Joint Bleeding Research Articles

Joint Health Markers in Hemophilia: The State of the Art

Recurrent joint bleeds in hemophilia lead to (irreversible) joint damage, so-called hemophilic arthropathy causing major morbidity amongst hemophilia patients. Progression of arthropathy is monitored by clinical examination and imaging

Joint status and related risk factors in patients with severe hemophilia A: a single-center cross-sectional study

ABSTRACT Objectives Hemophilic arthropathy is the most common complication of severe hemophilia A. This study aims to investigated joint status and related risk factors in patients with severe hemophilia A (PWSHA). Methods This single-center study included 31 patients. Six index joints (both elbows, knees, and ankles) were evaluated using the Hemophilia Early Arthropathy Detection with UltraSound in China (HEAD-US-C) and Hemophilia Joint Health Score (HJHS). Treatment adherence was measured using the Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS-Pro). We analyzed the influence of age, treatment delay (the interval between diagnosis and the initiation of treatment), prophylaxis, and treatment adherence on joint outcomes. Results All patients were male (median age, 22 years). The median age at diagnosis was 1 year; that at initial treatment was 5 years. All patients experienced joint bleeding. HEAD-US-C and HJHS scores were positively correlated (R = 0.70, P < 0.0001). Median [range] HEAD-US-C and HJHS scores were 15 [0-36] and 32 [2-49], respectively. Age was positively correlated with both HEAD-US-C (P = 0.002) and HJHS scores (P < 0.0001). The difference of HEAD-US-C scores between groups with ≤1 year and >1 year treatment delay was close to significant (P = 0.055). HJHS scores were significantly different between these two groups (P = 0.03). Joint assessment scores were not significantly different between on-demand and low-dose prophylaxis groups. VERITAS-Pro scores were correlated with both HEAD-US-C and HJHS scores (P = 0.046 and P = 0.005, respectively). Conclusions Hemophilic arthropathy was pervasive in PWSHA. Age and poor adherence were significantly correlated with joint damage. Prompt treatment and adherence improvement may reduce severity.

A roadmap for better management for synovitis in haemophilia.

A roadmap for better management for synovitis in haemophilia.

Efficacy of Individualized Preventive Treatment of Patients with Severe Hemophilia A Guided by Multiple Clinical Parameters and Pharmacokinetics

Objective: The objective of the study was to investigate the effect of multiple clinical parameters (age, weight, blood types, and bleeding types) on FVIII pharmacokinetic parameters (PK parameters) in adult patients with severe hemophilia A (SHA), draw up individualized preventive treatment plans, and observe clinical efficacy. Methods: Forty SHA patients treated in our hospital from January 2018 to May 2019 were enrolled, with their age, weight, blood types, bleeding types, and PK parameters measured to analyze the effects of clinical parameters on PK parameters. Individualized preventive treatment was developed, and patients were followed up for 1 year. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and annual FVIII dosage were observed and compared before and after treatment. Results: Weight, blood types, and bleeding types could affect the PK parameters of FVIII. A prophylaxis plan was formulated under the guidance of FVIII half-life. After 1 year of follow-up, the mean ABR dropped from 36.54 to 4.06, decreased by 88.9%, the mean AJBR dropped from 28.36 to 2.75, decreased by 90%, and annual FVIII dosage increased by 47%. The dosage of FVIII in 8 patients after was less than that before prophylaxis, and the average half-life time of these 8 patients was 13.32 h. Conclusions: (1) Weight, blood types, and bleeding types of adult SHA patients could affect FVIII half-life. As body mass index increased, FVIII half-life was significantly prolonged. The FVIII half-life of patients with type O blood was significantly shorter than those with other blood types, and the FVIII half-life of knee joint bleeding was conspicuously shorter than those of elbow joint bleeding. (2) Individualized preventive treatment could markedly reduce the number of bleeds. For patients with a long half-life period, the total annual FVIII dosage could be reduced to achieve bleeding prevention.

Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B without Inhibitors (ATLAS-A/B)

Fitusiran, an Investigational siRNA Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: First Results from a Phase 3 Study to Evaluate Efficacy and Safety in People with Hemophilia a or B without Inhibitors (ATLAS-A/B)

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.

Platelet-rich plasma vs platelet-rich plasma plus hyaluronic acid for haemophilic knee arthropathy treatment.

