Search

Abstract Apoptotic vesicles (apoVs) are apoptotic cell‐derived nanosized vesicles that play a crucial role in multiple pathophysiological settings. However, their detailed characteristics, specific surface markers, and biological properties are not fully elucidated. In this study, we compared mesenchymal stem cell (MSC)‐derived apoVs and exosomes from three different types of MSCs including human bone marrow MSCs (hBMSCs), human adipose MSCs (hASCs), and mouse bone marrow MSCs (mBMSCs). We established a unique protein map of MSC‐derived apoVs and identified the differences between apoVs and exosomes in terms of functional protein cargo and surface markers. Furthermore, we identified 13 proteins specifically enriched in apoVs compared to exosomes, which can be used as apoV‐specific biomarkers. In addition, we showed that apoVs inherited apoptotic imprints such as Fas to ameliorate haemophilia A in factor VIII knockout mice via binding to the platelets’ FasL to activate platelet functions, and therefore rescuing the blood clotting disorder. In summary, we systemically characterized MSC‐derived apoVs and identified their therapeutic role in haemophilia A treatment through a previously unknown Fas/FasL linkage mechanism.

Poor management of either type 1 diabetes or haemophilia A can lead to complications such as organ dysfunction and haemarthropathy. Here, we describe the case of an 8-year-old boy diagnosed with severe haemophilia A shortly after birth. At 2 years old, he was also diagnosed with type 1 diabetes. After six years, the haemophilia treatment was changed from a plasma-derived factor VIII (FVIII) concentrate (octanate®, Octapharma, Lachen, Switzerland) to Nuwiq® (simocotocog alfa, Octapharma, Lachen, Switzerland), a recombinant FVIII (rFVIII) product from a human cell line, which allowed for a personalised treatment schedule that supported good adherence. The dosing regimen could be reduced to two weekly rFVIII infusions. The patient has experienced no spontaneous bleeds since switching to rFVIII and shows no signs of joint damage after over seven years of FVIII prophylaxis. rFVIII was well tolerated, with no treatment-related adverse events observed. This case illustrates the importance of treatment personalisation for young patients and their families managing concomitant diseases.

Acquired haemophilia A (AHA) is a rare severe bleeding disorder resulting from the production of autoantibodies directed against coagulation factor VIII. At presentation, bleeding events can be severe, and an early diagnosis and treatment are of major importance. The current study aims to analyse the treated patients who have been diagnosed with AHA for a better understanding of our population and treatment outcome. We conducted a retrospective study with 26 patients who had been diagnosed with AHA and who were treated in our hospital between January 2006 and January 2021. The patients ranged in age from 30 to 85 years old: 46.10% were men, 46.10% had no known underlying condition, 27% had an underlying malignancy, 7.60% presented with other diseases: psoriatic arthritis and Paget's disease, and 19.30% presented with AHA during puerperium. All of the patients had bleeding events and were treated with bypass agents for this as well as with immunosuppressive therapy to eradicate the inhibitor. A total of 53.80% of the patients had major bleeding. Sixty-nine percent of the patients achieved complete remission, but 26.90% died during the follow-up, although bleeding was not the cause of death in any of these cases. Our observations underline the importance of clinical suspicion and early referral to centres with experience and laboratory facilities for managing AHA. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a bispecific monoclonal antibody developed to address the unmet needs of clotting factor replacement therapy and has become the benchmark for optimal prophylaxis in managing patients with haemophilia A with inhibitors. We describe the emicizumab rollout and pharmacokinetic strategies and their use in paediatric patients. Methods: The evolving real‐world experience in using emicizumab has confirmed its safety, efficacy and pharmacokinetic profile in paediatric, adolescent and adult patients receiving emicizumab at various prophylactic dosing regimens. The emicizumab current global rollout includes over 100 countries with 29 low to middle‐income countries accessing emicizumab through the World Federation of Haemophilia (WFH) Humanitarian Aid Program. The diversity of emicizumab dosing and pharmacokinetic tools such as the Calibra® and the WAPPS‐Hemo platforms make it possible to achieve prophylaxis goals in line with the WFH Haemophilia treatment guidelines recommendations, with minimal drug wastage. The emerging experience from long term clinical trials and long‐term real‐world follow‐up confirm the safety, efficacy, and pharmacokinetic profile of emicizumab in paediatric haemophilia A patients. A few questions, including inhibitor recurrence, concurrent use of emicizumab with various replacement therapies and inhibitor eradication, are being addressed through multiple ongoing clinical studies. Conclusion: The current global rollout of emicizumab is remarkable, and versatile dosing regimens and evolving pharmacokinetic tools such as the Calibra® and WAPPS‐Hemo platforms make it a treatment choice available also for pharmacokinetic guided personalised treatment. Data from paediatric studies are consistent with those seen in adolescent and adult Haemophilia A. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia A (HA) is an x‐linked recessive disease due to deficiency of coagulation factor VIII (FVIII). The development of neutralizing antibodies (inhibitors) against infused FVIII is a major concern. B cell activating factor (BAFF) has been implicated in several autoimmune diseases. Aim: We aimed to evaluate the possible association of BAFF rs9514828 gene polymorphism and the risk of the development of FVIII inhibitor in children with severe HA. Methods: This cohort study was carried out on 100 newly diagnosed boys with severe HA who were never treated before with FVIII concentrate. Assessment of serum levels of BAFF and BAFF rs9514828 genotyping at first diagnosis was performed and the patients were followed up for the completion of a total of 50 exposure days or the development of inhibitors whichever occurred first. The patients were divided as positive or negative according to the presence or absence of inhibitors. Results: The risk allele for BAFF rs9514828 (T) was significantly more frequent in the inhibitor positive patients than the inhibitor negative patients (P =.003). In addition, CT+TT genotypes were associated with increased risk of FVIII inhibitor development. Receiver operating characteristics (ROC) analysis showed that BAFF levels could predict the development of FVIII inhibitors at a cut‐off value of ≥.92 with a sensitivity of 85.9% and a specificity of 80.2%. Conclusion: BAFF rs9514828 gene polymorphism could be independent risk factor and elevated BAFF levels might be useful prognostic marker for the development of FVIII inhibitor in newly diagnosed children with severe HA. [ABSTRACT FROM AUTHOR]

