BACKGROUND: Factor VIII inhibitors are measured using labour and resource expensive Nijmegen or Bethesda assays, which lack sensitivity for low-titre-inhibitors, and show high variations in quality surveys, mainly because of manual assay procedures.
METHODS: A new rapid, fully automated, factor VIII inhibitor assay is presented, the core of which is use of full-length recombinant FVIII (rFVIII) (Kovaltry®) as inhibitor substrate instead of plasma FVIII, resulting in rapid binding of inhibitors to rFVIII due to absence of VWF. Dramatic shortening of incubation time facilitated full automation on an analyser capable of three subsequent sample dilution steps and three reagent additions. Equal volume mixtures of sample and rFVIII (1.0 U/mL) were incubated 10 minutes/37°C, whereafter remaining FVIII-activity was analysed with a kinetic chromogenic assay, allowing inhibitor-activity calculation without preceding FVIII-activity calibration, using a Ceveron s100 analyser.
RESULTS: Mean titre in 60 non-haemophiliacs was 0.0BU/mL (SD 0.1), yielding a Limit-of-Blank of 0.1BU/mL and Lower-Limit-of-Quantification of 0.2BU/mL. Analyses were performed with the new method and a Nijmegen Assay in 28 inhibitor-positive clinical samples, 14 containing emicizumab and 14 without. Correlation coefficient in emicizumab-free type-I-inhibitor samples was r=1.0. Emicizumab dependency of the method was excluded in spiking experiments with inhibitor-positive-samples. Reproducibility was tested by analysing seven samples in three laboratories on five days, twice daily; CV of all samples were <15%.
CONCLUSIONS: We present development data of a sensitive and specific, rapid, automated FVIII inhibitor assay generating results within 20 minutes, is less resource intensive than standard assays, with potential to improve assay variability.

BACKGROUND: As a result of centralisation of haemophilia care to a limited number of intramural settings, many persons with haemophilia have to travel long distances to attend their haemophilia specialised treatment centre. However, regular physiotherapy treatment can be provided by primary care physiotherapists in the person\'s own region. Due to the rarity of the disease most primary care physiotherapists have limited experience with this population. This study aims to provide a clinical practice guideline for primary care physiotherapists working with persons with bleeding disorders.
METHODS: A list of the most urgent key-questions was derived from a previous study. Literature was summarised using the grading of recommendations assessment, development, and evaluation (GRADE) evidence-to-decision framework. Recommendations were drafted based on four 90 min consensus meetings with expert physiotherapists. Recommendations were finalised after feedback and >80% consensus of all stakeholders (including PWH, physiotherapists, haematologists and the corresponding societies).
RESULTS: A list of 82 recommendations was formulated to support primary care physiotherapists when treating a person with a bleeding disorder. These recommendations could be divided into 13 categories: two including recommendations on organisation of care, six on therapy for adult patients with bleeding disorders and five on therapy adaptations for paediatric care. Therapy recommendations included treatment after a joint- or muscle bleed, haemophilic arthropathy, chronic synovitis, non-haemophilia related conditions and orthopaedic surgery.
CONCLUSIONS: An evidence-based practice guideline, based on current evidence from literature and clinical expertise, has been developed for primary care physiotherapists treating a person with haemophilia. To improve care, the recommendations should be implemented in daily practice.

BACKGROUND: Valoctocogene roxaparvovec is an adeno-associated virus vector serotype 5 (AAV5)-mediated gene therapy approved for severe haemophilia A (HA).
OBJECTIVE: To report the safety and efficacy of valoctocogene roxaparvovec 7 years after dosing in a phase 1/2 clinical study (NCT02576795).
METHODS: Males ≥18 years with severe HA (factor VIII [FVIII] ≤1 international unit [IU]/dL) who were previously receiving exogenous FVIII and had no history of FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec treatment and were followed for 7 (6 × 1013 vg/kg; n = 7) and 6 (4 × 1013 vg/kg; n = 6) years.
RESULTS: In the last year, one participant in each cohort reported treatment-related adverse events (AEs): grade 1 (G1) hepatomegaly (6 × 1013), and G1 splenomegaly and G1 hepatic steatosis (4 × 1013). During all follow-up, mean annualized treated bleeds and exogenous FVIII infusion rates were ≥88% lower than baseline values. At years 7 and 6, mean (median) FVIII activity (chromogenic assay) was 16.2 (10.3) and 6.7 (7.2) IU/dL in the 6 × 1013 (n = 5) and 4 × 1013 (n = 4) cohorts, respectively, corresponding to mild haemophilia. Regression analyses of the last year estimated rate of change in FVIII activity was -0.001 and -0.07 IU/dL/week for the 6 × 1013 and 4 × 1013 cohorts, respectively. Two participants (6 × 1013) resumed prophylaxis in year 7: one after a non-treatment-related G4 serious AE of spontaneous internal carotid artery bleed, and the other to manage bleeds and FVIII activity.
CONCLUSIONS: The safety and efficacy of valoctocogene roxaparvovec remain generally consistent with previous reports, with good haemostatic control for most participants. Two participants returned to prophylaxis.