Repeated joint bleeding leads to chronic synovitis, cartilage damage and bone alterations which result in haemophilic arthropathy and are associated with pain, functional impairment and poor quality of life. There are evidence that Hyaluronic Acid (HA) and Platelet-rich Plasma (PRP) have different mechanisms of action in the treatment of arthropathy for this reason we decided to use both components. The aim of this study is to compare, the efficacy, safety and duration of a single intra-articular injection of PRP against PRP+HA for pain, bleeding episodes and joint health, in the same patient with bilateral hemophilic knee arthropathy. Twenty-one men patients (42 knee joints) were treated with intra- articular injections of PRP or PRP+HA. All of them were haemophilia type A severe. The mean age was 36.6 years (21-72). All patients were evaluated for: Haemophilia Joint Health Score (HJHS), pain (VAS), the number of bleeding episodes (BE) in the last 30 days, before treatment, at three and six months after treatment. Statistically significant improvement were shown for both knee joints at three and six months after treatment for VAS and BE (P < 0.00001). The HJHS score did not significantly improve for either knee in the 6-month period after injection. A single PRP or PRP+HA injection is safe and effective in treating haemophilic arthropathy of the knee for up to 6 months follow-up, reducing pain, bleeding episodes and delaying total knee arthroplasty.

Detecting low blood concentrations in joints using T1 and T2 mapping at 1.5, 3, and 7 T: an in vitro study

BackgroundIntra-articular blood causes irreversible joint damage, whilst clinical differentiation between haemorrhagic joint effusion and other effusions can be challenging. An accurate non-invasive method for the detection of joint bleeds is lacking. The aims of this phantom study were to investigate whether magnetic resonance imaging (MRI) T1 and T2 mapping allows for differentiation between simple and haemorrhagic joint effusion and to determine the lowest blood concentration that can be detected.MethodsSolutions of synovial fluid with blood concentrations ranging from 0 to 100% were scanned at 1.5, 3, and 7 T. T1 maps were generated with an inversion recovery technique and T2 maps from multi spin-echo sequences. In both cases, the scan acquisition times were below 5 min. Regions of interest were manually drawn by two observers in the obtained T1 and T2 maps for each sample. The lowest detectable blood concentration was determined for all field strengths.ResultsAt all field strengths, T1 and T2 relaxation times decreased with higher blood concentrations. The lowest detectable blood concentrations using T1 mapping were 10% at 1.5 T, 25% at 3 T, and 50% at 7 T. For T2 mapping, the detection limits were 50%, 5%, and 25%, respectively.ConclusionsT1 and T2 mapping can detect different blood concentrations in synovial fluid in vitro at clinical field strengths. Especially, T2 measurements at 3 T showed to be highly sensitive. Short acquisition times would make these methods suitable for clinical use and therefore might be promising tools for accurate discrimination between simple and haemorrhagic joint effusion in vivo.

Sports and Children with Hemophilia: Current Trends.

Hemophilia is a sex-linked recessive disorder characterized by a lack of blood factors necessary for clotting. This review aims to investigate the benefits of sports activities in children with hemophilia in terms of both physical and psychological wellness. Sports activity is necessary for children with hemophilia to preserve joints’ range of motion, reduce joint bleeding, improve muscle mass and strength, enhance proprioception and prevent secondary chronic diseases. In the past, high-impact sports were usually forbidden in children with hemophilia because of their high bleeding risk. Recent studies, however, have shown that prophylaxis therapy can allow a hemophilic child to take part in vigorous activities or high-impact sports. The benefits of sports activity in children with hemophilia are expressed by a better muscular trophism and an improved bone mineral density. Moreover, physical activity has a positive impact on children’s psychosocial well-being. Due to prophylaxis therapy, the quality of life of children with hemophilia is similar to their peers, and this has allowed an improvement in sports participation, including team sports.

Efficacy, safety, and immunogenicity of rurioctocog alfa pegol for prophylactic treatment in previously treated patients with severe hemophilia A: a systematic review and meta-analysis of clinical trials

Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A. Methods: This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales. Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety. Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.