Introduction: Muscular atrophy and overweightness develop arthropathy in persons with haemophilia (PWH), and exercise increases their muscle strength and decreases their body weight. Musculoskeletal ultrasonography may be a non‐invasive, safe, valid, and reliable tool to investigate muscle thickness (MT) and pennation angle (PA) after exercise training. Objectives: The present study was conducted to evaluate the effects of 6 weeks of resistance training (RT) and combined resistance and aerobic training (CT) on MT and PA in overweight persons with moderate haemophilia A. Materials and methods: Forty‐two persons with moderate haemophilia A with a mean age of 35–55 years and a BMI of 25–30 kg/m2 were randomly assigned to three groups of 14, namely RT, CT, and control. The RT group performed 40 minutes of RT, and the CT group performed 20 min of RT and 20 min of aerobic training. The PA and MT of the biceps brachii (BB), triceps brachii (TB), vastus medialis (VM), vastus lateralis (VL), and medial gastrocnemius (MG) were measured before and after the intervention using B‐mode ultrasonography. Results: Significant increases were observed in the MT of VM, VL, MG, BB, and TB and PA of VM, VL, and MG in the RT and CT groups compared to the control group (p <.001). No significant differences were observed between the intervention groups. Conclusion: Both RT and CT were effective in enhancing MT and PA in overweight persons with moderate haemophilia A. [ABSTRACT FROM AUTHOR]

rVIII-SingleChain is indicated for treatment and prophylaxis of bleeding in patients with haemophilia A (HA). The safety and efficacy of rVIII-SingleChain have previously been shown in the AFFINITY clinical trial programme. This survey evaluated clinical experience following a switch to rVIII-SingleChain from the perspective of both physicians and patients. A web-based survey (July–September 2019) involving 14 Haemophilia Treatment Centres (HTCs) collected data about HA patients who were under treatment with rVIII-SingleChain for ≥ 12 months, as reported by their physicians. In addition, about half of these patients were separately interviewed. Out of 91 patients receiving rVIII-SingleChain in the 14 participating HTCs, 48 had been treated for ≥ 12 months; among those 48, 38% were ≤ 18 years, 37% 19–40 years and 25 % ≥ 41 years; 73% of them had severe HA and 85% were being treated with prophylactic therapy. Twenty-six patients accepted to be separately interviewed: mean age was 30 years; 62% had severe HA and 85% were receiving prophylaxis. Focusing on those patients who were already in prophylaxis with prior FVIII (all but one with recombinant factors), infusion frequency was significantly reduced from 3–2 per week following the switch to rVIII-SingleChain (mean, 2.74 vs. 2.44, respectively; p=0.013), as reported by physicians; the rate of patients needing 3 infusions per week dropped from 74% with previous products to 44% with rFVIII-SingleChain. The annual mean factor consumption was 4740 IU/Kg (median, 4500 IU/Kg; min, 2.215 IU/Kg; max, 7.200 IU/Kg) with prior product and 4320 IU/Kg (median, 4320 IU/Kg; min, 2.215 IU/Kg; max, 6.646 IU/Kg) with rVIII-SingleChain. Both physicians and patients reported a significant reduction in annual total bleeding rates with rVIII-SingleChain compared with prior product (mean 2.15–0.96 and 2.46–0.71 events/year, p = 0.031 and p = 0.018, respectively). Mean satisfaction ratings (from 1; dissatisfied, to 5; very satisfied) for rVIII-SingleChain were quite high for both physicians (4.14, 86% satisfied/very satisfied) and patients (4.18, 86% satisfied/very satisfied). This survey suggested that switching to rVIII-SingleChain allowed patients to reduce their injection frequency without increasing factor consumption or compromising clinical results. Both physicians and patients reported a positive experience with rVIII-SingleChain after 1 year of treatment. [ABSTRACT FROM AUTHOR]

Background: Haemophilia bears substantial humanistic and economic burden on children and their caregivers. Characterising the differential impact of severe versus moderate paediatric haemophilia is important for clinical and health policy decisions. We analysed health-related quality of life (HRQoL), annual direct medical (excluding factor treatment costs), non-medical and societal costs among children and adolescents with moderate and severe haemophilia A or B without inhibitors from the European CHESS-PAEDs study. Information was reported by physicians and caregivers; patients aged ≥ 8 years self-reported their HRQoL. Descriptive statistics summarised demographic and clinical characteristics, costs, and HRQoL scores (EQ-5D-Y). Regression models estimated differences in HRQoL and costs for moderate versus severe haemophilia adjusting for age, body mass index z-score, country, number of comorbidities, and weight-adjusted annual clotting factor consumption.Results: The analytic sample comprised 794 patients with a mean age of 10.5 years; most had haemophilia A (79%) and 58% had severe haemophilia. Mean predicted direct medical costs in moderate patients were two-thirds of the predicted costs for severe disease (€3065 vs. €2047; p < 0.001; N = 794), while societal costs were more than half of the predicted costs for children with severe haemophilia (€6950 vs. €3666; p < 0.001; N = 220). Mean predicted HRQoL scores were 0.74 and 0.69 for moderate and severe disease, respectively (p < 0.05; N = 185).Conclusion: Children with haemophilia and their caregivers displayed a significant economic and humanistic burden. While severe patients showed the highest direct medical and societal costs, and worse HRQoL, the burden of moderate haemophilia on its own was substantial and far from negligible. [ABSTRACT FROM AUTHOR]

Background: The lifelong nature of haemophilia makes patient-centred and societal assessments of its impact important to clinical and policy decisions. Quantifying the humanistic and economic burden by severity is key to assessing the impact on healthcare systems. We analysed the annual direct medical (excluding factor replacement therapy costs) and non-medical costs as well as societal costs and health-related quality of life (HRQoL) of mild, moderate and severe disease among adults with haemophilia A or B without inhibitors in Europe. Participants in the CHESS II study reported their HRQoL, non-medical costs, and work impairment; physicians provided costs and consultation history from the medical chart. Descriptive statistics summarized patient characteristics, costs, and HRQoL scores. Regression models estimated differences in outcomes for moderate and severe versus mild disease, adjusting for age, body mass index, country, comorbidities, weight-adjusted factor consumption and education.Results: The analytic sample included 707 patients with a mean age of 38 years; the majority of patients had haemophilia A (81%), and 47% had severe disease, followed by moderate (37%) and mild disease (16%). Patients with severe or moderate disease had on average higher direct costs, €3105 and €2469 respectively, versus mild disease. Societal costs were higher for patients with severe and moderate disease by €11,115 and €2825, respectively (all P < 0.01). HRQoL scores were also significantly worse for severe and moderate patients versus those with mild disease.Conclusion: Severity of haemophilia is predictive of increasing economic and humanistic burden. The burden of moderate disease, as measured by direct costs and HRQoL, did not appear to be substantially different than that observed among patients with severe haemophilia. [ABSTRACT FROM AUTHOR]

