Emicizumab prophylaxis in people with hemophilia A and inhibitors: a systematic review and meta-analysis.

BACKGROUND: Until recently, the treatment of people with hemophilia A and inhibitors (PwHAi) was based on the use of bypassing agents (BPA). However, the advent of emicizumab as prophylaxis has demonstrated promising results. OBJECTIVES: We aimed to compare the bleeding endpoints between PwHAi on BPA and those on emicizumab prophylaxis. DESIGN AND SETTING: Systematic review of interventions and meta-analysis conducted at the Universidade Federal de Goiás, Goiânia, Goiás, Brazil. METHODS: The CENTRAL, MEDLINE, Scopus, and LILACS databases were searched on February 21, 2023. Two authors conducted the literature search, publication selection, and data extraction. The selected publications evaluated the bleeding endpoints between PwHAi on emicizumab prophylaxis and those on BPA prophylaxis. The risk of bias was evaluated according to the Joanna Briggs Institute criteria. A meta-analysis was performed to determine the annualized bleeding rate (ABR) for treated bleeds. RESULTS: Five publications (56 PwHAi) were selected from the 543 retrieved records. Overall, bleeding endpoints were lower during emicizumab prophylaxis than during BPA prophylaxis. All the publications had at least one risk of bias. The only common parameter for the meta-analysis was the ABR for treated bleeds. During emicizumab prophylaxis, the ABR for treated bleeds was lower than during BPA prophylaxis (standard mean difference: -1.58; 95% confidence interval -2.50, -0.66, P = 0.0008; I2 = 68.4%, P = 0.0031). CONCLUSION: Emicizumab was superior to BPA in bleeding prophylaxis in PwHAi. However, both the small population size and potential risk of bias should be considered when evaluating these results. SYSTEMATIC REVIEW REGISTRATION: CRD42021278726, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=278726.

Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.

Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important.

[Methodological recommendations for surgical care in patients with hemophilia A receiving prophylactic therapy with emicizumab]. / Metodicheskie rekomendatsii po okazaniyu khirurgicheskoi pomoshchi u patsientov s gemofiliei A, poluchayushchikh profilakticheskuyu terapiyu emitsizumabom.

Methodological recommendations for surgical care in patients with hemophilia A receiving prophylactic therapy with emicizumab. Recommendations of the expert group. Moscow, 2024.

Structural alterations and pain perception at the ankle joint in patients with haemophilia.

BACKGROUND: Patients with haemophilia (PwH) suffer from chronic pain due to joint alterations induced by recurring haemorrhage. OBJECTIVES: This study aimed to investigate the relationship between structural alterations and pain perception at the ankle joint in PwH. PATIENTS/METHODS: Ankle joints of 79 PwH and 57 healthy controls (Con) underwent ultrasound examination (US) and assessment of pain sensitivity via pressure pain thresholds (PPT). US discriminated between joint activity (synovitis) and joint damage (cartilage and/or bone degeneration) applying the HEAD-US protocol. Based on US-findings, five subgroups were built: PwH with activity/damage, PwH with activity/no damage, PwH with no activity/no damage, controls with activity/no damage and controls with no activity/no damage. RESULTS: Joint activity and joint damage were significantly increased in ankles of PwH compared to Con (p ≤.001). Subgroup analysis revealed that structural alterations negatively impact pain perception. This is particularly evident when comparing PwH with both activity/damage to PwH with no activity/no damage at the tibiotalar joint (p = .001). At the fibulotalar joint, no significant differences were observed between PwH subgroups. Further analysis showed that both joint activity and joint damage result in an increase in pain sensitivity (p ≤.001). CONCLUSION: The data suggest a relation between joint activity, joint damage and pain perception in PwH. Even minor changes due to synovitis appear to affect pain perception, with the effect not intensifying at higher levels of inflammation. In terms of joint damage, severe degeneration leads to a sensitised pain state most robustly, whereas initial changes do not seem to significantly affect pain perception.

Chain-mediating effects of kinesiophobia and self-efficacy on pain catastrophizing and physical activity in haemophilia patients.

