Hemophilia Research Articles

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.

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.

Stromal Cell-Derived Factor 1 Alpha (SDF-1α), Cartilage Oligomeric Matrix Protein (COMP) and Circulating microRNAs 208a-3p and 221-3p: Potential Signature Biomarkers of Hemophilic Arthropathy

Introduction. Hemophilia A is a rare constitutional bleeding disorder due to a deficiency in Factor VIII. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition difficult to diagnose with current strategies (ultrasound and magnetic resonance imaging [MRI]), with possible delayed diagnosis. MRI, the gold standard, is not of easy access nor cheap and requires sedation in young children. Ultrasound is liable to inter-operator variability and difficult to apply to such joints as ankles, especially in children for whom this is the most frequently involved location of hemophilic arthropathy. Circulating MicroRNAs are a group of endogenous, small, non-coding RNA molecules that regulate gene expression ; and knowledge on the potential roles of miRNAs in haemophilia is very limited. Aim. The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. We also investigated microRNA expression in patients with haemophilia A with and without inhibitors, compared to healthy controls. Methods In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson radiologic score. For miRNAs analysis, all RNAs were extracted from plasma samples. We synthesised complementary DNA from the RNA samples, and used to quantitative PCR and microarray analysis to allow us to look at changes in expression levels. Results Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. We also identified two microRNAs of interest, the microRNA 208a-3p was significantly downregulated in hemophilia patients with arthropathy but not in patients without arthropathy and the microRNA 221-3p had a clear tendency for statistically significant down regulation in hemophiliacs with arthropathy. Interestingly, miRNA 221-3p has been shown to be involved in rheumatoid arthritis. Dysregulation of this microRNA leads to a reduced anti-inflammatory response and drives macrophages into a pro-inflammatory state. Conclusion Two plasma proteins SDF-1 alfa and COMP and two circulating micro-RNAs have been identified as potential biomarkers that could help physicians to assess the presence and severity of hemophilic arthropathy.

Physical Activity, Bleedings and Quality of Life in Patients with Haemophilia a without Inhibitors - a Multicenter, Observational Italian Study with a Wearable Device

Introduction: Haemophilia A (HA) is characterized by spontaneous or traumatic recurrent bleedings, especially in joints and muscles, which can cause haemophilic arthropathy, impaired function, and in turn, reduce physical and social activities and negatively impact the quality of life (Franchini M at al., Semin Thromb Hemost, 2022 Nov; Mannucci PM et al., N Engl J Med, 2001 Jun). Despite regular physical activity (PA) being strongly recommended by guidelines as a key element to improve well-being and mental health, the perception of an associated increased risk of bleeding and bleed-related issues discourage people with hemophilia A (PWHA) (Makris M at al, Haemophilia, 2013 Jan; Matlary RED at al., Haemophilia, 2022 Nov; Srivastava A et al., Haemophilia, 2020 Aug 1) Methods: This cohort study (NCT04165135 - POWER) is a multicenter study conducted in 18 investigational Italian sites aimed at gathering data on activity status, bleeding, QoL, and health status, through the use of a wearable device and an ePRO app, in individuals with moderate or severe HA without inhibitors receiving standard of care (SoC) treatment. This population was observed for 12 months or up to 18 months if the therapy with a newly approved product was initiated during the study. The study started in January 2020 and has been completed in April 2022 with the last data collection. Results: A total of 103 male patients represented the Intention To Treat Population (ITT). Of them, 97 (94.2%) had severe (FVIII <1%) and 6 (5.8%) moderate (FVIII 1-2%) HA without inhibitors. They were aged 12-50 years (17, 16.5% aged 12-17 years [adolescents]; 46, 44.7% aged 18-30 years [young], and 40, 38.8% aged 31-50 years [adults]); 21 subjects switched to a newly approved agent for HA during the study and were followed for additional six months after the switch. Eighty-eight (85%) completed the study. The primary outcome measures included the duration and type of PA, distance covered, calories burned, body weight, heart rate, sleep data, active minutes, metabolic equivalents for tasks (METs), and step counts. The secondary measurements included the documentation of PA by type and intensity, the description of the population in terms of adherence to WHO Guidelines, disease severity, and treatment regimen for HA, health status, joint health status, and BMI. PA data were collected continuously through a fitness tracker worn by the patient. HRQoL questionnaires, joint health assessments, intensity of pain and bleeding episodes were recorded by the patient through an ePRO app (Petracca F. at al., JMIR Form Res 2021) Only 54/103 subjects (52.4%), which represented the Evaluable Population (EVL), were using the fitness tracker for at least 10 hours in 50% of their days for a period of at least 6 months in the study; adolescents were the least compliant age group. The fitness tracker's analysis of the type of activity collected showed low weekly rates for all activities (no differences in the different physical activities). High-intensity physical activities were poorly represented in all the subgroups. Approximately 51% of the subjects (including all adolescents) had sedentary behavior (Figure1). The mean METs per day were lower in adults. The EQ-5D utility score did not change during the observational period. The mean EQ-5D VAS progressively worsened, indicating a situation of discomfort and pain during the study. The results of HRQoL showed that a sedentary condition was associated with a worse quality of life, a higher risk of hospitalization, and a worse joint status compared to active patients. At least one bleeding (mean 2.9; median 2.0) was reported in 43.7% of the subjects (Figure 2), with a higher proportion in sedentary than active subjects. The physical activity in the 2 days preceding the bleeding was comparable to the one observed in the overall observational period. Adherence to the treatment regimen was quite poor overall (mean 55%) and only 26.2% of the subjects had an adherence ≥ 80%. Conclusion: The results from this study show that patients with HA without inhibitors have a lower-than-expected physical activity. Despite the poor PA, around half of the subjects reported bleeds, especially in the sedentary population. This suggests that other causes than PA, such as treatment adherence and type of treatment, might affect the number, frequency, and severity of bleedings. This study has been sponsored and financially supported by Roche Italy.