Background: Gene therapy has the potential to change the life experience of people with haemophilia and family members. Few studies have sought to explore the impact of gene therapy on both individuals and families. The aim of this study was to capture real-life experiences of gene therapy in People with haemophilia and their families.Results: Sixteen participants with severe haemophilia (11 haemophilia A, five haemophilia B), mean age 41.4 years (range 23-75 years), took part in a single qualitative interview; ten were accompanied by a family member. Mean time since transfection was 3.56 years (range 1-10 years). Participants saw their involvement in gene therapy as a positive experience, freeing them from the personal burden of haemophilia and furthering treatment options for the wider haemophilia community. However, participants reported being unprepared for the side effects of immunosuppression. Some also reported feeling unsupported and having little control over what was happening as their factor levels became the focus of the process.Conclusion: The results suggest that strategies need to be put into place to enable PwH fully to understand the process of gene therapy, and thereby make an informed choice as to whether it is a treatment they might wish for themselves. These include early and ongoing education, increased provision of psychosocial support and ongoing qualitative research. [ABSTRACT FROM AUTHOR]

Introduction: The emergence of durable and potentially curative cell and gene therapies (also known as advanced therapy medicinal products) with high price tags is challenging conventional health care payment systems. Among these are gene therapies in various phases of development for haemophilia A and B. The emergence of these therapies comes with clinical and economic uncertainties for payers, providers, patients, and manufacturers. These include uncertainties about expression of the intended physiological response, patient outcomes, and duration of treatment effect, along with potentially high upfront costs, variable additional costs, and uncertainties about uptake of the therapy among indicated patient populations. These clinical and economic uncertainties raise interest among payers, providers, and manufacturers in risk‐sharing arrangements, including alternative payment models (APMs). Summary: APMs differ from traditional fee‐for‐service payment for health care. For example, some APMs are designed to reward clinicians and provider organizations for delivering high‐quality and cost‐effective care. The APMs described here, outcomes‐based models (or value‐ or performance‐based models) and finance‐based models, are designed to mitigate or otherwise manage financial risks associated with health care payment, including instances in which patient outcomes for costly therapies are uncertain. We examine how such APMs may be applicable in the context of emerging gene therapies for haemophilia A, including considerations in determining whether any particular APM may be most suitable. KEY POINTS OF CONSIDERATION: Gene therapies for haemophilia are among the emerging durable and potentially curative cell and gene therapies with high price tags that are challenging conventional payment systems.These therapies present clinical and economic uncertainties for payers, providers, patients, and manufacturers, including regarding expression of the intended physiological response, duration of treatment effect, patient outcomes, potentially high upfront costs and variable additional costs, and uptake among potentially indicated, diverse patient subgroups.These uncertainties raise interest among payers, manufacturers, and providers in risk‐sharing arrangements, including alternative payment models (APMs) such as various outcomes‐based and finance‐based models.This paper describes a taxonomy of APMs. Then, for the particular context of gene therapy for haemophilia A, we present a set of factors to be considered when determining whether an APM risk‐sharing arrangement may be appropriate for a given gene therapy, and, if so, which APM may be most suitable.[Correction added on 21 February 2022, after first online publication: the 'Key Points of Consideration' have been added in this version.] [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B. Methods: Subjects with haemophilia (n = 120) underwent bone‐density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high‐dose prophylaxis (n = 41) was compared to BMD in subjects with mild haemophilia (n = 33) and to severe haemophilia treated with intermediate‐dose prophylaxis (n = 32) or on‐demand replacement therapy (n = 14). Results: Subjects with severe haemophilia on high‐dose prophylaxis showed BMD at total hip comparable to subjects with mild haemophilia (median BMD 955.8 and 977.4 mg/cm2 (P =.17), respectively). No difference in BMD was found related to type of prophylactic regimen (median BMD 955.8 and 942.4 mg/cm2, in high‐dose and intermediate dose groups, respectively; P =.70). Subjects with severe disease treated on‐demand had significantly lower BMD compared to subjects on a high‐dose prophylactic regimen (median BMD 771.8 and 955.8 mg/cm2 (P =.001), respectively). BMD decreased significantly with age, regardless of severity of haemophilia disease. In a multivariate analysis, adjusted for disease status and age, type of prophylactic regimen was not significantly associated with osteoporosis development. Conclusion: We show that BMD differs in persons with severe haemophilia on propylaxis as compared to those treated on‐demand, but that type of prophylactic regimen does not reflect on BMD. The difference between treatment groups was mainly explained by an age difference between groups. However, patients on prophylaxis displayed a high degree of normal BMD not far from mild haemophilia at comparative age. [ABSTRACT FROM AUTHOR]

Introduction: Inhibitor development affects about 30% of patients with severe haemophilia A (HA) and results from different environmental and genetic risk factors. Previously, we identified the missense variant rs3754689 in the LCT gene linked with this predisposition. Since rs3754689 variant is benign and is located in a conserved haplotype region, we hypothesized that the association signal captured by this variant is located in coinherited, neighbouring genes. Aim: To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, DARS and miR128‐1 genes. Methods: Targeted sequencing was performed in 246 severe HA patients (72 with and 174 without inhibitor): 181 previously and 65 newly enrolled. Results: Forty‐one common and 152 rare variants passed the quality control. Logistic regression analysis of common variants identified rs3754689 and four additional variants (.011 < P <.047; FDR ranging.2‐.38). Logistic regression analysis performed only in the 220 Italian patients showed similar results (.004 < P <.05; FDR ranging.12‐.22). Three of these variants (rs3213892 and rs3816155 in the LCT intron 13 and rs961360 in the R3HDM1 intron10‐exon11 junction) may affect the expression of UBXN4 and R3HDM1, respectively. Rare variants did not show association with inhibitor development. Identified variants were not replicated in the multi‐ethnic SIPPET cohort of 230 severe HA patients. Conclusion: Due to the limited sample size that may be responsible of the high FDR values, we could not confirm with certainty the analysed association. Further evaluation of the expression levels of analysed genes will confirm or not their role in inhibitor development. [ABSTRACT FROM AUTHOR]

Introduction: The large interpatient variability in the pharmacokinetic (PK) parameters of recombinant Factor VIII (rFVIII) observed in haemophilia A hinders efficient and cost‐beneficial prophylactic regimen initiation. Identification of factors influencing the PK of rFVIII may shed more light on personalised treatment. Aim: This study aimed to develop a population PK model in the Taiwanese haemophilia A and evaluate the current national health insurance (NHI) reimbursement guidelines of Taiwan for haemophilia treatment. Methods: A population PK analysis was established based on 69 Taiwanese with moderate or severe haemophilia A. A nonlinear mixed‐effects modelling (NONMEM®) was used to estimate PK parameters and their variabilities. A Monte Carlo simulation was performed to evaluate different prophylactic regimens. Results: A two‐compartment model with first‐order elimination best described the rFVIII data. Weight‐based allometric scaling was related to clearance and central volume of distribution. Blood type and baseline von Willebrand factor (VWF) were significant covariates for clearance. For single dose simulations, a time achieving target level (> 1 IU/dL) was associated with increasing rFVIII dose and VWF level. The multiple dose simulations showed that > 96.4% of patients with high VWF level (> 200%) had predicted trough level > 1 IU/dL for all dosing regimens (15‐40 IU/kg, two to three times weekly). However, for twice weekly dosing, lower percentage (47.62‐62.20%) of patients with blood group O and low VWF level (< 50%) achieved a predicted trough level > 1 IU/dL. Conclusion: The population PK of rFVIII was successfully developed. Dose adjustment based on blood type and VWF level should be considered. [ABSTRACT FROM AUTHOR]

