= -0.56, p=0.017*, right quadriceps; r= -0.36, p=0.0048**, left quadriceps). Therefore, Quadriceps muscle thickness significantly correlated with HJHS knee, HEAD-US knee, and HAL. Calf muscle thickness significantly correlated with the HJHS ankle. After adjusted age and BMI, calf muscle thickness was significantly associated with the HJHS ankle. Muscle thickness was also observed to correlate with Haem-A-QoL and HAL. 6MWT was found to significantly correlated with HJHS total, HEAD-US total, Haem-A-QoL, and HAL ( r= -0.42, p=0.0231*, HJHS; r= -0.52, p=0.0037**, HEAD-US; r= -0.60, p<0.0001***, Haem-A-QoL; r= 0.64, p<0.001***, HAL). Conclusion: For the first time, limbs muscle thickness and the distance of 6MWT were linked to assessment of joint health, quality of life and activity participation in PwHA. Ultrasound measurement of muscle thickness appears to be a reliable tool for the assessment of muscle mass in PwHA.The 6MWT also appears to be useful tool for assessment of physical capacity and endurance in PwHA. Disclosures: No relevant conflicts of interest to declare.

Real-World Data on Hemophilia a Patients Transitioning from Bay 81-8973 to Bay 94-9027 and from Bay 14-2222 to Bay 81-8973 and then to Bay 94-9027 in the Athndataset

Background: The ATHNdataset is sponsored by the American Thrombosis and Hemostasis Network, including 17,109 hemophilia A people as of the cutoff date, 4/30/22. Patients with Hemophilia A are transitioning more and more from standard half-life (SHL) products to extended half-life (EHL) recombinant factor VIII (rFVIII) products Objective: To evaluate the effect of Hemophilia A patients transitioning from BAY 81-8973 (Kovaltry ®) to BAY 94-9027 (Jivi ®) and from BAY 14-2222 (Kogenate FS ®) to BAY 81-8973 and then to BAY 94-9027 in a real-world setting. Methods: The ATHNdataset was queried for patients treated with BAY 94-9027 that had BAY 81-8973 as a prior medication as well as for the latter that had BAY 14-2222 as a prior medication. Data included demographic data, treatment history, and bleed rates. Query dates were between January 1, 2010 and April 30, 2022. Summary: A total of 205 patients were treating with BAY 94-9027 and 354 with BAY 81-8973 at data cut-off. Thirty patients that treated with BAY 94-9027 had BAY 81-8973 listed as one of their prior medications. Of these, 90% had severe Hemophilia A, while 7% had moderate and 3% had mild disease. All were male, with an average age of 37 years at data cut-off; 80% being White and 90% not Hispanic, Latino or of Spanish origin. Overall, 24/30 patients were consistently treated prophylactically with BAY 81-8973 and with BAY 94-9027. The mean annualized total bleed rate (Total ABR) on BAY 81-8973 was 0.47 and 0.42 on BAY 94-9027, while the annualized joint bleed rate (Joint ABR) was 0.28 on both products and the annualized spontaneous bleed rate (Spontaneous ABR) was 0.17 and 0.30, respectively. The most frequent dosing regimen on BAY 81-8973 was 3x/week or more often, while on BAY 94-9027 more than 80% of patients were using a less frequent regimen than 3x/week, with 2x/week being the most common. (Figure 1) In addition, a sub-analysis was performed on the same patients that transitioned from BAY 81-8973 to BAY 94-9027, to include those patients that also used BAY 14-2222 as a prior medication to BAY 81-8973. A total of 12 patients transitioned from BAY 14-2222 to BAY 81-8973 and then to BAY 94-9027. Of these, all (100%) had severe Hemophilia A and were male. The average age was 33 years at data cut-off; 83% being White and 92% not Hispanic, Latino or of Spanish origin. Overall, 8/12 patients were treating consistently prophylactically with BAY 14-2222, BAY 81-8973 and BAY 94-9027. For these patients, the mean Total ABR on BAY 14-2222 was 3.59, on BAY 81-8973 it was 1.10 and 0.72 on BAY 94-9027, while the Joint ABR was 0.30 on BAY 14-2222, 0.64 on BAY 81-8973 and 0.34 on BAY 94-9027. The Spontaneous ABR was 0.14, 0.35 and 0.67, respectively. (Figure 2) The most frequent dosing regimen on BAY 14-2222 and BAY 81-8973 was 3x/week, while on BAY 94-9027 nearly 90% of patients were using a less frequent regimen than 3x/week, with 2x/week being the most common. Conclusions: The data show that hemophilia A patients who transitioned to BAY 94-9027 from BAY 81-8973, or those that transitioned from BAY 14-2222 to BAY 81-8973 and then to BAY 94-9027 did experience similar or decreased total annual bleed rates with a decrease in their prophylaxis regimen frequency when transitioning to BAY 94-9027 in the real world. The therapeutic burden of frequent infusions can be reduced when patients transition between rFVIII product classes (SHL to EHL), without change in their annual bleed rate. These data should be interpreted with caution owing to limitations of real-world studies and further studies are needed to confirm the impact of switching to BAY 94-9027 and BAY 81-8973 in real-world settings. Additional studies are needed to expand on these results.