Post-Immune Tolerance Induction Prophylactic FVIII Infusions May Not be Necessary for Tolerized Hemophilia a Patients on Emicizumab

Background: Hemophilia A is a hereditary bleeding disorder characterized by low factor VIII (FVIII) activity. Patients with severe bleeding phenotypes are at risk for significant bleeding-related morbidity and mortality including the development of hemophilic arthropathy. In recent years, prophylaxis with emicizumab, a bispecific monoclonal antibody, has supplanted prophylactic FVIII infusions due to its ease of self-administration, long half-life, and low annual bleeding rate (ABR), independent of tolerization status to alloantibodies against FVIII (inhibitors). However, it is unclear if emicizumab FVIII-mimic activity is sufficient to achieve hemostasis in moderate-severe bleeds, and therefore, FVIII replacement may still be necessary. Despite its well-established benefits, the use of emicizumab in previously untreated patients (PUPs), and patients with under 20 exposures to FVIII is still not well understood due to a lack of long-term experience and understanding of its impact on the pathophysiology of FVIII inhibitors. Further investigation is also needed regarding the risk of inhibitor recurrence in patients with previous inhibitors and the concomitant use of emicizumab. At our institution, patients on emicizumab with a history of inhibitors do not continue post-immune tolerance induction prophylactic FVIII infusions. We also initiate emicizumab before 20 exposures to FVIII, and sometimes before immune tolerance induction (ITI). We explored our patient population to understand inhibitor incidence and recurrence amidst emicizumab prophylaxis. Methods: We performed a single center retrospective analysis of patients served by the Hemophilia Center of Western Pennsylvania. We identified patients with Hemophilia A on emicizumab prophylaxis. Relevant data was collected including demographics, inhibitor status at time of transition to emicizumab and in the available follow-up period, bleeding events after transition, and number of FVIII exposures before and after transition. Inhibitor recurrence was defined as laboratory evidence of inhibitor using chromogenic Bethesda assay and/or unexplained breakthrough bleeding events despite on-demand FVIII infusions. Results: Data was reviewed for 36 patients on emicizumab prophylaxis. Three patients were lost to follow-up. Median age was 15.3 years (range 1.2 - 82). Median follow-up time on emicizumab was 3.5 years (range 0.5 - 5). Two patients had < 20 FVIII exposures prior to emicizumab, and one of those had an inhibitor before emicizumab. In total, 15 patients (45%) were diagnosed with an inhibitor prior to emicizumab. Of these, 8 patients (53%) were tolerized prior to emicizumab, and 7 patients (47%) were not tolerized prior to emicizumab. Median peak inhibitor titer was 4.2 Bethesda units (range 0.7 - 281 Bethesda units). After transition to emicizumab, no tolerized patients for which inhibitor status was tested during the follow-up period had inhibitor recurrence, and 1 non-tolerized patient's inhibitor became undetectable after 4 years of emicizumab therapy (the same patient who had developed an inhibitor with < 20 FVIII exposures prior to emicizumab). Mean ABR was 0.33 events/year for tolerized patients (median 0, range 0 - 3); 0.17 events/year for non-tolerized patients (median 0, range 0 - 1); and 0.60 events/year for patients with no history of inhibitor (median 0, range 0 - 4). Mean number of FVIII exposures per year was 0.09 for tolerized patients (median 0, range 0 - 1); 0.07 for non-tolerized patients (median 0, range 0 - 1); and 1.2 for patients with no history of inhibitor (median 0, range 0 - 20). Conclusion: In our small cohort, no patient who was tolerized prior to emicizumab had recurrence of clinical or laboratory evidence of inhibitor while on emicizumab therapy, despite infrequent exposure to FVIII infusion. We did not have enough power to determine whether patients with < 20 FVIII exposures before emicizumab developed inhibitors, though one such patient had inhibitor resolution on emicizumab without ITI. Consistent with other works, overall ABRs in all patients on emicizumab therapy were low. These findings add to other studies on the safety of emicizumab and its impact on the natural history of FVIII inhibitors. Our study also suggests that continuing post-ITI prophylactic FVIII infusions in tolerized patients on emicizumab may not be necessary. Larger-scale studies are required to substantiate our findings.