Introduction: The development of inhibitory antibodies is a severe complication of clotting factor replacement therapy in patients with severe haemophilia A (HA). Current World Federation of Hemophilia (WFH) guidelines for haemophilia care indicate that eradication of inhibitors is best achieved through immune tolerance induction (ITI) therapy. Aim: The European Collaborative Haemophilia Network conducted a survey to determine whether ITI is still used in the routine management of patients with HA, and whether the availability of emicizumab prophylaxis has influenced treatment decisions. Methods: The survey was conducted in late 2020/early 2021 in 18 centres representing 17 countries in the Europe/Middle East region treating a total of 4955 patients, and included sections specific to patient and centre demographics, treatment protocols (both ITI and prophylactic), inhibitor development and initiation of ITI, treatment success, and the incidence of adverse events. Results: While our results indicate that ITI can still be considered a mainstay of treatment for patients with HA with inhibitors, less than daily dosing of ITI in combination with emicizumab prophylaxis is becoming commonplace across the spectrum of disease severity, with initiation being guided by bleeding patterns. The most frequently cited reasons for not initiating emicizumab prophylaxis were availability or reimbursement issues. Conclusion: ITI remains a mainstay for haemophilia treatment of patients with HA with inhibitors, but emicizumab has become a preferred first‐line approach to protect against bleeds and represents an alternative to burdensome ITI in certain patient groups. [ABSTRACT FROM AUTHOR]

The bleeding risk in individuals with inherited bleeding disorders (IBDs) during exodontia is traditionally managed with perioperative coagulation factors and/or desmopressin, in conjunction with systemic and topical perioperative tranexamic acid and meticulous primary closure. Factor replacement is costly, requires specialist input, and carries a risk of developing factor VIII (FVIII) inhibitors. This prospective study was performed to determine whether the use of a standardized Floseal and anti-fibrinolytic protocol could reduce postoperative bleeding in patients with IBDs undergoing dental extraction, as compared to factor replacement. All patients >18 years old attending Queensland Haemophilia Centre between November 2014 and July 2019 who required dental extractions were referred to the Oral and Maxillofacial Unit. Patients were consented for intraoperative Floseal administration instead of factor replacement. All other operative measures remained the same. The bleed rate was assessed against a historical control cohort. There were 34 extraction events in 32 patients. Four of the patients reported postoperative bleeding requiring factor supplementation or desmopressin; the bleeding rate was 11.8%. While not statistically significant, this was a reduction in the bleed rate compared to the traditional protocol (P = 0.35). Third molar extractions were 10.33 times more likely to cause postoperative bleeding (P = 0.018). The Floseal protocol was equipotent to the traditional perioperative factor replacement protocol. Floseal use is more economical, eliminates the risk of peri-procedural FVIII inhibitor development, and provides a haemostatic option for patients with very rare factor deficiencies, pre-existing clotting factor inhibitors, and those with anaphylaxis to clotting concentrates. [ABSTRACT FROM AUTHOR]

Abstract Aim To identify the effect of enhanced recovery after surgery (ERAS) and rapid rehabilitation concepts on the outcomes of patients with haemophilia A undergoing total knee arthroplasty. Design Randomized controlled trial. Methods The primary endpoint was postoperative hospital stay. The secondary endpoints were pain scores, joint function scores, haemoglobin levels at 3 and 7 days after surgery and satisfaction with hospitalization. Results Thirty‐two patients were enrolled. Compared with the routine nursing group, the ERAS group showed shorter postoperative hospital stay (14.2 SD 0.8 vs. 16.6 ± 1.3 days, p

Coagulation factor replacement therapy for the X-linked bleeding disorder Haemophilia, characterized by a deficiency of coagulation protein factor VIII (FVIII), is severely complicated by antibody (inhibitors) formation. The development of FVIII inhibitors drastically alters the quality of life of the patients and is associated with a tremendous increase in morbidity as well as treatment costs. The ultimate goal of inhibitor control is antibody elimination. Immune tolerance induction (ITI) is the only clinically established approach for developing antigen-specific tolerance to FVIII. This work aims to establish a novel cost-effective strategy to produce FVIII molecules in fusion with cholera toxin B (CTB) subunit at the N terminus using the Bacillus subtilis expression system for oral tolerance, as the current clinical immune tolerance protocols are expensive. Regions of B-Domain Deleted (BDD)-FVIII that have potential epitopes were identified by employing Bepipred linear epitope prediction; 2 or more epitopes in each domain were combined and cDNA encoding these regions were fused with CTB and cloned in the Bacillus subtilis expression vector pHT43 and expression analysis was carried out. The expressed CTB-fused FVIII epitope domains showed strong binding affinity towards the CTB-receptor GM1 ganglioside. To conclude, Bacillus subtilis expressing FVIII molecules might be a promising candidate for exploring for the induction of oral immune tolerance., (© 2024. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Objectives: To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan., Methods: This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period., Results: The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69-10.38). The mean (SD) total consumption of turoctocog alfa ( n  = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis., Discussion: The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens., Conclusion: Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

The treatment of endocarditis in patients with haemophilia remains challenging and proper management should include a multidisciplinary team approach, appropriate hemostatic therapy, and careful postoperative monitoring. Catheter-related infections, children, endocarditis, factor VIII, haemophilia A, Staphylococcus aureus, central venous catheters Keywords: catheter-related infections; central venous catheters; children; endocarditis; factor VIII; haemophilia A; Staphylococcus aureus EN catheter-related infections central venous catheters children endocarditis factor VIII haemophilia A Staphylococcus aureus 367 369 3 01/27/23 20230101 NES 230101 INTRODUCTION Prophylaxis with factor VIII replacement is considered the standard of care for children with haemophilia A.[1] Venous access is critical for regular prophylaxis; therefore, in some pediatric patients, it is required to implant a central venous catheter (CVC).[2] The most common complications associated with the central venous catheter are infections, venous thrombosis and mechanical complications.[[3]] Endocarditis secondary to CVC in immunocompetent children with haemophilia is an infrequent but severe complication with an unpredictable course.[[5], [7]] We report a case of successfully treated catheter-related tricuspid valve infective endocarditis (TVIE) in a child with severe haemophilia A complicated by an anti-FVIII inhibitor. The authors also emphasize that a catheter-related bloodstream infection should be suspected in a child with a fever of unknown origin, haemophilia and implanted CVC. [Extracted from the article]