Advancing Hemophilia Prophylaxis: Personalized Low-Dose CFC and Emicizumab in Resource-Limited Settings

Introduction: Hemophilia, a congenital bleeding disorder resulting from clotting factor deficiency, significantly impacts the lives of persons due to recurrent bleeding. Prophylaxis, involving clotting factor replacement, has been recognized as a vital approach to reduce complications and to improve the quality of life in people with hemophilia. However, access to this remains limited, in low-income countries like India. This study examines the effectiveness of personalized low-dose clotting factor concentrates (CFC) prophylaxis and Emicizumab in children with hemophilia, aiming to achieve zero annual bleed rates (ABR), thereby enhancing their well-being and reducing healthcare burden. Patients and Methods: This retrospective observational study was conducted at the Hemophilia Treatment Centre (HTC) in Aluva, Kerala, India, spanning from May 31, 2022, to June 1, 2023. Study included children under 18 years with hemophilia A/B, with or without inhibitors, who had commenced prophylaxis with personalized low-dose CFC since 2015 and completed one year of prophylaxis. The total sample size was 31. Data on ABR, Annual Joint Bleed Rate (AJBR), Hemophilia Joint Health Status (HJHS) score, and Functional Independence Score Hemophilia (FISH) were extracted from the HTC registry.Standard half-life CFCs were used for prophylaxis, with a starting frequency of twice a week for Factor VIII and once a week for Factor IX. Patients were regularly followed up in the Hemophilia Clinic, and the frequency/doses of prophylaxis were increased in case of breakthrough bleeds. Additionally, children were advised to organize peak activities to coincide with the days of CFC injections. Personalization of doses was not based on pharmacokinetic software but was determined through close monitoring and individual adjustments.Health education on identifying and managing bleeding episodes followed ISTH guidelines. Prophylaxis outcomes were assessed with changes in ABR and AJBR during the last year of prophylaxis and compared to the bleed rates in the one year prior to prophylaxis. Changes in HJHS and FISH were documented for older children. All analysis were done using SPSS version24. For quantitative variables results were presented as mean with standard deviation and for qualitative variables, results were presented in percentages. Comparison achieved with standard paired t-test, and p value < 0.05 considered as significant. Results: Out of 36 children receiving prophylaxis, 31 met the inclusion criteria. Among them,10 (32%) received Emicizumab prophylaxis, while 21 (68%) were managed with personalized low-dose CFC prophylaxis. Hemophilia A constituted 24(77%) of cases, mostly classified as severe disease-29 (94%). Table :1 summarises the patient characteristics, prophylaxis dose, cost and outcome measures of the study population.The personalized low-dose CFC prophylaxis had significant measurable improvements, reducing the ABR from 14.90 to 2.90( p 0.000) and the AJBR from 4.95 to 1.43( p 0.004). Additionally, HJHS improved from 3.30 to 0.95( p 0.102), and FISH increased from 29.90 to 32.00( p 0.020).Children on Emicizumab achieved exceptional results, with all reporting zero ABR ( p 0.027), and AJBR ( p 0.131) even with lower than recommended doses(1.02mg/kg/week). In contrast, personalized low-dose CFC prophylaxis (Factor VIII: 36.35/kg/week, Factor IX:32/kg/week) showed varied outcomes, with only 4(19%) achieving zero ABR. HJHS and FISH were not evaluated in Emicizumab group as 7(70%) were belonging to the age group of less than 5 years. Conclusion: This study highlights the effectiveness of personalized low-dose CFC prophylaxis and Emicizumab in reducing bleeding rates and improving musculoskeletal health and functional independence in children with hemophilia. Emicizumab prophylaxis demonstrated remarkable outcomes, achieving zero bleeds even with lower doses. However, personalized low-dose CFC prophylaxis struggled to achieve zero bleed rates for most of them. The findings underscore the need for alternative strategies and increased accessibility to Emicizumab and other newer drugs to achieve the goal of zero bleed rates for children with hemophilia in resource-limited settings. The study's results provide hope for achieving zero bleed rates, ultimately enhancing the well-being of children with hemophilia in resource-limited regions.