Physical therapy for end-stage hemophilic arthropathy: a case report

This report introduces a young adult who has been in bed for more than ten years with end-stage hemophilic arthropathy. He didn’t have access to factor VIII (FVIII) in the early stage of hemophilia due to the high costs of clotting replacement therapy. As a result, he is experiencing some difficulties, such as joint contracture, muscular atrophy, severe pain, and poor function of cardiopulmonary. He came to visit us for a comprehensive rehabilitation program, and, finally, he achieved the basic goal of self-care in daily life.

Factor X deficiency: An overlooked cause of bleeding in the newborn

Abstract Inherited factor X (FX) deficiency is a rare autosomal recessive bleeding disorder, presenting with various bleeding manifestations ranging from nonspecific bruising to life-threatening intracranial hemorrhage. It is often misdiagnosed as hemorrhagic disease of the newborn. It is characterized by prolonged prothrombin time, as well as activated partial thromboplastin time, and needs FX level assay for definitive diagnosis. Here, we describe a case of a newborn with FX deficiency who presented with frank umbilical stump bleeding.

Changes in Health-Related Quality of Life, Pain and Functional Parameters in People with Hemophilia and People with Osteoarthritis - a Comparative Follow-up of Physiotherapeutic Training (Physio-FUN Study)

Background: Spontaneous joint bleeding is common in people with hemophilia (PWH). These bleeds lead to reduced physical activity and thus to a weakening of the musculature. Common sequelae of this are synovitis and cartilage damage. In the long term, secondary osteoarthritis, so-called hemophilic arthropathy, occurs with changes and progressive destruction of joint structures (Lafeber et al., 2008). Hemophilic arthropathy is age-independent and can lead to severe movement restrictions and significant limitations in health-related quality of life (HRQoL) of affected PWH (Varaklioti et al., 2018). To prevent advanced stages of arthropathy not only regular assessment of musculoskeletal status and early detection of symptoms, but also daily rehabilitation exercises at home, and implementation of appropriate physiotherapy and medical training are important (Bossard et al., 2008). Home exercises and manual therapy can be used without causing bleeding or pain to improve pain, HRQoL and functionality (Tat et al., 2021). The primary aim of the Physio-FUN study was to assess the subjective (Hemophilia Exercise Project Test-Questionnaire [HEP-Test-Q]) and objective physical functioning (Hemophilia Joint Health Score [HJHS]) during the course of 1-year applied physiotherapy comparing PWH with arthropathy and patients with osteoarthritis (PWO). Methods: In this prospevtive, controlled monocentric cohort study it was planned to enroll 20 adult PWH A or B compared to 20 gender-matched adult PWO without a bleeding disorder. Patients with a blood pressure ≥ 180/110 mmHg were excluded. A positive ethical approval for the study was obtained by the Ethics Committee North Rhine, Germany. After informed consent had been obtained, the study participants underwent examinations based on clinician-reported outcomes (ClinRO) and performance outcomes (PerfO) and completed different patient-reported outcomes (PROs). ClinROs included ultrasound, functional movement screen (FMS) and the collection of anthropometric and clinical data; PerfOs included cardiopulmonary performance, 6-minute walk test (6MWT), blood pressure measurement before and after 6MWT, joint mobility (neutral-zero method) and Functional Movement Screen (FMS) to evaluate movement pattern quality; PROs included the assessment of sociodemographic data, HRQoL (SF-12), Physical Activity Questions (EPIC - Simple Index), pain sensation scale (SES) and Borg Rating of Perceived Exertion (RPE) measuring physical activity intensity level. All patients took part in regular physiotherapy (once a week) at the ARZD as prescribed by a physician. During the study, PWH continued to receive their usual hemophilia treatment regimen without study-related changes. Over a period of 12 months, ClinROs, PerfOs and PROs were collected repeatedly on a quarterly basis. Each patient was supposed to participate in 5 measure points (baseline, every 12 weeks over a one-year period). Ultrasound examinations were performed at baseline and at the conclusion at MZP5 in all patients. Results: At baseline 17 PWH (mean age 43.29±13.1 years) and 12 PWO (mean age 61.42±8.5 years) were enrolled; most PWH had HA (88.2%) were severely affected (58.8%) and 6/17 had a knee endoprosthesis. 88.2% of PWH had a disabled card (most with a disability degree of ≥ 80) compared to 45.5% of PWO (most with a disability degree of 50). PWH had a significant worse orthopaedic joint status ( p<.002) and subjective physical functioning ( p<.001) compared to PWO; PWH had a mean HJHS of 26.76±18.0 vs. 11.0±5.7 and a mean HEP-Test-Q of 48.12±16.4 vs. 67.08±9.1. PWO reported highest impairments in the domain ‘mobility’, while PWH suffered mainly under reduced ‘endurance’. With respect to their age, height and weight most of the PWH were below the predicted lower limit of the 6MWD compared to the PWO who all were above the lower limit of the 6MWD. No difference was found between the groups regarding FMS (11.34±3.8) and RPE before (11.5±3.3) after 6MWT (11.5±3.3). Conclusions: Our study took place during the Corona pandemic and was quite time consuming for the participants, resulting in a failure to reach the desired number of cases and lead to a high drop-out rate over the duration of the project. Although PWH were significantly younger than PWO, they had a significantly worse subjective (HEP-Test-Q) and objective physical functioning (HJHS).