Blood disorders that can contribute to abnormal bleeding can have a detrimental effect during cardiac surgery. Patients who are known to have such pathologies should be investigated thoroughly and cautious measures would need to be taken when cardiac surgery is needed in this cohort. The majority of current literature for cardiac surgery in patients with von Willebrand Disease and haemophilia are case reports. Nevertheless, evidence shows that optimising factor levels pre, intra and postoperatively offers outcomes similar to that of patients without these disorders. Preoperative screening followed by appropriate iron therapy reduces mortality for patients with anaemia. In this group, haemoglobin levels can be improved postoperatively through iron supplementation. The management strategy of cardiac surgery for people with blood disorders requires a multidisciplinary approach that is highly individualised for each patient. It is essential to adequately adjust preoperative, perioperative and postoperative care to the patient's blood disorder in order to achieve outcomes similar to that of patients without blood disorders. [ABSTRACT FROM AUTHOR]

Haemophilia is a recessive congenital hereditary haemorrhagic disorder characterised by the decrease in, or absence of, the functional activity of factor VIII (Haemophilia A) or factor IX (Haemophilia B). The haematological medical treatment for these patients is systemic replacement therapy with factor VIII or factor IX concentrates. Dental implants are considered the gold standard for the replacement of missing teeth. There is no evidence or safe protocol for their use in patients with haemophilia. The objective of this study was to evaluate the clinical osseointegration and the incidence of postoperative bleeding in patients with haemophilia. The patients included in this study were over 18 years old with a diagnosis of haemophilia. A surgical implant protocol was implemented, supported by systemic and local haemostatic measures. Age, type of haemophilia, pre- and post-factor levels, gingival index, surgical duration, oedema, and pain were recorded for each case. In the event of haemorrhage, the bleeding index was determined. At four months, the success of the implant was evaluated using the absence of pain, suppuration, and clinical mobility as parameters. Fifteen surgeries were performed and 21 implants were placed in 10 patients. All the implants were successful in terms of the evaluated parameters. Among the 15 surgeries performed, bleeding was detected in three. The preliminary results found in this study seem to establish that the proposed surgical implant and haemostatic protocol is a predictable treatment for the placement of dental implants in patients with haemophilia. [ABSTRACT FROM AUTHOR]

Introduction: Joint damage in haemophilia often requires surgical correction. However, the surgery effect on bleeding rates and other clinical joint outcomes can be unclear. Aim: To investigate the effects of joint surgery on joint annualized bleeding rates (JABRs) and physical health outcomes in patients with haemophilia A undergoing N8‐GP prophylaxis. Methods: Patients in the pathfinder 2 trial received N8‐GP prophylaxis, enrolling in the pathfinder 3 trial for indicated surgery. Patients returned to pathfinder 2 post‐surgery, continuing N8‐GP prophylaxis until end‐of‐trial. JABRs were calculated from bleeding across all joints for pre‐surgery (immediately before surgery) and post‐surgery (to pathfinder 2 study end) periods. Joint‐health‐related outcomes were derived from patient records. Results: Data (41 joint surgeries; n = 30) were analysed statistically using datamining and descriptively. Pre‐surgery mean JABR was higher in patients who later were operated than in 146 non‐operated patients (p =.004). In operated patients, mean JABR decreased from 1.33 pre‐surgery to.37 post‐surgery (p =.011). In all but three patients, JABR improved or remained the same post‐surgery. In the three patients whose JABR remained at one (all with multiple joint arthropathy), post‐surgery bleeds were mostly at non‐operated sites. Two of the three patients whose JABR increased post‐surgery had undergone surgery for reasons unlikely to improve JABR. Mobility parameters often improved in patients whose JABR remained at zero. Conclusion: Patients with haemophilia treated with N8‐GP prophylaxis benefit from surgeries. However, this analysis could not differentiate the relative contributions of surgical interventions and prophylactic treatment to the improvement of JABR. [ABSTRACT FROM AUTHOR]

Introduction: Immune Tolerance Induction (ITI) is the first‐choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries. Aim: To assess the effectiveness of a low‐dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high‐titre inhibitors. Methods: A prospective, single‐arm study was conducted in children with HA (FVIII < 1 IU/dl), high‐titre inhibitors and poor prognostic factors for successful ITI. Patients were treated with ∼50 IU/kg plasma‐derived FVIII containing von Willebrand factor (pdFVIII/VWF) concentrate (Koate‐DVI, Grifols) three times a week. Time to achieve tolerance, total and partial success were analysed after ITI. Annual bleeding rate (ABR), number of target joints, FVIII recovery and school absence were compared before and after ITI. Results: Twenty patients with median (range) age of 6.2 (3–12) years and pre‐ITI inhibitor titre of 36.5 (12–169) BU were enrolled. ITI lasted ≤12 months (early tolerization) in 45% of patients. Median follow‐up was 12 months (3–22) and total response rate was 80% (60% total success; 20% partial success). Patients with two and three poor prognosis factors achieved overall success rate of 60% and 50%, respectively. ABR, target joints and school absence were reduced after ITI by 60%, 50% and 44.1%, respectively. In successful ITI tolerized patients, FVIII recovery was 90 (60–100)%. Conclusion: A low‐dose ITI therapy using a pdFVIII/VWF concentrate achieved at least partial tolerance in 80% of patients, and reduced annual bleeds in children with high inhibitor titres and at least one poor prognosis factor for ITI treatment success. [ABSTRACT FROM AUTHOR]