BACKGROUND: There is a lack of research on the relationship between pain catastrophizing, kinesiophobia, and physical activity (PA) in people with haemophilia (PWH), and the underlying mechanisms connecting these variables remain unclear. AIM: The study's aim was to clarify the roles of kinesiophobia and self-efficacy in the relationship between pain catastrophizing and PA in PWH. METHODS: This cross-sectional study included adult PWH at the Haemophilia Centre of a Tertiary hospital in Beijing, China. The following questionnaires were used to collect data: the general information, the International Physical Activity Short Questionnaire, the Pain Catastrophizing Scale, the Tampa Scale of Kinesiophobia Scale, and the Exercise Self-Efficacy Scale. RESULTS: The study included a total of 187 PWH, including 154 having haemophilia A and 33 having haemophilia B. The median interquartile range of PA was 594 (198, 1554) MET-min/wk. There were significant differences in PA of patients based on age stage, treatment modality, highest pain score within the last seven days, and presence of haemophilic arthropathy (p < .05). It was showed that pain catastrophizing could directly predict PA (p < .001), accounting for 38.13% of the total effect. Pain catastrophizing also had indirect effects on PA through the mediating factors of kinesiophobia or self-efficacy, and through the chain-mediating effect of kinesiophobia and self-efficacy, accounting for 38.40%, 17.07%, and 6.40%, respectively. CONCLUSION: The study discovered that PWH have limited PA due to pain catastrophizing. This not only directly affects their activity but also indirectly influences it through kinesiophobia and self-efficacy.

Relationship between plasma tissue Factor Pathway Inhibitor (TFPI) levels, thrombin generation and clinical risk of bleeding in patients with severe haemophilia A or B.

INTRODUCTION: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. AIM: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. METHODS: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT). RESULTS: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. CONCLUSION: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.

Incidence of deep venous thrombosis in patients with hemophilia undergoing bilateral simultaneous total knee arthroplasty: a retrospective cohort study.

BACKGROUND: Hemophilic arthropathy usually affects the knees bilaterally. In order to reduce costs and improve rehabilitation, bilateral simultaneous total knee arthroplasty (TKA) can be performed. However, pharmacological prophylaxis for deep venous thrombosis (DVT) remains controversial in patients with severe hemophilia. The purpose of this study was to establish the incidence of DVT in severe hemophilia A patients undergoing bilateral simultaneous TKA without pharmacological thromboprophylaxis. METHODS: Consecutive patients with severe hemophilia A undergoing bilateral simultaneous TKA at a single center between January 2015 and December 2020 were retrospectively reviewed. All patients received a modified coagulation factor substitution regimen. Tranexamic acid (TXA) was used for hemostasis in all patients during surgery. All patients followed a standardized postoperative protocol with routine mechanical thromboprophylaxis, and none received anticoagulation. D-dimer was measured preoperatively, on the day of the operation and on postoperative days 1, 7 and 14. Ultrasound (US) of the lower extremities was performed before (within 3 days of hospitalization) and after surgery (days 3 and 14) to detect asymptomatic DVT. Patients were followed up until 2 years after surgery for the development of symptomatic DVT or pulmonary embolism (PE). RESULTS: 38 male patients with severe hemophilia A underwent 76 simultaneous TKAs. Mean (± standard deviation) age at the time of operation was 41.7 (± 17.1) years. Overall, 47.3% of patients had D-dimer concentrations above the threshold 10 µg/mL on day 7 and 39.5% on day 14. However, none of the patients had DVT detected on postoperative US, nor developed symptomatic DVT or PE during the 2-year follow-up. CONCLUSIONS: The risk of DVT in patients with severe hemophilia A after bilateral simultaneous TKA is relatively low, and routine pharmacological thromboprophylaxis may not be needed.

Assessment of jaw bone mineral density, resorption rates, and oral health in patients with severe hemophilia: a case-control study.

