Joint Bleeding Research Articles

Patient perspective on living with mild hemophilia in Germany: results from a nationwide survey.

The disease burden and bleeding risk of patients with mild hemophilia may be underestimated. Their health-related quality of life (QoL) may be negatively impacted by insufficient treatment and bleed-related joint damage connected to a potentially delayed diagnosis. This study aims to gain information on the care reality and QoL of patients aged ≥12 years with mild hemophilia in Germany. An anonymous cross-sectional patient survey using standardized questionnaires was conducted in a validated electronic patient-reported outcome system. Medical specialists, hemophilia centers, patient organizations, and support groups across Germany invited the patients. A total of 43 patients (35 patients with hemophilia A, 5 patients with hemophilia B, and 3 patients for whom the information was missing) with a median age of 33 years were analyzed. The median age at diagnosis was 6.0 years (interquartile range [IQR] 2.0-15.0), and the median factor activity was 14.0% (IQR 12.0-25.0). Nearly 85% of the patients received factor concentrates in the past, and the most common reasons for the treatment were surgery or joint bleeding (each 65.6%). Half of the patients who provided feedback experienced complications during bleeding episodes. Prophylactic treatment with factor concentrates was rare (10.3%). The patients had minor problems regarding their health status. Bleeding complications and joint bleeding, in particular, may be highly underestimated in patients with mild hemophilia, highlighting a medical need in this population. Patients with a potential benefit from prophylaxis need to be identified. Mild hemophilia has a negative impact on patients' QoL. Hemophilia centers satisfied the patients' needs. Further research is needed to address the current lack of awareness and improve adequate treatment in the future.

Ultrasound in addition to clinical assessment of acute musculoskeletal complaints in bleeding disorders: impact on patient management

BackgroundUltrasound is increasingly used for musculoskeletal assessment in hemophilia care. ObjectivesTo evaluate the impact of point-of-care ultrasound added to clinical assessment for diagnosis and treatment of acute musculoskeletal episodes in a heterogeneous cohort of children and adults with hemophilia and von Willebrand disease (VWD). MethodsThis prospective cross-sectional study consecutively included children and adults with hemophilia or VWD who visited the outpatient clinic with acute musculoskeletal complaints between March 2020 and May 2023. For all episodes, initial diagnosis and treatment determined by clinical assessment were recorded on a case report form. Subsequently, a physiotherapist (M.A.T. and J.B.) with knowledge of the clinical diagnosis performed point-of-care ultrasound. After ultrasound, updated diagnosis and treatment were recorded. Diagnosis and treatment before and after ultrasound were compared, and proportions of change with 95% CIs were determined. ResultsWe evaluated 77 episodes in 67 patients (median age, 24 years; IQR, 13-42 years). Before ultrasound, 37 joint bleeds, 13 muscle bleeds, and 27 other diagnoses were diagnosed. After ultrasound, 33 joint bleeds, 11 muscle bleeds, and 33 other diagnoses were confirmed. The diagnosis changed in 28 of 77 episodes (36%; 95% CI, 26%-48%). Nine joint bleeds and 2 muscle bleeds were missed by clinical assessment. Ultrasound findings changed treatment strategy in 30 of 77 episodes (39%; 95% CI, 28%-51%). ConclusionUltrasound in addition to clinical assessment of acute musculoskeletal complaints in people with hemophilia and VWD has an impact on diagnosis (36%) and treatment (39%), which supports the use of ultrasound in acute musculoskeletal complaints in hemophilia and VWD.

Von willebrand disease and gastrointestinal bleeding: case presentation

Introduction: Von Willebrand diseases is a hereditary bleeding disorder caused by a quantitative or qualitative deficiency of von Willebrand factor, characterized by light mucocutaneous bleeding, although other bleeding such as gastrointestinal and joint bleeding may occur in severely affected patients. It treatment is fundamentally based on replacement therapy and the use of desmoprecin. Objective: Describe the characteristics and clinical evolution of a patient who presented upper gastrointestinal bleeding as a form of presentation of von Willebrand disease. Conclusions: von Willebrand diseases hould be suspected in patients with abnormal bleeding symptoms without apparent causes.

The imperative to prevent joint bleeding in everyone living with hemophilia

The imperative to prevent joint bleeding in everyone living with hemophilia

Joint bleeds in mild hemophilia: Prevalence and clinical characteristics.