Introduction: Turoctocog alfa (NovoEight®) is a B‐domain‐truncated recombinant factor VIII (FVIII) approved for patients with haemophilia A. Aim: To investigate the long‐term safety and efficacy of turoctocog alfa in routine clinical practice. Methods: Guardian 5 was a prospective, multinational, non‐interventional, post‐authorisation safety study. Male previously treated patients (> 150 exposure days [EDs]) of any age with severe/moderately severe haemophilia A (FVIII ≤ 2%) and a negative inhibitor test prior to first dosing (independent of FVIII‐inhibitor history) were included to receive prophylaxis or on‐demand treatment. The primary endpoint was the proportion of patients developing FVIII inhibitors (≥.6 Bethesda Units [BU]) after baseline visit, measured as per routine practice of each study site during clinic visits. Secondary endpoints included haemostatic effect, annualised bleeding rate (ABR), and adverse reactions assessment. The study concluded when 50 patients reached 100 EDs/patient minimum. Results: Seventy patients were screened and 68 exposed to turoctocog alfa; 63 (92.6%) were on prophylaxis and five received on‐demand treatment. Six (8.8%) patients reported a history of positive inhibitors. During the study, patients were exposed to turoctocog alfa for a mean (standard deviation) of 131.9 (99.0) days/patient. Fifty‐five of 58 patients who completed the study were tested for FVIII inhibitors; no positive tests were reported. Overall success rate of turoctocog alfa for treatment of bleeds was 87.3%. Among patients receiving prophylaxis, median (range) ABR was 1.97 (.0–25.5) bleeds/year; estimated ABR (negative binomial model) was 3.65 (95% confidence interval: 2.53–5.25). Conclusion: Turoctocog alfa was safe and efficacious for haemophilia A treatment in routine clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: In several countries, molecular diagnosis of haemophilia A (HA) and B (HB) is hampered by a lack of resources for DNA analysis. The advent of next‐generation sequencing (NGS) has enabled gene analysis at a reasonable cost. Aim: Describe a collaboration between Cuban and Spanish researchers to identify candidate variants and investigate the molecular epidemiology of 106 Cuban haemophilia patients using NGS. Patients/methods: The molecular analysis protocol included well‐established LR‐PCR procedures to detect F8 inversions, NGS with a 30‐gene panel to sequence F8 and F9, and multiplex ligation‐dependent probe amplification to identify large structural variants. Results: One‐hundred and thirty‐one candidate variants were identified along F8, F9, and VWF; 72 were unique and 28 (39%) had not been previously recorded. Putative variants were identified in 105/106 patients. Molecular characterization enabled confirmation and reclassification of: 90 HA (85%), 15 HB (14%), and one type 2N VWD (1%). Null variants leading to non‐production of FVIII or FIX were common in severe HA (64%), moderate HA (74%), and severe HB (60%), whereas missense variants were frequent in mild HA (57%) and moderate or mild HB (83%). Additional variants in VWF were identified in 16 patients. Conclusion: This is the first description of the molecular epidemiology of HA and HB in Cuba. Variants identified in index cases will be of value for local implementation of familial studies and prenatal diagnosis using the molecular approaches available in Cuba. The results of this protocolled genetic study improved the accuracy of the clinical diagnosis and will facilitate management of these patients. [ABSTRACT FROM AUTHOR]

Background: Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). Aim: To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. Patients and methods: In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow‐up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty‐six of them (48%) were prospectively evaluated. Results: ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P =.033), inhibitor titres ≤5 BU/ml at ITI start (P =.001), peak titres ≤100 BU/ml during ITI (P <.001) and missense mutations and small insertions/deletions of FVIII gene (P =.027) predicted complete inhibitor eradication. A score that considers the cumulative number of these variables predicted complete response with positive predictive values up to.81 at ITI start and.91 during ITI, respectively. Patients who had no bleeding (OR, 3.45, 95% CI: 1.4–8.6) nor other adverse events (OR 2.6, 95%CI: 1.3–5.3) during ITI had higher chances of complete response. During the 120‐month follow‐up (median), 2/70 patients who had achieved complete response relapsed (2.9%). Conclusions: This Registry, with a centralized review of outcomes, homogeneous data collection (half of which prospective) and long‐term follow‐up, provides insights for optimizing ITI, with a rationale for further studies in the currently evolving scenario of inhibitor management in HA patients. [ABSTRACT FROM AUTHOR]

Evaluation of anti-factor VIII antibodies in haemophilia A subjects switching products following a provincial tender Haemophilia A, inhibitor, recombinant factor VIII, bleeds, factor VIII usage, switching products Keywords: bleeds; factor VIII usage; haemophilia A; inhibitor; recombinant factor VIII; switching products EN bleeds factor VIII usage haemophilia A inhibitor recombinant factor VIII switching products e1 e4 4 01/13/22 20220101 NES 220101 In 2018, following a provincial tender process, most persons with haemophilia A (PWHA) in the province of Quebec (Canada) were switched to the two recombinant B-domain-truncated factor VIII (FVIII) known as Zonovate® (NovoNordisk, Mississauga, Canada) and Nuwiq® (Octapharma AG, Lachen, Switzerland) with an estimated market distribution of respectively 53% and 47%. [Extracted from the article]

Introduction: Challenges with personalised prophylaxis in haemophilia remain, including designing unique dosing schedules that require continual adjustments and monitoring using complex sampling procedures. Aim: To assess long‐term efficacy and pharmacokinetic outcomes with fixed‐dose N8‐GP prophylaxis. Methods: Descriptive analyses were performed on data from the pathfinder 2 and pathfinder 5 trials of patients with severe haemophilia A. Bleed frequency and reoccurrence were assessed in relation to several clinical criteria of interest. Bleed risk relative to time since last dose was assessed using calculated annualised bleeding rate (ABR). Long‐term ABR and mean factor VIII (FVIII) trough levels were assessed in patients who received consistent N8‐GP prophylaxis every 4 days (Q4D). Results: During pathfinder 2, 117/136 patients with study‐drug exposure of ≥600 days experienced bleeding episodes; 8.6% of bleeds were reoccurring bleeds; bleed reoccurrence decreased over time. For patients who received consistent Q4D prophylaxis across the trial (n = 61), mean ABR decreased from 3.5 bleeds/year (Year 1) to 1.6 bleeds/year (Year 6); mean FVIII trough levels stabilised at approximately 5% (Year 6). Across patients who received prophylaxis at some point during pathfinder 2 (n = 177), 125/126 (99%) reoccurring bleeds were joint bleeds. For patients receiving Q4D prophylaxis, bleeding risk generally increased as the time since the last prophylaxis dose increased. A similar reduction in ABR and stabilisation of trough level was observed in pathfinder 5. Conclusion: Long‐term exposure (> 5 years) to fixed‐dose N8‐GP prophylaxis resulted in a protective haemostatic effect, with reduction in bleed frequency and reoccurrence, and stabilisation of FVIII trough level over time. [ABSTRACT FROM AUTHOR]