A Comparison of Health-Related Quality of Life, Pain and Functional Parameters between People with Hemophilia and People with Osteoarthritis - Preliminary Results of the Physio-FUN Study

Background: Spontaneous joint bleeding is common in people with hemophilia (PWH) leading to reduced physical activity and weakening of the musculature. Common sequelae of this are synovitis and cartilage damage. Following, secondary osteoarthritis, so-called hemophilic arthropathy, occurs with changes and progressive destruction of joint structures (Lafeber et al., 2008). Hemophilic arthropathy can lead to severe movement restrictions and significant limitations in health-related quality of life (HRQoL) (Varaklioti et al., 2018). To prevent advanced stages of arthropathy not only regular assessment of musculoskeletal status and early detection of symptoms, but also daily rehabilitation exercises at home, and implementation of appropriate physiotherapy and medical training are important (Bossard et al., 2008). Home exercises and manual therapy can be used without causing bleeding or pain to improve pain, HRQoL and functionality (Tat et al., 2021). The primary aim of the Physio-FUN study was to assess subjective (HEP-Test-Q]) and objective physical functioning (HJHS]) during the course of 1-year applied physiotherapy comparing PWH with arthropathy and patients with osteoarthritis (PWO). Methods: In this prospective, controlled monocentric cohort study it was planned to enroll 20 adult PWH A or B compared to 20 matched adult PWO without a bleeding disorder. Patients with a blood pressure ≥ 180/110 mmHg were excluded. A positive ethical approval for the study was obtained by the Ethics Committee North Rhine, Germany. After informed consent had been obtained, the study participants underwent examinations and completed questionnaires for Clinical Outcome Assessments (COAs) (see table 1); clinical, anthropometric and socio-demographic data were collected. All patients took part in regular physiotherapy (once a week) at the ARZD as prescribed by a physician. During the study, PWH continued to receive their usual hemophilia treatment regimen without study-related changes. Over a period of 12 months, Clinical Outcome Assessment (COAs) were collected repeatedly on a quarterly basis. Each patient was supposed to participate in 5 measure points (baseline, every 12 weeks over a one-year period). Ultrasound examinations were performed at baseline and at the conclusion at MZP5 in all patients. Results: At baseline 17 PWH (mean age 43.29±13.1 years) and 12 PWO (mean age 61.42±8.5 years) were enrolled; most PWH had HA (88.2%), were severely affected (58.8%), had a target joint (52.6%) and 6/17 had a knee endoprosthesis. 88.2% of PWH had a disabled card (most with a disability degree of ≥ 80) compared to 45.5% of PWO (most with a disability degree of 50). PWH had a significant worse orthopaedic joint status ( p<.003) and subjective physical functioning ( p<.001) compared to PWO; PWH had a mean HJHS of 26.76±18.0 vs. 11.0±5.7 and a mean HEP-Test-Q of 48.12±16.4 vs. 67.08±9.1. PWO reported highest impairments in the HEP-Test-Q domain ‘mobility’, while PWH suffered mainly under reduced ‘endurance’. The NNM showed a significant impairment in the mobility of the left ( p<.001) and right ( p<.013) ankle, 58.3% PWO had no impairments compared to 58.9-76.5% of PWH with moderate-severe impairments. This was confirmed by the ultrasound showing a worse progression of their disease ( p<.001) compared to PWO (mean HEAD-US 11.41±6.5 vs. 3.75±3.3). PWH had a worse HRQoL ( p<.001) (mean PCS of 37.51±8.3 vs. 49.45±7.2) and reported a significant higher ( p<.001) emotional distress due to pain (mean SES affective 30.0±12.8, SES sensory 20.94±6.2 vs. SES affective 16.75±2.6, SES sensory 12.08±2.5). Compared to PWO, PWH had a significant lower PAL-value ( p<.045) describing the level of physical activity over the period of 24 hours, most had a sedentary job (87.5% vs. 50%). Most of the PWH were below the predicted lower limit of the 6MWD compared to the PWO who all were above the lower limit. No difference was found between the groups regarding FMS and RPE before and after 6MWT and in the MCS. Conclusions: Although PWH were significantly younger than PWO, they had a significantly worse subjective and objective physical functioning; in addition they had a worse HRQoL, HEAD-US, NNM, PAL and a higher pain experience. Our study took place during the Corona pandemic and was quite time consuming for the participants, resulting in a failure to reach the desired number of cases and led to a high drop-out rate over the duration of the project.