Early Findings on the Use of Motion Capture during Simulated Sports Activities to Better Understand Hemophilic Arthropathy

Many persons with hemophilia (PwH) have joint bleeding despite prophylaxis. We hypothesize that movement biomechanics play a significant and largely unexplored role in joint bleeding, which could be exploited to develop personalized rehabilitation programs. We have designed a clinical study to test this hypothesis. Here we show data from the first 3 enrollees as case studies of what could potentially be learned.Data were collected from 3 participants with hemophilia A, ages 10-30 years, on prophylaxis with emicizumab, with at least 1 joint bleed in the lower extremity in the past year, using motion capture techniques with force plates and reflective markers collected through a Vicon system. Motion lab activities were designed to simulate sports activities and included walking (barefoot and shod), squatting (double and single leg), hopping on one foot, and jumping from a 30-cm box. Two patients (B and C) routinely take additional factor VIII prophylaxis prior to physical activity and did so before coming to the motion lab. Hemophilia Joint Health Score (HJHS) was obtained by an experienced physical therapist prior to motion lab collection to gauge degree of hemophilic arthropathy by physical exam. A subset of participants and activities are shown graphically.Participant A (not shown) had a higher HJHS in the right knee than left (3 vs 0) and had HJHS of 4 in bilateral ankles, with most recent bleed in the right ankle 8 months prior; primary physical activity was walking. This participant showed subtle differences between the right and left in all activities, including less weight on the right leg during double leg squat, and right single leg hop lower than the left.Participant B had a higher HJHS in the right knee than the left (3 vs 0) and in the right ankle than the left (7 vs 6), and he had had multiple episodes of knee pain but no change in HJHS since 2 years prior. Knee MRIs performed outside of the study were consistent with tendinosis of bilateral quadriceps rather than bleeding. Primary sports were basketball, hiking, biking, and skiing. Participant B had subtle differences between the right and left side that seemed to protect the right, including mildly decreased right knee flexion with weight acceptance during walking (more pronounced when wearing shoes), lower power generation by the right ankle than the left in walking, and lower peak ground reaction force (GRF) on the right than left in forward hopping. Some motions seemed to protect the left side more, with less power generation and absorption by the ankle (double and single leg squats) and hip (single leg squat only), right single leg squat somewhat deeper than the left, and slower time to step onto the left foot than the right.Participant C had a higher HJHS in the right knee than left (2 vs 1) and in the right ankle than left (5 vs 3) but had had worsening HJHS in bilateral ankles compared to his previous scores, with bleeds in both knees in the past year. Primary physical activities were baseball (pitching), basketball, biking, skiing, and golf. He had recently been diagnosed with Osgood Schlatter (patellar tendon/tibial tuberosity inflammation) of the left knee, which had been causing pain for several months, but no bleeding in that knee. Movement analysis reflected left knee pain, including very little flexion with weight acceptance when walking; very little power absorption or generation from the knee in walking, hopping, and squatting; shallower squats and lower hops on the left; and lower ground reaction force on the left than the right with walking. Perhaps related to the left knee protection, both ankles were consistently more plantarflexed in walking, and there was increased power generation in the right ankle compared to the left.These findings suggest the presence of subtle asymmetry related to hemophilic arthropathy and previous bleeding, which were more pronounced in more strenuous activities than with walking. The results of participant C could suggest that pain, even if unrelated to hemophilia, could cause compensatory movement mechanisms that could lead to increased bleeding risk in other lower extremity joints.Ongoing analysis will include tracking of bleeding over 1 year following motion analysis, enrollment of additional participants, comparison with controls, and performing detailed statistical analysis to determine which movement parameters correlate best with HJHS and lower extremity bleeding risk. [Display omitted] DisclosuresWarren: Novo Nordisk: Consultancy; Hema Biologics: Consultancy; Bayer: Research Funding; CSL Behring: Research Funding; Genentech: Research Funding. Funk: Biomarin: Consultancy; Sanofi Genzyme: Speakers Bureau; Toronto Sick Kids Hospital: Patents & Royalties: Hemophilia Joint Health Score Royalties; Partners: Honoraria.