Copyright of Gyermekgyógyászat is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The D-dimer (DD) assay is an essential biological test for the diagnosis and monitoring of thrombotic conditions. DD testing is usually not performed as part of the routine laboratory management of patients with hemophilia (PWH). There is an increasing concern about the risk of thrombotic complications in PWH, which is likely related to age, cardiovascular risk factors, invasive thrombogenic procedures, over-correction of Factor VIII (FVIII) or FIX, or administration of new therapeutic agents mimicking FVIII or rebalancing coagulation. Objective: This retrospective study sought to assess the basal DD levels in PWH treated prophylactically with FVIII, and to evaluate potential changes after switching to emicizumab. Method: Patients over 18 years of age treated with emicizumab within a single center over the period 2017-2022 were included in the study. Result: DD levels were measured in 40 adult PWH (37 severe/ three moderate / two with FVIII inhibitor) with a median age of 46 years (range: 19-82; Q1-Q3: 30,25-56,5), before and at least 3 months after emicizumab initiation. No significant changes were revealed, with DD median values of 257 ng/mL (range: 250-2876; Q1-Q3: 250-493,5) before and 250 ng/mL (range: 50-6205; Q1-Q3: 250-380,25) after the switch (p = 0.9). Conclusion: Most adult PWH on prophylaxis using FVIII display DD levels within the normal range, which remain unchanged after switching to emicizumab. In view of these reassuring results, monitoring of DDs at the start of emicizumab treatment does not appear necessary but could be considered when combined with other bypassing agents or high dose FVIII. [ABSTRACT FROM AUTHOR]

Background Medication adherence is an important issue, not just health-related, for patients with haemophilia. Poor medication adherence to long-term therapies limits the potential of effective treatments to improve patients' health-related quality of life. Objective The aim of this study was to investigate the association of reported medication adherence and health-related quality of life in patients with haemophilia. Setting Data were collected from patients at University Hospital Centre Zagreb, Croatia and at University Medical Centre Ljubljana, Slovenia. Method Adult male patients with severe or moderate haemophilia receiving prophylactic treatment were eligible for the study. Main outcome measure Implementation phase of medication adherence was assessed with the self-reported VERITAS-Pro instrument and health-related quality of life with SF-36v2. Results A total of 82 participants were included in the study (median age was 44.50, range 18–73 years). The majority of our participants reported being adherent to medication (83%). Participants showed better health in the mental health domains and Mental Component Summary than in the physical health domains and Physical Component Summary. After controlling for demographic, socioeconomic and clinical predictors, better reported medication adherence explained an additional 4–6% of better health variance in Bodily Pain and Social Functioning domains and Mental Component Summary. Conclusion We found that reported medication adherence can contribute to better health-related quality of life in patients with haemophilia. Since life with a chronic condition is demanding, it is an important finding that medication adherence to replacement therapy can improve life conditions for patients with haemophilia. [ABSTRACT FROM AUTHOR]

Introduction: Persons with haemophilia (PWH) used to represent a population with a high prevalence of hepatitis C virus (HCV) infection due to the use of contaminated blood products. Although the goals of antiviral therapy are the same as the general population, long real-life follow-up data regarding their outcomes are still scarce. Our aim was to report the outcomes of HCV infection and the results of antiviral therapy in PWH. Methods: A retrospective analysis was performed in a single-centre cohort of PWH with positive HCV antibody. Outcomes registered were rate of spontaneous clearance of HCV, sustained virologic response (SVR) achievement, development of end-stage liver disease, and all-cause and liver-related mortality. Results: Out of 131 PWH, 73 (55.7%) had positive HCV antibody. During a median follow-up time of 22 years, 46 patients (63.9%) developed chronic hepatitis C, of which 16 (34.8%) developed cirrhosis. Treatment was pursued in 34 PWH. Most (n = 32) were first treated with interferon (IFN)-based regimens with SVR rates of 40.6%. Direct-acting antivirals were used in 14 IFN-experienced and 2 naïve patients, with an overall SVR rate of 100%. Overall, 17 patients (23.3%) died during the follow-up, only 4 related to liver disease. Of these, none had achieved SVR. Conclusions: We describe the outcomes of a cohort of Portuguese PWH and hepatitis C exposure after two decades of follow-up, with a lower mortality than previously described. Our response rates to HCV treatment were comparable to those in the general population and stress the importance of early treatment.

Adherence to treatment recommendations in patients with chronic disease is complex and is influenced by numerous factors. Haemophilia is a chronic disease with reported levels of adherence ranging from 17–82%.

The ankle joint is the most common site of bleeding for people with haemophilia (PWH) in the developed world. Recent surveys suggest that PWH do not always have access to non-surgical musculoskeletal interventions and that when provided; there is considerable heterogeneity in clinical practice.

Abstract Background Hemophilic arthropathy is a debilitating morbidity of hemophilia caused by recurrent joint bleeds. We investigated if the joint bleed volume, before initiation of treatment, was linked to the subsequent degree of histopathological changes and the development of bone pathology in a mouse model of hemophilic arthropathy. Methods FVIII knock‐out (F8‐KO) mice were dosed with a micro‐CT blood pool agent prior to induction of hemarthrosis. Eight hours after induction, the bleed volume was quantified with micro computed tomography (micro‐CT) and recombinant FVIII treatment initiated. On Day 8, inflammation in the knees was characterized by fluorescence molecular tomography. On Day 14, knee pathology was characterized by micro‐CT and histopathology. In a second study, contrast agent was injected into the knee of wild‐type (WT) mice, followed by histopathological evaluation on Day 14. Results The average joint bleed volume before treatment was 3.9 mm3. The inflammation‐related fluorescent intensities in the injured knees were significantly increased on Day 8. The injured knees had significantly increased synovitis scores, vessel counts, and areas of hemosiderin compared to un‐injured knees. However, no cartilage‐ or bone pathology was observed. The bleed volume before initiation of treatment correlated with the degree of synovitis and was associated with high fluorescent intensity on Day 8. In F8‐KO and WT mice, persistence of contrast agent in the joint elicited morphological changes. Conclusion When applying a delayed on‐demand treatment regimen to hemophilic mice subjected to an induced knee hemarthrosis, the degree of histopathological changes on Day 14 reflected the bleed volume prior to initiation of treatment.

Abstract Background Haemophilic arthropathy is a chronic and debilitating joint disease caused by recurrent spontaneous joint bleeds in patients with haemophilia. Understanding how characteristics of individual joint bleeds relate to the subsequent development of arthropathy could improve management and prevention of this joint disease. Here, we aimed to explore relations between joint bleed characteristics and development of bone pathology in a mouse model of haemophilic arthropathy by using novel in vivo imaging methodology. Methods We characterised induced knee bleeds in a murine model of haemophilic arthropathy by quantitative in vivo fluorescence molecular tomography (FMT) and by measurements of changes in the diameter of the injured knee. Wild-type mice and non-injured haemophilic mice acted as controls. Development of arthropathy was characterised by post mortem evaluation of bone pathology by micro-CT 14 days after bleed-induction. In an in vitro study, we assessed the effect of blood on the quantification of fluorescent signal with FMT. Results In most injured haemophilic mice, we observed significant loss of trabecular bone, and half of the mice developed pathological bone remodelling. Development of pathological bone remodelling was associated with significantly increased fluorescent signal and diameter of the injured knee just 1 day after induction of the bleed. Further, a correlation between the fluorescent signal 1 day after induction of the bleed and loss of trabecular bone reached borderline significance. In the in vitro study, we found that high concentrations of blood significantly decreased the fluorescent signal. Conclusion Our results add novel insights on the pathogenesis of haemophilic arthropathy and underline the importance of the acute phase of joint bleeds for the subsequent development of arthropathy.