Three-Year Interim Analysis Results of the AOZORA Study to Evaluate the Long-Term Safety and Joint Health in Children with Hemophilia A without Factor VIII Inhibitors Receiving Emicizumab

Background: Recurrent joint bleeding from a young age in people with hemophilia A (PwHA) may lead to hemophilic arthropathy, resulting in limited movement and chronic pain. Emicizumab is a bispecific monoclonal antibody that bridges activated factor (F) IX and FX to substitute for activated FVIII and provides stable plasma concentrations and maintenance of trough levels within the therapeutic range. Limitations in long-term joint health preservation have been reported with FVIII prophylaxis (Warren et al. Blood Adv 2020); it is expected that emicizumab may overcome these limitations, as joint health improvements have been demonstrated in PwHA aged 12-39 years (Kiialainen et al. Haemophilia 2022). Here, we report the 3-year interim analysis of the ongoing, open-label, Phase IV AOZORA study (JapicCTI-194701), analyzing long-term safety and joint health in pediatric PwHA without FVIII inhibitors receiving emicizumab (Shima et al. BMJ Open 2022). Methods: Eligible participants were aged <12 years with severe hemophilia A (HA) without FVIII inhibitors. Participants entered AOZORA as emicizumab-naïve or following the Phase III HOHOEMI study (Shima et al. Haemophilia 2019). Primary endpoints include adverse events (AEs), and joint health and function assessed by magnetic resonance imaging (MRI) and the Hemophilia Joint Health Score (HJHS) version 2.1. MRI evaluation uses the International Prophylaxis Study Group (IPSG) MRI scale; a positive IPSG score indicates pathological changes in the knee and/or ankle joints. Exploratory endpoints include annualized bleed rate (ABR) for treated bleeds and treated joint bleeds. All participants will receive emicizumab for 6 years from their first dose until study end. Results: Data cut-off was the last day of Week 145 for individual participants. Ten participants entered from HOHOEMI and 20 participants were newly enrolled. The median (range) age was 4.2 (0.7-11.1) years, all participants were male, and 27 (93.1%) participants had been treated with prior FVIII prophylaxis ( Table 1). One participant had 1 target joint (knee) at Week 1. In AOZORA, 5 (16.7%) participants experienced 7 emicizumab-related AEs: 6 injection site reactions in 5 participants and 1 case of anemia in 1 participant. Seven serious AEs, reported as unrelated to emicizumab, occurred in 5 (16.7%) participants. No thrombotic events or thrombotic microangiopathies occurred. Twenty-nine participants at Week 1 and 26 participants at Week 145 were assessed using the IPSG MRI scale. At Week 145, MRI scores remained at 0 for 11 (42.3%) of the 26 participants. Of 116 joints assessed at Week 1, 28 (24.1%) had soft tissue changes (effusion/hemarthrosis, synovial hypertrophy and/or hemosiderin deposition; Table 2). At Week 145, 104 joints were assessed and 33 (31.7%) of those had soft tissue changes. Of 10 (8.6%) joints with synovial hypertrophy and hemosiderin at Week 1, all had improved at Week 145 and synovial hypertrophy and hemosiderin were no longer present in 9 joints. One new joint developed synovial hypertrophy and hemosiderin at Week 145. The rest of the soft tissue changes were effusion/hemarthrosis, present in 21 (18.1%) joints at Week 1 and 31 (29.8%) at Week 145. Thirty participants at Week 1 and 27 participants at Week 145 were assessed using the HJHS v2.1. Eighteen (66.7%) participants' HJHS scores remained at 0 from Week 1 to Week 145 and 1 (3.7%) participant's remained at 4; 6 (22.2%) participants' scores improved; 2 (7.4%) participants' scores worsened. Mean (standard deviation) HJHS total score improved from 0.90 (1.79) at Week 1 to 0.44 (1.05) at Week 145. The mean (95% confidence interval [CI]) ABR for treated bleeds was 3.7 (0.94-9.80) prior to emicizumab and 0.7 (0.01-5.10) while receiving emicizumab. The mean (95% CI) ABR for treated joint bleeds was 0.4 (0.00-4.55) prior to emicizumab and 0.2 (0.00-4.04) while receiving emicizumab. Conclusions: This 3-year interim analysis of the AOZORA study confirmed the safety profile of emicizumab. The proportion of joints with effusion/hemarthrosis increased by Week 145. However, all joints with synovial hypertrophy and hemosiderin, which are strongly associated with the progression of arthropathy (Gualtierotti et al. J Thromb Haemost 2021), improved by Week 145. These results suggest that emicizumab is effective in maintaining and improving joint health in pediatric PwHA.