Pseudotumours are uncommon complications of haemophilia, occurring in 1%-2% of patients with haemophilia.1 , 2 It is a slowly expanding haematoma as a result of recurrent haemorrhage, surrounded by a fibrous capsule. It can occur in both bone and soft tissue, and progressive enlargement may result in bone destruction and/or muscle and skin necrosis. Pseudotumours by themselves are usually painless though its mass effect can result in nerve compression resulting in pain or neurologic symptoms. It may also predispose to pathologic fractures (as in our case) and superimposed infections.2 , 3.

Haemophilia presents a significant challenge to the quality of life of affected individuals. Evaluating the health-related quality of life (HRQoL) of people with haemophilia (PwH) provides a valuable mean of assessing their perception of overall care outcomes, while also identifying influential factors across various age and condition severity demographics. This observational retrospective study determined the HRQoL of 100 adult PwH in Northern Greece through comprehensive analysis and interpretation of their HRQoL levels, particularly in domains concerning their physical, emotional, and mental well-being, obtained through the Haem-A-QoL index questionnaire. Disease severity and young age were significantly associated with the administration of prophylactic treatment (84.2% of patients with severe haemophilia and 65.2% of patients aged 18-30). The mean Haem-A-QoL score was 40.11 ± 17.38, with the lowest HRQoL observed in the 46-60 age group (46.16), and the highest in the ≥61 age groups (35.16). Notably, the \'Sports/Leisure\' and \'Physical Health\' domains exhibited the highest scores, in contrast to \'Family Planning\' and \'Relationships/Sexuality\'. Individuals with mild haemophilia recorded the lowest mean score (39.38), while those with a severe condition exhibited the highest (41.23). Age, disease severity, and physical activity emerged as primary determinants significantly affecting HRQoL outcomes.

BACKGROUND: Non-factor replacement therapies are emerging as prophylactic treatment options in haemophilia A or B (HA/HB) with and without inhibitors. Concizumab is an anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody preventing factor (F)Xa inhibition and enhancing thrombin generation. Based on experience with other non-factor therapies and extended half-life products, there is a focus on potential interference with common clinical coagulation assays used to monitor patients treated with concizumab.
OBJECTIVE: To evaluate the impact of concizumab on standard clinical coagulation assays.
METHODS: Plasma samples (normal, HA/HB with/without inhibitors) in the presence/absence of added concizumab (250-16,000 ng/mL) were analysed in clinical assays including activated partial thromboplastin time (aPTT), prothrombin time (PT), FVIII and FIX one-stage clot and chromogenic substrate assay, assays for detecting FVIII or FIX inhibitors and other assays for coagulation factors.
RESULTS: Concizumab did not impact PT assays, but resulted in a small shortening of aPTT (up to 5 s in haemophilia plasma and 0.4 s in normal plasma). Concizumab had no, or only a minor impact on FVIII and FIX activity assays or Bethesda inhibitor assays. FXI and FXII activity in normal plasma, as measured by single factor aPTT-based assay, was significantly increased in the presence of concizumab (+11% each). This was also the case for FVII and FX measured by PT-based assays using plasma with 25% of FVII or FX (+64% and +22%, respectively).
CONCLUSIONS: The presence of concizumab did not, or only slightly, influence the outcome of standard clinical coagulation assays relevant for HA and HB.