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

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

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

Health-related quality of life and its associated factors among hemophilia patients: experience from Ethiopian Hemophilia Treatment Centre

BackgroundHemophilia is a rare genetic condition that is often overlooked and underdiagnosed, particularly in low-income countries. Long-term spontaneous joint bleeding and soft tissues can have a significant negative impact on a patient’s health-related quality of life (HRQoL). The objective of this study was to assess HRQoL and its associated factors in Ethiopian patients with hemophilia.MethodsA cross-sectional survey was conducted among patients with hemophilia at Tikur Anbessa Specialized Hospital (TASH) in Addis Ababa, Ethiopia. Patients were recruited consecutively during follow-up visits. The European Quality of Life Group’s 5-Domain Questionnaires at five levels (EQ-5D-5L) and Euro Quality of Life Group’s Visual Analog Scale (EQ-VAS) instruments were used to assess HRQoL. The EQ-5D-5L utility score was computed using the disutility coefficients. We applied the Krukal-Wallis and Mann–Whitney U tests to determine the differences in EQ-5D-5L and EQ-VAS utility scores between patient groups. A multivariate Tobit regression model was used to identify factors associated with HRQoL. Statistical analyses were performed using STATA version 14 and statistical significance was determined at p < 0.05.ResultsA total of 105 patients with hemophilia participated in the study, with a mean (standard deviation (SD) age of 21.09 (± 7.37] years. The median (IQR) EQ-5D-5L utility and EQ-VAS scores were 0.86 (0.59–0.91) and 75 (60.0–80.0), respectively. Age was significantly negatively associated with the EQ-5D-5L utility index and EQ-VAS (β = -0.020, 95 CI = -0.034, -0.007) and β = -0.974, 95% CI = -1.72, 0.225), respectively. The duration since hemophilia diagnosis (β-0.011, 95% CI, 0.001–0.023) and living out of Addis Ababa (β = -0.128, 95% CI, -0.248-, -0.007) were also significantly negatively associated with the EQ-5D-5L utility index..ConclusionThe median EQ-5D-5L utility and EQ-VAS scores of patients with hemophilia were 0.86 (0.59–0.91) and 75 (60.0–80.0), respectively. Older age, living far from the Hemophilia Treatment Center (HTC), and longer duration since diagnosis were significantly negatively associated with HRQoL. HRQoL may be improved by providing factor concentrates, decentralizing HTCs in different parts of the country, increasing awareness of bleeding disorders among health professionals, and providing psychosocial support to affected patients.

The effectiveness and safety of octocog alfa in patients with hemophilia A: up to 7-year follow-up of the real-world AHEAD international study.

Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited. To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice. The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study. This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1-5%; severe, FVIII <1%]. Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34-56% of prophylaxis patients versus 20-40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events. These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment. ClinicalTrials.gov: NCT02078427.

Blood-Induced Arthropathy: A Major Disabling Complication of Haemophilia.

Haemophilic arthropathy (HA) is one of the most serious complications of haemophilia. It starts with joint bleeding, leading to synovitis which, in turn, can cause damage to the cartilage and subchondral bone, eventually inducing degenerative joint disease. Despite significant improvements in haemophilia treatment over the past two decades and recent guidelines from ISTH and WFH recommending FVIII trough levels of at least 3 IU/dL during prophylaxis, patients with haemophilia still develop joint disease. The pathophysiology of HA is complex, involving both inflammatory and degenerative components. Early diagnosis is key for proper management. Imaging can detect joint subclinical changes and influence prophylaxis. Magnetic resonance imagining (MRI) and ultrasound are the most frequently used methods in comprehensive haemophilia care centres. Biomarkers of joint health have been proposed to determine osteochondral joint deterioration, but none of these biomarkers has been validated or used in clinical practice. Early prophylaxis is key in all severe haemophilia patients to prevent arthropathy. Treatment is essentially based on prophylaxis intensification and chronic joint pain management. However, there remain significant gaps in the knowledge of the mechanisms responsible for HA and prognosis-influencing factors. Better understanding in this area could produce more effective interventions likely to ultimately prevent or attenuate the development of HA.