Primary total knee arthroplasty in hemophilic arthropathy

Advanced hemophilic knee arthropathy is a frequent and devastating manifestation of severe hemophilia with significant implications for activities of daily living. Hemophilic arthropathy is caused by repeated bleeding, resulting in joint degeneration, pain, deformity and disability. In patients with hemophilia and advanced disease, total knee arthroplasty (TKA) has proven to be the most successful intervention, improves physical function and reduces knee pain. Hemophilic patients carry additional risks for complications and required specific pre/postoperative considerations. Expert treatment center should be used to improve patient outcome. Hemophilic patients present significant surgical challenges such as joint destruction, bone loss, severe ankylosis and oligoarticular involvement. The surgeon performing the arthroplasty must be experienced to manage such problems.

Plasma-derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency.

Hereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life-threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma-derived FX (pdFX), a single-factor, high-purity, high-potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on-demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD. Five studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5IU/dL), moderate (FX:C ≥1 and<5IU/dL), or severe (FX:C<1IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open-label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies. When used as an on-demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged 'excellent' for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated. Together, these studies support the use of pdFX for on-demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

Неврологическая патология и симптоматика при некоторых кожных заболеваниях

This article examines two conditions in which neurological symptoms prominently manifest alongside dermatological manifestations. The first condition, Rosolimo–Melkersson–Rosenthal syndrome, encompasses three cardinal features: macrocheilia, fissured tongue, and facial nerve palsy, with macrocheilia often presenting as the monosymptom. When the clinical presentation is limited to macrocheilia, dermatologists typically manage the treatment, while cases with evident facial nerve palsy are referred to neurologists. The second condition is herpes zoster, the clinical manifestations of which unequivocally necessitate dermatological intervention. Apart from cutaneous eruptions, the primary focus shifts to neurological involvement, presenting as neuropathic disorders (agonizing pain syndromes concurrent with eruptions) and post-herpetic neuralgia, which can endure for an extended period. Consequently, the management of such patients involves collaboration between dermatologists and neurologists.

Joint Dysfunction as a Cause of Spontaneous Subclinical Bleeding in Infants with Hemophilia.

Hemophilia is an inherited hemorrhagic disorder; its main clinical manifestations being bleeding in muscles and joints. Ankles, knees, and elbows are the most frequently affected joints, followed by shoulders and hips. The clinical signs of joint involvement are reduced mobility, swelling and walking difficulties. Bleeding episodes in patients with hemophilia are usually divided into traumatic and spontaneous, but we believe that the latter are not truly spontaneous but rather the result of joint stresses owing to motion actions that create dysfunctions starting from infancy. Pharmacological prophylaxis with factor replacement therapies or non-replacement drugs markedly reduces musculoskeletal hemorrhages. However, the onset of subclinical joint stress can be reduced only by associating this therapeutic approach with the accurate observation of the child motion patterns and restoring them if dysfunctional, thereby primarily preventing subclinical bleeding and ultimately the onset or progression of hemophilic arthropathy.

Joint status, pain and quality of life in elderly people with haemophilia: A case-control study.