Emicizumab Prophylaxis for the Treatment of Chinese Hemophilia A Patients in the Real World: A Multi-Center Retrospective Analysis

Background The real-world experiences of Hemophilia A (HA) patients receiving emicizumab prophylaxis in China are insufficient due to the high cost and later approval of emicizumab. In this study, we retrospectively analyzed Chinese HA patients with or without factor VIII (FVIII) inhibitors receiving emicizumab prophylaxis with the aim to investigate the efficacy and safety of emicizumab as well as the current status and effect of different doses of emicizumab in a real-world setting. Methods HA patients with or without FVIII inhibitors receiving emicizumab prophylaxis between June 2019 and June 2023 in China were included in the study. Data of HA patients including children and adults were retrospectively gathered from 27 hospitals all over the country. For each patient, the anonymized data were collected and telephone follow-ups were conducted to make sure the intact information collected as much as possible. Low dose and higher dose of emicizumab were defined as monthly dose <3 mg/kg and monthly dose ≥3 mg/kg, respectively. All analyses were performed using SPSS software version 25.0 (IBM Corporation, Armonk, New York, USA). Intraindividual comparisons were performed by nonparametric paired tests. Results A total of 127 male patients (10.2% [n=13] ≥18 years old; 89.8% [n=114] <18 years old) were enrolled in our study (severe: moderate = 103:24). Of these, 42 (33.1%) had FVIII inhibitors at initiating emicizumab. The median (interquartile range [IQR]) duration of emicizumab treatment was 16.0 (9.0-30.0) months. The median (IQR) annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) after emicizumab were 0.5 (0-1.5) and 0 (0-0), respectively (calculated in patients treated with emicizumab >6 months). Among the 127 patients, 67 (52.8%) patients had no bleeds at all. No intracranial hemorrhage occurred after emicizumab. Adverse events were reported in 12 (9.4%) patients and 10 (83.3%) were injection-site reactions. There were no deaths, thromboembolic events, or thrombotic microangiopathies in our study. Two (8.0%) patients had treated epistaxis after emicizumab with low dose compared with 0 (0.0%) with higher dose ( P =0.037). Four (16.0%) patients had target joints after emicizumab with low dose compared with 1 (1.0%) with higher dose ( P =0.005) (Table 1). There were no significant differences between low dose and higher dose of emicizumab prophylaxis in ABR, AJBR, the proportion of zero bleeds, the proportion of adverse events, and so on. The median (IQR) ABR was 5.0 (2.0-14.0) with prior treatment compared with 0.5 (0-1.5) with emicizumab, an 90% reduction in ABR with P value <0.001 (Table 2).Also, the use of emicizumab was also associated with significant reduction in AJBR ( P <0.001), number of target joints ( P <0.001), number of intracerebral hemorrhages ( P <0.001), inhibitor titer ( P =0.016), and days away from school/work ( P <0.001). Conclusion In this multi-center study, we indicated the efficacy and safety of emicizumab and that low dose and higher dose of emicizumab had similar efficacy in Chinese HA patients without increasing adverse events.

Real Word Data on Levels of Emicizumab and Their Correspondence with the Global Hemostatic Capacity and the Spontaneous Joint Bleeding in Patients on Emicizumab Prophylaxis

Introduction: Emicizumab has improved the management of patients with hemophilia A. However, few real-world data are available on drug plasma levels and their correspondence with global hemostatic capacity (GHC) and annualized spontaneous joint bleeding rate (ASJBR). Aims: Evaluation of the correlation between emicizumab plasma levels, GHC and ASJBR in patients on emicizumab prophylaxis. Methods: Multicenter, observational and cross-sectional study was performed in 4 Spanish hospitals. Emicizumab plasma levels and thrombin generation capacity (TGT, Genesia ®, Stago ®) of patients on emicizumab prophylaxis were determined in a central laboratory. Kinetics of clot formation was evaluated by rotational thromboelastometry (ROTEM ®, naTEM ® test, Werfen ®) in one center. Time on emicizumab prophylaxis and the number of spontaneous joint bleeds (SJB) was collected retrospectively using the clinical history. Results are expressed as median (25 th-75 th percentiles) or mean ± standard deviation depending on data distribution. A p-value < 0.05 was considered statistically significant. Results: Twenty-eight patients were included: 18 aged ≥12 years (age= 20.1 [14.7-38.9] years old) (group 1) and 10 patients aged <12 years (age= 6.1 [3.2-8.9] years old) (group 2) (p< 0.001). Globally, emicizumab levels were 46.3 ± 11.9 mcg/mL and similar between both groups: 45.2 ± 13.1 mcg/mL (group 1) and 45.9 ± 7.3 mcg/mL (group 2) (p=0.870) (Figure 1). No correlation was detected between emicizumab levels and TGT or ROTEM ®. Compared with healthy controls, patients presented lower values of thrombin generation: Peak (% compared to controls) = 41.4 (33.3-53.0) % and endogenous thrombin potential (ETP%) = 54.9 (38.9-73.4) %. However, on the contrary, ROTEM ® showed a similar procoagulant profile (example: CT and CT+CFT; p>0.05) or even higher (example: lower CFT values in patients; p= 0.023) compared to healthy subjects (Table 1). Throughout a follow-up period of 57.0 (32.3-102.3) weeks, none of the patients presented SJB (ASJBR =0). Conclusions: Emicizumab treatment provided excellent protection to patients throughout the study period. The wide interpatient variation on emicizumab plasma levels does not appear to have an impact on the development of SJB. TGT and ROTEM ® showed contradictory results: TGT describes lower thrombin generation capacity in patients compared to healthy controls, while ROTEM ® showed a similar or even higher procoagulant function in patients. Additional studies are required to explain these findings and their clinical significance.