Association of Hemophilia a Inhibitor Status and Patient-Reported Outcomes with Work Productivity and Health-Related Quality of Life

Introduction: Persons with hemophilia suffer from recurrent bleeds, especially hemarthrosis, which results in joint damage. Hemophilia inhibitor status impacts bleeding, which is associated with acute and chronic pain. To better characterize the impact of inhibitor status, we compared patient-reported outcomes (bleed rate, pain, and joint health), work productivity and activity impairment (WPAI), and health-related quality of life (HRQoL) by inhibitor status, and investigated the correlation of patient-reported outcomes with WPAI and HRQoL.Methods: The U.S. Hematology Utilization Group Studies Part VIII prospectively collected data to examine the cost and burden of hemophilia in persons with hemophilia A (PwHA) aged ≥2 years obtaining care at four federally-supported hemophilia treatment centers. From April 2019 to May 2021 we enrolled PwHA with and without inhibitors at a 1:2 ratio. Parents/adult participants completed a survey at enrollment to collect sociodemographic and clinical characteristics, self-reported bleeds in the last month, pain, and joint stiffness (5-item scale). We also measured WPAI and HRQoL using EQ-5D-3L. Clinical chart review documented hemophilic severity, inhibitor level and treatment regimen. Participants were classified into three groups: 1) active inhibitor (inhibitor titer ≥1.0 Bethesda Units (BU) six months prior to enrollment), 2) tolerized inhibitor (history of inhibitor titer ≥1.0 BU, immune tolerance induction (ITI) and/or currently using factor VIII for prophylaxis), and 3) no inhibitor. Patient-reported data were compared across these groups using Chi-square tests for categorical variables and generalized linear models for continuous variables. Association of bleeds, pain, and joint stiffness with HRQoL and WPAI were assessed using Pearson correlation.Results: Among 80 PwHA enrolled, 9 (11%) had active inhibitors, 22 (27.5%) had tolerized inhibitors, and 49 (61.3%) had no inhibitors. Mean age was 24.9±14.3 (standard deviation) years, 66.3% were adults, 87.5% had severe hemophilia, and 87.5% used prophylaxis. Mean age of the non-inhibitor group (29.3±13.5) was older than the tolerized inhibitor group (16.3±9.5 years, p<0.05) or the active inhibitor group (21.9±19.1, p>0.05). The non-inhibitor group had a lower rate of severe hemophilia (81.6%) or prophylactic treatment (81.6%) than those in the active (100%) or tolerized groups (95.5%, p=0.13). Larger proportions of participants with active inhibitors (66.7%) and no inhibitors (57.1%) reported having bleeds in the last month compared to those with tolerized inhibitors (22.7%, p=0.01). Participants without inhibitors had a greater mean number of bleeding episodes (1.09±standard error (SE) 0.26 vs. 0.23±0.38, p=0.03), specifically joint bleeds (0.58±0.16 vs. 0.08±0.24, p=0.03,) than the tolerized group. Those with active inhibitors reported significantly higher mean joint stiffness scores (35.1±2.6 vs. 27.5±1.9, p=0.006) or more joint pain (77.8% vs. 54.5%, p=0.23) than the tolerized group. Mean EQ-5D index score was significantly lower in the active inhibitor group (0.79±SE (0.07) than in the tolerized group (0.96±0.05, p=0.03). Joint bleeding, chronic pain, and joint stiffness were negatively correlated with the EQ-5D visual analogue scale, and index scores (all correlation coefficients |r|>0.43, all p<0.001). Number of bleeds and the joint stiffness score in children were positively correlated with their parents' level of impairment while working (r=0.41, p=0.04; r=0.62, p=0.001) and overall work impairment (r=0.41, p=0.046; r=0.60, p=0.002). Joint bleeding, chronic pain, and joint stiffness in adults were positively correlated with proportion of work time missed (r=0.31, p=0.03; r=0.39, p=0.006; r=0.48, p=0.0004), overall work impairment (r=0.37, p=0.007; r=0.41, p=0.003; r=0.42, p=0.002), and activity impairment (r=0.33, p=0.02; r=0.63, p<0.0001; r=0.59, p<0.0001), respectively.Conclusions: This study is limited to a small sample skewed toward a younger age in the tolerized inhibitor group. PwHA in the active and no inhibitor groups experienced greater clinical burden as measured by bleeds compared to the tolerized group. Those with active inhibitor displayed lower HRQoL scores than the tolerized inhibitor group. Bleeds, chronic pain and joint stiffness were inversely correlated with HRQoL, resulting in lower work productivity and activity. [Display omitted] DisclosuresRoberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Khairnar: University of Maryland, Baltimore: Ended employment in the past 24 months; Roche: Current equity holder in publicly-traded company; Genentech Inc - A Member of The Roche Group: Current Employment. Decker-Palmer: Genentech Inc. –A member of the Roche Group.: Current Employment, Current equity holder in publicly-traded company. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Real-World Experience with Emicizumab Prophylaxis in the Milan Cohort: A Single-Center Experience