Elderly people with haemophilia (PwH) develop haemophilic arthropathy, pain, and reduced health-related quality of life (HR-QoL). The condition of elderly mild haemophilia patients have rarely been evaluated. This study aimed to compare joint status, pain, and HR-QoL between elderly with mild, moderate/severe haemophilia and healthy elderlies. Knee/ankle abnormalities were assessed by ultrasound (HEAD-US) and physical examination (HJHS 2.1). Pain severity and pain interference were investigated using the Brief Pain Inventory. Pressure pain thresholds (PPTs) were obtained at knees/ankles and forehead. Functional limitations were evaluated using the 2-Minute-Walking-Test, Timed-Up-and-Go and HAL. The EQ-5D-5L questionnaire evaluated HR-QoL. Healthy controls (HCs) and elderly individuals with moderate/severe and mild haemophilia were compared using Kruskal-Wallis and Mann-Whitney U tests. From the 46 elderly PwH approached, 40 individuals (≥60 years) with haemophilia A/B (17 moderate/severe; 23 mild) and 20 age-matched HCs were recruited. Moderate/severe PwH displayed worse joint status, lower PPTs, and poorer HR-QoL than mild PwH and HCs (p-value=.010-<.001). HEAD-US abnormalities were observed in 100% of knees and 94% of ankles in moderate/severe PwH, versus 50% of knees and 61% of ankles in mild PwH. Pain was reported by 80% and 57% of moderate/severe and mild PwH, respectively. Low PPTs, functional limitations, and poor HR-QoL scores were likewise observed in some mild PwH, yet without significantly differing from HCs. This study highlights poor joint/functional status, pain, and HR-QoL outcomes in elderly with moderate/severe haemophilia. A few mild haemophilia subjects presented joint abnormalities, pain, functional limitations, and poor HR-QoL, without significantly differing from HCs. Elderly individuals with mild haemophilia have not yet been extensively studied, whereas moderate/severe haemophilia individuals have proven to suffer from haemophilic arthropathy, pain, and poor health-related quality of life (HR-QoL). Using a case-control design, joint status, pain, and HR-QoL outcomes were examined in elderly haemophilia individuals and compared with those of healthy controls (HCs). Elderly moderate/severe haemophilia individuals exhibited worse joint status, increased joint pain sensitivity, and reduced HR-QoL compared with both mild haemophilia subjects and HCs. A subset of mild haemophilia subjects exhibited poor joint status, pain, and HR-QoL outcomes, without any differences noted when compared with HCs.

Five new F10 variants in hereditary factor x deficiency detected by high-throughput sequencing.

Factor X deficiency is a rare inherited bleeding disorder. To date, 181 variants are reported in the recently updated F10-gene variant database. This study aimed to describe new F10 variants. The F10 gene was analysed in 16 consecutive families with FX deficiency by a targeted high-throughput sequencing approach, including F10, F9, F8 genes, and 78 genes dedicated to haematological malignancies. We identified 19 variants (17 missense, one nonsense and one frameshift) and two copy number variations. Two patients presenting a combined FVII-FX deficiency showed a loss of one F10 gene copy (del13q34) associated with a missense variant on the remaining allele, leading to a FX:C significantly lower than the FVII:C level and explaining their unusual bleeding history. We reported five novel variants. Three missense variants (p.Glu22Val affecting the signal peptide cleavage site, p.Cys342Tyr removing the disulphide bond between the FX heavy and light chains, and p.Val385Met located in FX peptidase S1 domain) were detected at compound heterozygosis status in three patients with severe bleeding symptoms and FX:C level below 10 IU/dL. Two truncating variants p.Tyr279* and p.Thr434Aspfs*13 leading to an altered FX protein were found at heterozygous state in two patients with mild bleeding history. This study showed the feasibility and the interest of high-throughput sequencing approach for rare bleeding disorders, enabling the report of F10 gene screening in a 3-weeks delay, suitable for clinical use. The description of five new variants may contribute to a better understanding of the phenotype-genotype correlation in FX deficiency.

Open lift-drill-fill-fix for medial osteochondral lesions of the talus: surgical technique.