OBJECTIVE: To evaluate whether patients with haemophilia (PwH) can be enabled to perform ultrasonography (US) of their knees without supervision according to the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) protocol and whether they would be able to recognize pathologies.
METHODS: Five PwH (mean age 29.6 years, range 20-48 years) were taught the use of a portable US device and the HEAD-US protocol. Subsequently, the patients performed US unsupervised at home three times a week for a total of 6 weeks with a reteaching after 2 weeks. All images were checked for mapping of the landmarks defined in the HEAD-US protocol by a radiologist. In a final test after the completion of the self-sonography period, participants were asked to identify scanning plane and potential pathology from US images of other PwH.
RESULTS: On the images of the self-performed scans, 82.7% of the possible anatomic landmarks could be identified and 67.5% of the requested images were unobjectionable, depicting 100% of the required landmarks. There was a highly significant improvement in image quality following reteaching after 2 weeks (74.80 ± 36.88% vs. 88.31 ± 19.87%, p < .001). In the final test, the participants identified the right scanning plane in 85.0% and they correctly identified pathology in 90.0% of images.
CONCLUSIONS: Appropriately trained PwH can perform the HEAD-US protocol of their knee with high quality and are capable to identify pathologic findings on these standardized images. Asynchronous tele-sonography could enable early therapy adjustment and thereby possibly reduce costs.

BACKGROUND: The objectives were to describe the peri-operative management of people with inherited bleeding disorders in oral surgery and to investigate the association between type of surgery and risk of developing bleeding complications.
METHODS: This retrospective observational study included patients with haemophilia A or B, von Willebrand disease, Glanzmann thrombasthenia or isolated coagulation factor deficiency such as afibrinogenemia who underwent osseous (third molar extraction, ortho-surgical traction, dental implant placement) or nonosseous oral surgery between 2014 and 2021 at Bordeaux University Hospital (France). Patients and oral surgery characteristics were retrieved from medical records. Odds ratio (OR) and 95% confidence interval (CI) were estimated using logistic regression.
RESULTS: Of the 83 patients included, general anaesthesia was performed in 16%. Twelve had a bleeding complication (14.5%) including six after osseous surgery. The most serious complication was the appearance of anti-FVIII inhibitor in a patient with moderate haemophilia A. All bleeding complications were managed by a local treatment and factor injections where indicated. No association was observed between type of surgery (osseous vs. nonosseous) and risk of bleeding complications after controlling for sex, age, disease type and severity, multiple extractions, type of anaesthesia and use of fibrin glue (OR: 3.21, 95% CI: .69-14.88).
CONCLUSIONS: In this study, we have observed that bleeding complications after oral surgery in people with inherited bleeding disorders were moderately frequent and easily managed. However, in this study, we observed a serious complication highlighting the necessity of a thorough benefit-risk balance evaluation during the preoperative planning of the surgical and medical protocol.

暂无摘要。

BACKGROUND: Cardiovascular diseases (CVD) that require long-term anticoagulant and antiplatelet therapy presents a problem in people with haemophilia (PWH) who receive factor replacement therapy to reduce bleeding risk. Currently, there are no Japanese guidelines for the management of PWH with CVD.
OBJECTIVE: To develop expert guidance on managing CVD in PWH in Japan.
METHODS: A steering committee of four experts (two haemophilia specialists, one thrombosis specialist, one cardiologist) identified 44 statements related to five key themes. An online questionnaire was produced comprising a mix of 4-point Likert scale and multiple-choice questions that was sent to specialists in the management of PWH with CVD in Japan. Consensus was defined as high or very high if a respective ≥75% or ≥90% of respondents agreed with a statement.
RESULTS: Of 16 potential respondents, responses were received from 15 specialists. Of the Likert scale questions, 71% (29/41) achieved ≥90% agreement (very strong agreement), 17% (7/41) achieved 75%-89% agreement (strong agreement) and 15% (6/41) did not achieve consensus agreement. The three multiple-choice questions failed to identify a strong preference. Agreement on specific target trough clotting factor levels for managing certain clinical situations, such as when in the presence of non-valvular atrial fibrillation or myocardial infarction, was also achieved.
CONCLUSIONS: The results of this consensus study provide a framework for cardiologists and haematologists to manage PWH who are at risk of, or who have, CVD. Implementation of the recommendations provided herein may improve outcomes for PWH with CVD.