▪ INTRODUCTIONEmicizumab is a humanised bispecific monoclonal antibody, which replaces the function of factor VIII (FVIII) by bridging activated factor IX and factor X. Emicizumab is approved for prophylaxis of patients with Hemophilia A (HA), both with and without inhibitors. Real-world data on the efficacy and safety of emicizumab were recently reported from a few hemophilia treatment centers, but more data are needed to assess the efficacy and safety of emicizumab in comparison to standard prophylactic treatment. OBJECTIVETo evaluate the safety and efficacy of emicizumab prophylaxis in a single cohort of patients with HA, with and without inhibitors. METHODSWe performed an observational prospective study including patients affected with HA, with and without inhibitors, switched to emicizumab prophylaxis in the post-marketing era. Data regarding inhibitor status, Annualized Bleeding Rate (ABR), cause of bleeding, type and location of bleeds, Emicizumab Plasmatic Concentration [Emi] and activated partial thromboplastin time (aPTT) were collected for each patient. Hemophilia Joint Health Scores (HJHS) and General Health Visual Analogue Scale (GH-VAS) were collected by trained physiotherapists before switching to emicizumab and 12 months after treatment start. RESULTSA total of 22 patients, 21 with severe and 1 with moderate HA, were enrolled. Twenty patients were without inhibitor against FVIII and 2 adults with inhibitor were previously treated with bypassing agents. All patients started emicizumab prophylaxis with a loading dose of 3 mg/kg once weekly for 4 weeks, followed by a maintenance dosage of 1.5 mg/kg weekly. Within the children cohort, 3 were Previously Untreated Patients (PUPs) and 2 were previously treated with FVIII without developing inhibitor. The ABR showed a reduction of 74% in the entire cohort, as reported in Table 1. When stratifying for age groups, the ABR reduction was 70% for adults and 100% for children. Within the adults, the zero-bleeding patients increased from 2 to 11 patients (from 12 to 64%, respectively). In the adult cohort, 6 patients experienced 11 bleeding events over a mean follow-up of 300 days. Five out of 11 events were experienced in 6 months by a single patient who developed anti-drug antibodies (ADA) against emicizumab around the 5 th week ([Emi] 31.7 ug/ml). The prophylaxis with emicizumab was interrupted due to the treatment failure, which occurred despite spontaneous ADA clearance. Another patient developed ADA around the 9 th week ([Emi] 28.3 ug/ml), but without associated bleedings in up to 14 weeks of follow-up (minimum [Emi] 17 ug/ml). Of the remaining 5 adults who experienced bleedings during emicizumab prophylaxis, one patient developed spontaneous soft tissue bleeding, another one developed a spontaneous hemarthrosis in his target joint and the remaining 3 patients experienced post-traumatic joint bleedings, 2 out of 3 bleedings were in target joints. The analysis of the number of total joint bleedings before and after switching stratified for spontaneous and post-traumatic, revealed a reduction in target joint bleedings of 73% and a reduction of spontaneous and post-traumatic bleeding of 80% and 43%, respectively. All events were managed in outpatient clinic and required only a single infusion of FVIII concentrate. The plasmatic concentrations of emicizumab at steady state were within previous reported normal range for all patients, with exception of the two patients who developed ADA. Interestingly, steady state concentration was higher in children than in adults (median [Emi] 64.9 ug/ml and 49.85, respectively). The HJHS and GH-VAS scores at baseline and after 12 months of emicizumab prophylaxis available in 6 adults showed improvement in joint health and self-perceived global health, as shown in Figures 2 and 3. No thrombotic events were reported in the entire cohort. DISCUSSIONWe report our Milan single center experience on the use of emicizumab prophylaxis in children and adults with HA, with and without inhibitors. Our experience shows a good efficacy of emicizumab both in children and adults, with few post-traumatic bleedings occurring mainly in target joints of adult patients. In addition, physician's and self-assessed scores revealed an improvement of patient's joint health after 12 months of emicizumab prophylaxis. [Display omitted] DisclosuresPeyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