Low-dose emicizumab prophylaxis in patients with severe hemophilia A: a retrospective study bringing new hope for our patients

BackgroundLow-dose emicizumab can potentially offer a cost-effective treatment option in persons with hemophilia A, especially in developing countries. ObjectivesTo compare the efficacy and safety of low-dose emicizumab with those on low-dose factor (F)VIII prophylaxis via chart review. MethodsAfter ethics approval, chart data of 2 groups of patients were reviewed: group 1 (low-dose emicizumab, n = 10; 3 mg/kg monthly without a loading dose) and group 2 (low-dose FVIII prophylaxis, n = 10; 10-20 IU/kg of FVIII concentrates twice a week). Outcomes were target joints, annual bleeding rate, annual joint bleeding rate, Hemophilia Joint Health Score, nonactivated thromboelastometry–rotational thromboelastometry clotting time, plasma emicizumab levels, and direct costs of treatment. ResultsAll outcome measures were significantly better in the low-dose emicizumab group than in the low-dose FVIII prophylaxis group. For nonactivated thromboelastometry–rotational thromboelastometry, median values after 6 months in the low-dose emicizumab group were comparable with values seen in patients with mild hemophilia, while the values in the low-dose FVIII prophylaxis group were similar to those of patients with moderate hemophilia. The direct cost of low-dose emicizumab was found to be approximately US $6000 and that for low-dose recombinant FVIII prophylaxis used in our study was US $6282 (the cost may range from US $3432 to $7920 depending on the type of factor) when compared to approximately US $15 000 for standard-dose emicizumab. ConclusionLow-dose emicizumab offers a cost-effective treatment option and can improve access in developing countries. These findings need to be confirmed in a larger and better-controlled study.

Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial

AbstractSubcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30–0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors.

The use of emicizumab in children with hemophilia A without inhibitors in the real-world clinical setting

In our country, the use of emicizumab in children with hemophilia A without inhibitors (HA) in the real-world clinical setting is limited and is available only as few individual case reports. Our aim was to evaluate the effectiveness and safety of the prophylactic use of emicizumab in children with severe HA in the real-world clinical setting. We conducted a retrospective analysis of medical records of children with HA who had received emicizumab at 9 centers based in the Russian Federation. We assessed the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (ASBR), annualized joint bleeding rate (AJBR), annualized bleeding rate for bleeding episodes that required additional treatment with FVIII concentrate (ABRRT) and the number of hospital admissions for bleeding both before and after the treatment with emicizumab, as well as the occurrence and severity of adverse events during the therapy. Ethics committee approval was not required for this study because it involved the use of aggregated retrospective data from routine clinical practice that were fully anonymized. Two emicizumab administration regimens were compared with regard to their effectiveness. Before the treatment with emicizumab, ABR was 5.38 (95% confidence interval (CI) 3.90–7.64), ASBR – 4.16 (95% CI 2.99–5.94), AJBR – 2.7 (95% CI 1.87–4.03), and ABRRT – 4.8 (95% CI 3.37–7.08). After the initiation of the treatment with emicizumab, the bleeding rate plummeted: ABR decreased by 93.9% (95% CI 88.8–96.7), ASBR – by 96.9% (95% CI 93.1–98.6), AJBR – by 96.1% (95% CI 90.4–98.4%) and ABRRT – by 95.1% (95% CI 90.0–97.6). During the treatment with emicizumab, the rate of bleeding episodes that required hospital admission decreased from 1.58 (95% CI 0.98–2.68) to 0.04 (0.01–0.10), which amounted to 97.6% (95% CI 91.1–99.4). The median follow-up time for the patients treated with emicizumab was 15.5 months (range 9–29 months). When comparing the annualized bleeding rates in the groups of the patients who were preventively treated with emicizumab at doses of 3 mg/kg (administered once every 2 weeks) and 1.5 mg/kg (once per week), we didn't find any statistically significant differences. In the real-world clinical setting, the use of emicizumab in the children with HA led to a significant reduction in all bleeding episodes (by more than 90%), regardless of the administration regimen.

A single‐centre experience of 29 total ankle replacement in haemophiliac patients: Therapeutic management, factor consumption and cost

AbstractIntroductionIn patients with haemophilia, repeated bleeding in large joints leads to chronic haemophilic arthropathy, a rare disease that can be managed surgically with ankle arthrodesis or with total ankle replacement (TAR). TAR has been reported to provide good surgical results in the medium/long‐term and allow preservation of joint mobility but the medical therapeutic management of the patients has not been described.AimTo describe the medical therapeutic management of TAR.MethodsAll patients with haemophilia A/B, with haemophilic ankle arthropathy, and who underwent TAR between April 2006 and October 2019 were retrospectively included. Factor consumption, perioperative and early complications, volume of blood lost, and orthopaedic data were collected.ResultsA total of 25 patients underwent 29 TAR (mean age was 44.7 years [range: 26–65]). In the 17 patients with HA without history of anti‐FVIII inhibitor, the mean ± SD consumption the day of surgery was 116 ± 16 UI/kg when clotting factors were administered by continuous infusion, 106 ± 13 UI/kg when SHL factors were administered by bolus infusion, and 75 ± 22 UI/kg when EHL factors were administered by bolus infusion. During hospitalisation, the mean factor cost was €38,073 (83.7% of the total cost of surgery). Mean blood loss was significantly lower in patients treated with tranexamic acid (164 mL, range: 40–300) than in those not (300 mL, range: 70–800; p = .01). Six patients had haematoma. The 10‐year survival free of any prosthesis removal/arthrodesis was estimated to be 92.2% (95% CI [83; 100]).ConclusionThe medical therapeutic management of TAR is complex, carried out by a multidisciplinary team but effective in avoiding the occurrence of complications.