OBJECTIVE: Knowledge about oral hygiene, gingival bleeding, mineral density, and resorption of jaw bones in patients with hemophilia is limited. We evaluated the periodontal and bone status in such patients.  Material and methods: Forty-eight patients with severe type A/B hemophilia and 49 age- and sex-matched controls were included. Assessments included simplified oral hygiene index (OHI-S), calculus index, debris index, gingival index (GI), gingival bleeding time index (GBTI), and decayed, missing, and filled teeth index (DMFTI). Bone resorption was evaluated using panoramic mandibular index (PMI), mental index (MI), and alveolar crest ratio (ACR). Mineral density in the condyle, angulus, and premolar areas was assessed using fractal analysis, with fractal dimensions denoted as condyle fractal dimension (CFD) for the condyle, angulus fractal dimension (AFD) for angulus, and premolar fractal dimension (PFD) for premolar region. RESULTS: The mean scores were DMFTI = 11.77, OHI-S = 2.44, PMI = 0.268, MI = 5.822, GI = 3.02, GBTI = 2.64, ACR = 2.06, CFD = 1.31, AFD = 1.31, and PFD = 1.17 in the hemophilia group and DMFTI = 11.449, PMI = 0.494, MI = 7.43, GI = 0.67, GBTI = 0.98, OHI-S = 1.45, ACR = 2.87, CFD = 1.35, AFD = 1.35, and PDF = 1.23 in the control group. Differences were significant for all parameters (p < 0.005) except for the DMFTI index.  Conclusions: Because of poor oral hygiene, high bone resorption, and low bone mineral density in these patients, clinicians should consider potential bone changes when planning to treat these patients.

Paradox pain sensitivity using cuff pressure or algometer testing in patients with hemophilia.

INTRODUCTION: Pain is a common comorbidity in patients with hemophilia (PwH) due to hemophilic arthropathy. This study aims to explore pain sensitivity in PwH methodologically investigating in cuff pressure testing compared to algometer testing. METHODS: 37 PwH and 35 healthy control subjects (Con) enrolled in this study. Joint health status was assessed. Subjective pain was evaluated using numeric rating scales. Pain sensitivity was measured with pressure algometry and cuff pressure algometry. Pressure pain thresholds of the algometer (PPTa) were measured at knee, ankle joints, and forehead. Subsequently, thresholds of cuff pressure were measured at the left and right lower legs (PPTcuff). In both, lower values represent higher pain sensitivity. RESULTS: PwH exerted a worse joint health status than Con. Pain sensitivity was higher in PwH compared to Con as PPTa of the knee and ankle joints were lower in PwH. No difference was observed in PPTa at the forehead. Contrastingly, lower pain sensitivity was detected in PwH by higher PPTcuff values compared to Con in both legs. CONCLUSION: While PPTa of the knee and ankle joints are lower in PwH, PPTcuff are higher in PwH compared to Con. This reveals a paradox situation, highlighting that PwH experience local, joint- and hemophilic arthropathy-related pain, whereas pain sensitivity of non-affected soft tissue structures is lower. The reasons explaining the PPTcuff results remain elusive but might be explained by coping strategies counteracting chronic joint pain, resulting in lower sensitivity at non-affected structures.

Safety and tolerability of OP-724 in patients with haemophilia and liver cirrhosis due to HIV/HCV coinfection: an investigator-initiated, open-label, non-randomised, single-centre, phase I study.

OBJECTIVE: Patients with haemophilia and HIV who acquire hepatitis C virus (HCV) after receiving contaminated blood products can experience accelerated progression of liver fibrosis and a poor prognosis, making liver disease a prominent cause of mortality among these patients. In the current study, we aimed to evaluate the safety and tolerability of the potential antifibrotic agent OP-724-a CREB-binding protein/ß-catenin inhibitor-in this patient subset. DESIGN: In this single-centre, open-label, non-randomised, phase I trial, we sequentially enrolled patients with cirrhosis following HIV/HCV coinfection classified as Child-Pugh (CP) class A or B. Five patients received an intravenous infusion of OP-724 at doses of 140 or 280 mg/m2 for 4 hours two times weekly over 12 weeks. The primary endpoint was the incidence of serious adverse events (SAEs). Secondary endpoints included the incidence of AEs and improved liver stiffness measure (LSM), as determined by vibration-controlled transient elastography. This study was registered at ClinicalTrials.gov (NCT04688034). RESULTS: Between 9 February 2021 and 5 July 2022, five patients (median age: 51 years) were enrolled. All five patients completed 12 cycles of treatment. SAEs were not observed. The most common AEs were fever (60%) and gastrointestinal symptoms (diarrhoea: 20%, enterocolitis: 20%). Improvements in LSM and serum albumin levels were also observed. CONCLUSION: In this preliminary assessment, intravenous administration of 140 or 280 mg/m2/4 hours OP-724 over 12 weeks was well tolerated by patients with haemophilia combined with cirrhosis due to HIV/HCV coinfection. Hence, the antifibrotic effects of OP-724 warrant further assessment in patients with cirrhosis. TRIAL REGISTRATION NUMBER: NCT04688034.