MRI-Derived Radiomics of Hemophilic Arthropathy Is Associated with Severity of Joint Disease

IntroductionJoint bleeding resulting in synovial hypertrophy and articular cartilage damage are the hallmarks of hemophilic arthropathy. Early prophylaxis with extended half-life factor products and non-factor replacement therapies reduce joint bleeds but do not provide complete protection from development of arthropathy. MRI is the gold standard imaging technique to diagnose and monitor arthropathy in hemophilia. MRI changes that are associated with joint bleeding and development of arthropathy, however, are not sensitive enough to detect early changes in the synovial membranes after sub-clinical bleeding. Radiomics, the computerized extraction of sub-visual attributes from imaging scans can detect early changes of hemophilic arthropathy and help in more accurate characterizations of severe joint disease. The goal of this project was to develop and compare MRI radiomics with the International Prophylaxis Study Group (IPSG) score, an established MRI joint disease scale, in assessing the severity of joint disease.MethodsAfter IRB approval, knee MRI scans of 17 hemophilia patients with a history of joint bleeding and 12 age-matched healthy controls were included in this study. Manual annotations were performed in consensus by a board-certified musculoskeletal radiologist to include the prefemoral fat, suprapatellar fat pad and bursa . To ensure that the signal intensities from different cases were in tissue-specific correspondence, a landmark-based histogram transformation was used to align MRI signal intensity distributions across all cases. 560 radiomic features capturing MRI pixels texture heterogeneity (Gabor wavelets, Laws texture, Haralick and GoLIAGe co-occurrence patterns) were subsequently extracted on all MRI slices with ROI for all the cases. Top 2 radiomic features (F 2) for differentiating between abnormal joint changes and control were selected by Minimum Redundancy Maximum Relevance (mRMR) algorithm with 100 iterations of 3-fold cross-validation. Consensus hierarchical clustering was then applied on F 2, from which two patient clusters were generated. A disease severity score was calculated based on historical lifetime bleed events in the joint, designation of target joint status, and history of surgical synovectomy. A previously described 17-point MRI IPSG score was also calculated by 2 independent reviewers. Both the IPSG score and the F 2 were then fit into a linear regression model separately as predictors whereas the disease severity score was set to be the response variable. The Akaike's Information Criteria (AIC) and the root mean square error (RMSE) were used to evaluate the model fitness and the likelihood ratio (LR) test was applied for model comparison.ResultsThe dataset consisted of 17 males with moderate and severe hemophilia ranging in age from 10-55 years. The median disease severity score was 2 (0-11) and the median IPSG MRI Score was 2 (0-11). The top 2 radiomic features F 2, a Gabor wavelet feature and a Lawshc texture feature, yielded an AUC of 0.94 and an accuracy of 0.9 for differentiating between hemophilic joint changes and healthy control patients. Unsupervised clustering demonstrated good separation between the two classes (Fig panel A and B). The radiomic-based linear regression model (AIC: 86.67; RMSE: 2.86) was significantly better than the IPSG score-based model (AIC: 94.24; RMSE: 3.66) in joint disease severity characterizations (LR, p = 0.0083, Fig panel C).ConclusionsRadiomic analysis of knee MRI in hemophilia patients with history of joint bleeding is correlated with the severity of joint disease. Our study demonstrates the feasibility of developing and utilizing a radiomics based tool to detect the severity of joint damage in a small population of knee joint hemophilic arthropathy. We plan to perform an Independent validation of the radiomics signature in a larger dataset of hemophilia joint MRI scans [Display omitted] DisclosuresMadabhushi: Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers-Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Caris: Consultancy; Aiforia: Consultancy; Philips: Research Funding; AstraZeneca: Research Funding; Boehringer-Ingelheim: Research Funding; Bristol Meyers-Squibb: Research Funding. Ahuja: Sanofi: Membership on an entity's Board of Directors or advisory committees; XaTek, Inc: Patents & Royalties; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member .