Extravascular factor IX pool fed by prophylaxis is a true hemostatic barrier against bleeding

BackgroundFactor (F)IX can bind to type IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX. ObjectivesThe aim of the study was to evaluate the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds. MethodsThe capacity of 4 different FIX molecules (plasma-derived and recombinant) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knockout mice. ResultsA specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50 to 100 IU/kg, while plasma-derived FIX generated a FIX signal at all doses, including 50 IU/kg. Such a signal was also detected after five 100 IU/kg daily infusions of recombinant FIX, suggesting that FIX can accumulate in the extravascular space during prophylaxis. The extravascular procoagulant activity of FIX, assessed in saphenous vein bleeding assays, was significantly higher in hemophilia B mice after these 5 days of prophylaxis compared to a single infusion of 100 IU/kg of FIX and assessment of FIX activity 7 days later. ConclusionTaken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection toward bleeding.

IBC-Oxford University2023_BJSPoster_1Laparoscopic Sleeve Gastrectomy in a Patient with Severe Haemophilia A

Abstract Introduction Haemophilia A is an X linked inherited bleeding disorder caused by deficiency in coagulation factor VIII (FV III). To prevent spontaneous bleeding in muscles and joints, patients with severe Haemophilia A should receive prophylactic replacement therapy with dosing adjusted according to body weight. Case presentation A 19-year-old male patient who is well known to have Haemophilia A, that has been diagnosed shortly after birth during routine circumcision. The patient had presented to our clinic with BMI of 53.9 kg/m2. He was counselled for laparoscopic sleeve gastrectomy after failure of many trials to lose weight. He and his father were counselled for procedure pros and cons. Routine preoperative work up had been performed (Full labs, Abdomen Ultrasound, Dietician consultation, Anaesthesia consultation, Cardiology consultation). Haematological consultation had been done and consultant opinion was to give prophylactic factor VIII 7500 IU: 2 hours prior to surgery, 24 hours after surgery, 72 hours after surgery Extra precaution had been taken in the perioperative period in the form of careful cannulation, IM injections had been avoided completely, no anticoagulants, 1:1 Nursing care, careful patient handling and positioning, continuous monitoring (planned ICU admission for first 24 hours then HDU admission for 48 hours), senior Anaesthetist and senior Anaesthesia technician, on-table gastroscopy, smooth bougie tube placement (size 36F), careful haemostasis by way of slow Harmonic sealing, clipping of short gastrics, 1 minute stapler compression (All green reloads), full stapler line plication and omental patching, maintenance of stable blood pressure during surgery. Patient had an uneventful postoperative recovery, apart from mild bilateral subconjunctival haemorrhages that had subsided spontaneously. Conclusion Laparoscopic sleeve gastrectomy can be performed smoothly in patients with Haemophilia A with proper perioperative multidisciplinary care management.

Pharmacokinetics of Recombinant Human Coagulation Factor Ⅷ Preparations in Patients with Severe Hemophilia A

To calculate the pharmacokinetic parameters of recombinant human coagulation factor Ⅷ using myPKFiT in patients with severe hemophilia A, and provide an individualized treatment plan for patients. A total of 42 patients with severe hemophilia A who were treated with recombinant human coagulation factor Ⅷ were included from January 2021 to December 2021. myPKFiT was used to calculate the pharmacokinetic parameters of FⅧ, and the individualized treatment plan for hemophilia A patients was formulated. The median age of 42 patients with severe hemophilia A was 31（16-50） years old, the average weight was 54.0±9.9 kg, the half-life of FⅧ was 12.05±1.6 h, the time to more than 1% of the baseline was 62.3±15.3 h, and the 0 bleeding rate after the guidance of myPKFiT was significantly increased from 39% to 49%, the Annual bleeding rate was reduced from 3.6±2.5 to 2.1±2.0, and the Annual joint bleeding rate was reduced from 3.2±2.2 to 1.9±0.9, all of which were statistically different (P<0.05). Individualized therapy in patients with severe hemophilia A who were guided by myPKFiT assay of pharmacokinetics parameters can significantly reduce the annual bleeding rate and annual joint bleeding rate of patients.