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

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

Acquired bleeding disorders.

Acquired bleeding disorders can develop in previously healthy people irrespective of age or gender but are particularly common in patients with certain underlying conditions. Here, we review recent advances in the management of acquired haemophilia A (AHA), acquired von Willebrand syndrome (AVWS), and patients with hemostatic abnormalities due to chronic liver disease (CLD). Patients with AHA can now benefit from prophylaxis with emicizumab, a therapeutic antibody that mimics the function of activated coagulation factor VIII. The treatment of AVWS remains challenging in many situations and requires careful consideration of the underlying condition. Haemostatic abnormalities in CLD are often compensated by proportional reduction in pro and anti-haemostatic factors resulting in sustained or even increased thrombin generation. Consequently, bleeding in CLD is rarely caused by haemostatic failure and infusion of plasma or coagulation factor concentrates may not be effective.

Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.

Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.

Women and girls with inherited bleeding disorders: Focus on haemophilia carriers and heavy menstrual bleeding.

Raising awareness and improving recognition, accurate classification, and enhanced access to new treatments represent current key challenges for carriers of haemophilia. Women and girls carrying genes for haemophilia often experience significant bleeding and/or low factor levels. The bleeding associated with female haemophilia is frequently overlooked, has a weak correlation with factor levels, and manifests differently than in males, with heavy menstrual bleeding being a predominant symptom. Recent changes in terminology now allow the diagnosis of haemophilia in females with low factor levels and differentiate between symptomatic and asymptomatic carriers of the gene. Observations from real-world experiences and limited clinical trial data have highlighted the positive impact of various new haemophilia treatments for women and girls with clotting factor deficiencies. There is an urgent need for initiatives that increase their access to these treatments and encourage well-designed clinical trials focusing on female-specific outcomes. In women with inherited bleeding disorders, early recognition and optimal management of heavy menstrual bleeding are crucial. However, treatment options and guidance from high-quality clinical trials are currently insufficient. Menstrual health assessment should be a regular part of monitoring women and girls with inherited bleeding disorders throughout their lives, emphasizing the importance of gathering data to improve future management.

Challenges in ageing persons with haemophilia.

As treatments for individuals with inherited bleeding disorders improve, life expectancy increases and is approaching that of the normal population. Concomitant with this we are now seeing the problems of ageing in the bleeding disorder population. Although the clear-cut association between low clotting factor levels and risk of bleeding is well recognised, a relationship between high levels, some non-factor therapies and thrombotic risk also exists. The management of thrombosis in persons with inherited bleeding disorders is complex but manageable with modern treatments and collaboration in decision making between health care professionals and patients. Despite the improvements in treatment and reduction in bleeding, mostly musculoskeletal pain continues to be a major issue with advancing age. The management of pain amongst older people with haemophilia who may have multiple comorbidities should involve a person-centred, holistic, multi-disciplinary approach to support and optimise long-term physical functioning and overall quality of life.

Test-retest reliability of a mobile application of the patient reported outcomes burdens and experiences (PROBE) study.

INTRODUCTION: The Patient Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a patient-reported outcome tool that assesses quality of life and disease burden in people with haemophilia (PWH). AIM: To assesses the test-retest reliability of PROBE when completed using the mobile phone application. METHODS: We recruited PWH, including carriers, and individuals with no bleeding disorders who attended haemophilia-related workshops or via social media. Participants completed PROBE three times (twice on the app: T1 and T2, and once on the web, T3). Test-retest reliability was analysed for T1 versus T2 (app to app, time period one) and T2 versus T3 (app to web, time period two). RESULTS: We enrolled 48 participants (median age = 56 [range 27-78] years). Eighteen participants (37.5%) were PWH and seven (14.6%) were carriers. On general health domain questions, we found almost perfect agreement, except for a question on the frequency of use of pain medication in the last 12 months [Kappa coefficient (κ) .72 and .37 for time period one and two, respectively] and any use of pain medications (κ .75) for time period two. For haemophilia-related questions, we found substantial to perfect agreement, except for the questions on the number of joint bleeds in the previous 6 months for time period one (κ .49) and the number of bleeds in the previous two weeks for time period two (κ .34). CONCLUSIONS: The results demonstrate the reliability of the PROBE app. The app can be used interchangeably with the paper and web platforms for PROBE administration.