Emicizumab Outcomes in Hemophilia A Using Real-World Data from the Canadian Hemophilia Bleeding Disorder Registry

Background: The Canadian Hemophilia Bleeding Disorders Registry (CBDR) is a clinical database including data from all Canadian Hemophilia Treatment Centers (HTCs) to assist in the management of hemophilia and other bleeding disorders. The CBDR launched on July 1, 2015 and integrates the data entry platform for patients, myCBDR, allowing direct entry of treatments, bleeding events, and other patient reported outcomes (PRO) data. Health Canada approved emicizumab in August 2018 for the treatment of persons with hemophilia A (PwHA) with factor (F)VIII inhibitors, and for PwHA without FVIII inhibitors in 2019, enabling some patients without FVIII inhibitors to be provided compassionate access beginning November 2019.Our aim for this analysis was to use the CBDR data to describe the demographics of the emicizumab-treated PwHA population and assess its effectiveness, safety, treatment patterns, and the impact on disease burden.Methods: De-identified data were extracted from the CBDR database for all registered PwHA who had received emicizumab at least once up to December 31, 2020. Disease severity is defined by the level of endogenous clotting FVIII activity. Effectiveness outcomes include number of patients (%) with zero treated bleeds, joint bleeds, and spontaneous bleeds; annualized bleeding rates (ABR) for any bleeds and treated bleeds; Hemophilia Joint Health Score (HJHS); Patient Reported Outcomes Burdens and Experiences (PROBE); and EQ-5D-5L index and visual analog scale (VAS). ABRs were calculated as (total number of bleeds/duration of follow-up [days])*365.25. All analyses were performed based on the observed values, 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: 73 PwHA who received emicizumab at least once up to December 31, 2020 were identified. Demographic characteristics, severity, inhibitor status, and treatments are described in Table 1. Median (IQR) age for the entire cohort was 19.7 (10.0, 40.6) years with 45.2% ≤18 years. There were 64 PwHA with severe disease, 7 with moderate disease and 2 with mild disease; both cases with mild disease had current FVIII inhibitors. 49 PwHA had current FVIII inhibitors, 12 had a history of FVIII inhibitors, and 12 had no FVIII inhibitors. 5/73 (6.8%) received immune tolerance induction (ITI) treatment while on emicizumab. Two cases of rash (allergic or acute reactions) were reported (2/73, 2.7%) of which one (reported 6 days after administration) was possibly related to emicizumab according to the reporting HTC. No thromboembolisms or thrombotic microangiopathies were observed.Median ABR (IQR) for the entire study population was 0.0 (0, 0) and 59/73 (80.8%) had no recorded bleeds. In the 14/73 (19.2%) with recorded bleeds, median ABR (IQR) was 2 (1, 3); 8 of those 14 had joint bleeds and 7 had spontaneous bleeds. HJHS was recorded for 23, PROBE Score for 9, EQ-5D-5L for 9 and EQ-5D-5L VAS for 4 PwHA (Table 2).Conclusions: The Canadian population treated with emicizumab had severe disease and current or historical FVIII inhibitors. The bleed outcomes are consistent with earlier publications, showing 80.8% had no recorded bleeds. The CBDR will allow for longitudinal follow-up of this patient population. Our results can inform healthcare practitioners and regulatory authorities on the real-world safety and effectiveness outcomes of emicizumab in PwHA with and without FVIII inhibitors. [Display omitted] DisclosuresPoon: Roche: Honoraria; Pfizer: Honoraria; Novo Nordisk: Honoraria; Bioverativ/Sanofi: Honoraria; CSL-Behring: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; University of Calgary: Current Employment; Takeda: Honoraria. Lee: Roche: Honoraria; Pfizer: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; CSL Behring: Honoraria; Biovertiv/Sanofi: Honoraria, Research Funding; Bayer: Research Funding, Speakers Bureau; Takeda: Honoraria. Keepanasseril: McMaster University: Current Employment; NovoNordisk Canada: Consultancy. Ibrahim: McMaster University: Current Employment. Nissen: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of stock options in a privately-held company; Novartis: Consultancy; Actelion: Consultancy. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Santos: F. Hoffmann-La Roche Ltd.: Current Employment; Roche: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Baxter: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Takeda: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Iorio: McMaster University: Current Employment; Bayer (funding to the institution): Research Funding; BioMarin (funding to the institution): Research Funding; NovoNordisk (funding to the institution): Research Funding; Octapharma (funding to the institution): Research Funding; Pfizer (funding to the institution): Research Funding; Roche (funding to the institution): Research Funding; Sanofi (funding to the institution): Research Funding; Sobi (funding to the institution): Research Funding; Takeda (funding to the institution): Research Funding.