Osteochondral lesions of the talus (OLT) with afragment on the talar dome that fail conservative treatment and need surgical treatment can benefit from in situ fixation of the OLT. Advantages of fixation include the preservation of native cartilage, a high quality subchondral bone repair, and the restoration of the joint congruency by immediate fragment stabilization. To improve the chance of successful stabilization, adequate lesion exposure is critical, especially in difficult to reach lesions located on the posteromedial talar dome. In this study we describe the open Lift, Drill, Fill, Fix (LDFF) technique for medial osteochondral lesions of the talus with an osteochondral fragment. As such, the lesion can be seen as an intra-articular non-union that requires debridement, bone-grafting, stabilization, and compression. The LDFF procedure combines these needs with access through amedial distal tibial osteotomy. Symptomatic osteochondral lesion of the talus with afragment (≥ 10 mm diameter and ≥ 3 mm thick as per computed tomography [CT] scan) situated on the medial talar dome which failed 3-6months conservative treatment. Systemic disease, including active bacterial arthritis, hemophilic or other diffuse arthropathies, rheumatoid arthritis of the ankle joint, and malignancies. Neuropathic disease. End-stage ankle osteoarthritis or Kellgren and Lawrence score3 or4 [3]. Ipsilateral medial malleolus fracture less than 6months prior. Relative contra-indication: posttraumatic stiffness with range of motion (ROM) < 5°. Children with open physis: do not perform an osteotomy as stabilization of the osteotomy may lead to early closure of the physis, potentially resulting in symptomatic varus angulation of the distal tibia. In these cases only arthrotomy can be considered. The OLT is approached through amedial distal tibial osteotomy, for which the screws are predrilled and the osteotomy is made with an oscillating saw and finished with achisel in order to avoid thermal damage. Hereafter, the joint is inspected and the osteochondral fragment is identified. The cartilage is partially incised at the borders and the fragment is then lifted as ahood of amotor vehicle (lift). The subchondral bone is debrided and thereafter drilled to allow thorough bone marrow stimulation (drill) and filled with autologous cancellous bone graft from either the iliac crest or the distal tibia (fill). The fragment is then fixated (fix) in anatomical position, preferably with two screws to allow additional rotational stability. Finally, the osteotomy is reduced and fixated with two screws. Casting includes 5weeks of short leg cast non-weightbearing and 5weeks of short leg cast with weightbearing as tolerated. At 10-week follow-up, aCT scan is made to confirm fragment and osteotomy healing, and patients start personalized rehabilitation under the guidance of aphysical therapist.

Neuroinflammatory markers in patients with haemophilia and healthy controls: Where are the differences?

People with haemophilia (PwH) suffer from haemophilic arthropathy which is accompanied by acute and chronic inflammation. The aim of this study was to examine the neuroinflammatory network operative in PwH and to compare it to healthy controls. Blood samples were collected from 41 PwH (age 54.7±11.7 years) and 33 healthy controls (age 50.9±10.5 years) and the levels of 13 neuroinflammatory markers were analyzed by applying an antibody-based detection kit in a flow cytometer. From 13 analyzed markers, three-ß-nerve growth factor (ß-NGF), soluble receptor for advanced glycation endproducts (sRAGE) and Interleukin-18 (IL-18) differed significantly between the groups (ß-NGF p=.045; sRAGE p=.003; IL-18 p=.007). While ß-NGF was downregulated in PwH, sRAGE and IL-18 were upregulated. None of the analyzed markers corelated to the joint status of PwH while CCL2 (C-C motif ligand 2 chemokine) correlated to HIV infections in PwH (r=.313, p=.007). Correlation analyses of the markers studied also revealed many differences between PwH and controls suggesting a number of deregulations in PwH. The altered levels of sRAGE and ß-NGF in PwH, which have not been analyzed in PwH before, may help to understand the neuroinflammatory network operative in PwH. The general inflammatory processes in PwH and the involved biomarkers in PwH remain poorly understood. PwH could benefit from new therapies against neuroinflammation which may help to reduce inflammation or also chronic pain.

Effectiveness of Kinesiologic Taping on Function and Pain in Patients With Hemophilia A

ABSTRACT Background: Hemophilic arthropathy frequently results in musculoskeletal adjustments that impair functional capacity. Aim: We investigated the effects of kinesiologic taping on patients with hemophilic arthropathy in this study. Materials and Methods: Twenty-six patients were enrolled. Thirteen patients formed the Kinesiologic taping group (KT) and received the interventional protocol consisting of three kinesiologic taping sessions during three weeks; and 13 patients formed the control group (CG) and made three weeks of home exercises. All patients were evaluated using the Functional Independence Score in Hemophilia (FISH), Hemophilia Joint Health Score (HJHS), and Visual Analog Scale (VAS) at baseline, one week, and three weeks. Results: The mean scores for the VAS, HJSS, and FISH differed significantly before and after 3 weeks in both groups (P &lt; 0.001). However, the differences in medians after the treatment were significantly greater in the KT group than in the CG group (P &lt; 0.001). Conclusions: Kinesiologic taping was associated with physical improvement in hemophilia patients; however, also kinesiologic taping led to significant improvement in VAS scores.

OC 12.5 Correlation of Biomarkers, Conventional X Ray Score, Hemophilia Joint Healthy Score and Joint Sonography for Assessment of Hemophilic Arthropathy Severity

OC 12.5 Correlation of Biomarkers, Conventional X Ray Score, Hemophilia Joint Healthy Score and Joint Sonography for Assessment of Hemophilic Arthropathy Severity