Identifying Ideal Individuals for PK-Guided Dosing; Recreational Risks and Elevated Breakthrough Bleeding

Introduction PK-guided dosing is a useful tool for personalized FVIII prophylaxis for people living with Hemophilia A (PwHA). While many individuals can benefit from this intervention, certain subsets of the population of PwHA may see increased benefit and be considered ideal candidates for PK-guided dosing. We aim to identify sub-populations of interest who may have increased benefit of PK-guided dosing, namely those with high levels of bleeding risk from recreational activity, and PwHA with elevated levels of bleeding. Clinical and FVIII utilization outcomes are analyzed in these cohorts to determine if these populations have increased benefit from PK-guided dosing. Methods Based on a retrospective study of 132 PwHA with moderate to severe Hemophilia A (FVIII &amp;lt; 5%) to determine effects of PK-guided dosing on clinical and utilization outcomes (Young, 2022), 58 matched criteria for undergoing a PK for optimization of therapy with a given product. Individuals were stratified by recreational activity risk using a modification of the National Hemophilia Foundation's activity risk scale (Anderson, 2017, p. 22), grouping individuals into mild, moderate, and high recreational activity risk for bleeding. Bleeding rates prior to PK assessment were calculated, and individuals were classified into groups based on pre-index annualized bleed rate (ABR) ≥ 3 and pre-index ABR &amp;lt; 3, due to bimodal distribution. Index date was defined as date of the PK-guided prescription. Results Recreational activity risk was available for 56/58 individuals, and after PK-guided dosing 53/56 had no change in activity level. Analyses were limited to these 53, 28 with mild risk, 19 with moderate risk, and 6 with high risk. Individuals with high activity risk had severe Hemophilia A (FVIII &amp;lt; 1%), and had median age of 12 years (IQR: 12-17) at PK-guidance. Overall mean pre-index ABR was 3.6 (sd: 4.2), with majority of bleeds associated with joint or traumatic bleeds. High activity risk individuals had higher traumatic ABR prior to index date compared to those with low or moderate activity risk. Soccer was the most common high risk activity reported by 4/6 individuals (66.7%), with tackle football and martial arts reported in the remaining individuals. Individuals with mild/moderate risk did not differ from those with high activity risk by age, hemophilia severity, number of target joints, or pre-index ABR. Within these groups, we found significant decreases in ABR after PK-guidance among those with mild risk (-2.6 [95% CI:-4.4, -1.0]), driven by decrease in joint (-1.7 [-3.2, -0.4]) and traumatic (-1.2 [-2.2, -0.3]) bleeds. Similar trends were observed in high activity risk group for overall ABR ( -2.2 [-4.8, 0.4]), joint bleeds (-1.6 [-4.0, 0.2]) and traumatic bleeds (-1.1, [-2.4, 0.4]) but limited sample increased uncertainty of estimates. No change in ABR was identified for those with moderate activity risk. No major difference in mean weekly consumption (MWC) after PK guidance was observed in those with mild risk (+3.6 IU/kg [-6.2, 13.3]), but those with high risk trended towards increase in MWC (+11.0 IU/kg [-4.8, 26.7]) of FVIII for prophylaxis. Annualized cost of FVIII prophylaxis similarly trended towards increase in those with high activity risk (+$49270 [-$24698, $123237]). High levels of pre-index ABR was identified in 25/58 individuals with mean pre-index ABR of 8.2 (sd: 5.6). Individuals with high reported bleeding prior to PK-guidance were median 13 years (IQR: 8-20) of age at PK-guidance, with 88% having severe Hemophilia A. Significant decreases in ABR were observed after PK-guidance (-5.3 [95% CI: -7.2, -3.2]), driven by decrease in joint and traumatic bleeds. Significant increases in MWC (+18.11 IU/kg [7.0, 29.2]) and annualized cost (+$45783 [$17943, $73624]) of prophylaxis were observed in these individuals. Although quantity of FVIII used to treat breakthrough bleeds was not captured in this study, use of on-demand FVIII likely decreased with lower observed ABR. Conclusion Individuals with elevated bleeding levels are prime candidates for PK-guided dosing, with significantly lower bleeding rates observed after PK-guided dosing, leading to improved quality of life and decreased risks of joint degeneration. While sample was limited, individuals with high activity risk appear to benefit from PK-assessment as well, to attain increased bleed protection during recreational activities in spite of inherent risks.

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

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

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

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

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

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