Emicizumab Prophylaxis in Persons with Mild or Moderate Hemophilia A: Results from the Interim Analysis of the HAVEN 6 Study

Emicizumab Prophylaxis in Persons with Mild or Moderate Hemophilia A: Results from the Interim Analysis of the HAVEN 6 Study

Prophylaxis with rFIXFc Reduces the Frequency and Delays Time to First Spontaneous Bleed Event in Previously Untreated Patients with Hemophilia B: A Post Hoc Analysis of the PUPs B-LONG Trial

Prophylaxis with rFIXFc Reduces the Frequency and Delays Time to First Spontaneous Bleed Event in Previously Untreated Patients with Hemophilia B: A Post Hoc Analysis of the PUPs B-LONG Trial

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Comparing Exercise-Induced Musculoskeletal Bleeding in Murine Models of Hemophilia A and B

Background: Hemophilia A and B are recessive X-linked bleeding disorders characterized by the deficiency in coagulation factor VIII and factor IX. Patients with the severe form of the disease can experience bleeding into the joints and muscle either spontaneously or after provoking events including sporting injuries of different degree. Patients are prone to bleeding in the musculoskeletal system. While most research is focused on hemarthrosis, muscle hematomas are not well studied although being the second most common complication of hemophilia, accounting for 10-25% of diagnosed bleeding episodes. There is limited consensus regarding optimal diagnosis and treatment of muscle hematomas in patients with hemophilia. We are investigating the effect of physical activity on muscle and joint bleeds in mouse models of hemophilia.Aim: The objective of this study was to compare the severity of exercise-induced skeletal bleedings in two mouse models of hemophilia A and B.Methods: Hemophiliac F8-KO and F9-KO mice, aged from 8-12 weeks old, were subjected to either mild or moderate daily treadmill exercise for 5 days. The speed was set at 10 meters per minute for the mild intensity group and 15 meters per minute for the moderate intensity group; and the animals were exercised for 30 minutes daily. Mechanical stimulus with a brush was used to encourage the animals to run. Animals were monitored daily and on day 6 (24 hours after the treadmill exercise) the animals were sacrificed to assess bleeding events. The mice skin was carefully removed and the body was macroscopically evaluated for presence of bleeds. If muscle bleedings were present, they were assigned a score in accordance with a previously published protocol (Tranholm M et al., JTH 2015 Jan;13(1):82-91) with minor modifications.Results: The animals were closely monitored during the study periods, and all completed the study. Normal behaviour and appearances were observed. No external bleeding was recorded. No muscle hematoma was observed in the wild-type C57-strain, thus the group received the bleeding score of 0. For the mild exercise group, the mean muscle bleeding score of F8-KO strain was 5.50 (standard error = 2.81), while the mean muscle bleeding score of F9-KO strain was 1 (standard error: 2). The two-tailed P value between the hemophilia A and B group was significant (p<0.01). For the moderate exercise group, the mean muscle bleeding score of F8-KO strain was 4.667 (standard error = 3.51), while the mean muscle bleeding score of F9-KO strain was 2.8 (standard error = 2.86). The two-tailed P value between the hemophilia A and B group was 0.33.Discussions: The preliminary analysis of our data showed that musculoskeletal bleeding induced by exercise appears to be more severe in hemophilia A mice than hemophilia B. This is in accordance with previous observations that hemophilia B may be clinically milder than hemophilia A. In our study, there appears to be a more significant difference between the hemophilia A and B mice when the mice were subject to milder form of exercise. No statistical significance was found between the two groups when moderate exercise was given. Overall, this exercise model can be a useful tool to study the pathophysiology of musculoskeletal bleeding as well as to evaluate new therapeutic strategies in the prevention and management of muscle hematomas in hemophilia. [Display omitted] DisclosuresGross: Leo Pharma: Honoraria; Bayer: Honoraria; BMS-Pfizer: Honoraria; Valeo: Honoraria. Matino: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Spark: Other: research grants; Octopharma: Membership on an entity's Board of Directors or advisory committees, Other: research grants and personal fees; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: personal fees.