Background: Haemophilia A (HA; Factor VIII deficiency) is a congenital X-linked bleeding disorder characterized by trauma-related or spontaneous bleeding events, most notably arising within the intraarticular space and resulting in chronic inflammation and degeneration of affected joints. Endogenous clotting factor activity relative to normal levels determines the severity of HA symptoms, as mild (> 5-40%), moderate (1-5%), or severe (< 1%). Within the current environment of rapid evolution in HA management, we seek to understand the interplay of condition severity and health-related quality of life (HRQoL) to characterise and differentiate unmet needs among people with HA (PwHA)., Methods: A generalised linear regression model (GLM) was developed to explore the relationship between HA severity and EQ-5D-5 L index score from adult HA patients sampled in the "Cost of Haemophilia across Europe - a Socioeconomic Survey II" (CHESS II) cross-sectional, retrospective burden of illness study among adults with hereditary haemophilia A or B from eight European countries. HA patients of any severity with no active inhibitors during the 12 months prior to data capture and a completeEQ-5D-5 L response were included. A base GLM model was specified with covariates for demographic and clinical characteristics (age, body mass index, country, employment, HA severity, annual bleeding rate, problem joints, and chronic pain)., Results: Of 381 evaluable patients, 221 (58.0%) had severe HA, 96 (25.2%) had moderate HA, and 64 (16.8%) had mild HA. Among the covariates included in the GLM model and after controlling for haemophilia-related outcomes, a significant association was observed between mild HA and higher EQ-5D-5 L index score (average marginal effects, 0.084; p = 0.016) relative to severe HA. Patient country of residence and magnitude of HA-related chronic pain were also associated with significant differences in index scores, with the latter showing a negative relationship with HRQoL outcomes., Conclusions: Condition severity and chronic pain are significant predictors of HRQoL in PwHA. Durable bleeding protection and effective management of chronic pain have the potential to address unmet treatment needs in this population., (© 2024. The Author(s).)

Background: Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile., Treatment Goals: The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health-related quality of life impacted by haemophilia and its treatment., Conclusion: Capitalizing on the major potential of therapeutic innovations, 'Normalization' of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia-imposed limitations. To achieve this-being supported by the data reviewed in this manuscript-the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Valoctocogene roxaparvovec, a gene therapy evaluated in the phase 3 GENEr8-1 trial, supports endogenous factor VIII (FVIII) production to prevent bleeding in people with severe haemophilia A. Individuals receiving emicizumab, an antibody mimicking the function of activated FVIII, were excluded from GENEr8-1 enrolment since emicizumab was an investigational therapy at the time of trial initiation., Aim: Utilize pharmacokinetic simulations to provide guidance on best practices for maintaining haemostatic control while transitioning from emicizumab prophylaxis to valoctocogene roxaparvovec., Methods: To estimate bleeding risk at weekly intervals following valoctocogene roxaparvovec infusion, a published emicizumab pharmacokinetic model was used to simulate emicizumab concentrations and merged with FVIII activity time-course data for participants in GENEr8-1. The analysis investigated three approved emicizumab dosing regimens for two transition scenarios that varied whether the last dose of emicizumab was administered on the same day or 4 weeks after valoctocogene roxaparvovec infusion., Results: Simulations demonstrated administering the last emicizumab dose the day of valoctocogene roxaparvovec infusion and 4 weeks after offered similar levels of haemostatic control, and bleeding risk was similar for all emicizumab dosing regimens. An algorithm was developed to provide guidance for discontinuation of emicizumab. Theoretical cases based on GENEr8-1 participants are presented to illustrate how decisions may vary among individuals., Conclusion: Pharmacokinetic simulations demonstrated no clinically meaningful difference in bleeding risk caused by decaying emicizumab levels and rising gene therapy-derived endogenous FVIII for all examined emicizumab doses and dosing regimens. Therefore, multiple approaches can safely transition individuals from emicizumab prophylaxis to valoctocogene roxaparvovec., (© 2024 BioMarin Pharmaceutical Inc and The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Aim: To evaluate the impact of haemophilia A without inhibitors on humanistic outcomes in patients and caregivers. Herein, we report a cross-sectional analysis of the baseline data of persons with haemophilia (PWH) participating in the prospective study HEMOLIFE., Methods: These data are part of a prospective, observational, and multicentre study currently being conducted in 20 hospitals in Spain by haematologists. We included subjects 12 years or older diagnosed with haemophilia. The evaluations included the Maladjustment Scale, Haemophilia-Specific Quality of Life Questionnaire for Adults (HaemoQol)/HaemoQol Short Form (Children), haemophilia-specific version of the Work Productivity and Impairment Questionnaire plus the Classroom Impairment Questionnaire (WPAI+CIQ:HS), Haemophilia Activity List (HAL)/Paediatric Haemophilia Activities List (pedHAL), visual analogue scale (VAS) for evaluating pain, Coping Pain Questionnaire-Reduced (CAD-R), and Hospital Anxiety and Depression Scale (HADS)., Results: A total of 81 PWH were recruited at 18 centres; 66 PWH were ≥18 years (i.e., adults), and PWH 15 were <18 years (i.e., paediatric patients). Out of the 79 evaluable subjects, 16 (20%) showed an impact of haemophilia on daily life, and the areas most affected were "leisure time" (58% showed maladjustment) and "work/studies" (47% showed maladjustment). Patients reported a higher impact of haemophilia on quality of life (mean [SD] of the transformed score) in the dimensions of "sport" (49.4 [28.6]), "physical health" (40.5 [25.8]) and "future" (37.7 [28.9]). In adults, according to HAL scores, greater impairment of function was observed in "lying/sitting/kneeling/standing," "function of legs" and "leisure activities and sports," with mean normalized scores of 64.7, 65.1 and 69.0, respectively. Productivity was mostly impacted by presenteeism. The pain was infrequent and moderate. According to the HADS scores, nine (11.5%) patients had clinical anxiety and depression., Conclusion: PWH without inhibitors exhibited impairments in adjustment, quality of life and functionality, especially related to leisure and sports activities, and exhibit relevant levels of anxiety and depression., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Reduced doses of emicizumab improve the affordability among patients in developing countries. However, the relationship between variant dose selection and efficacy in the real world of China is still unclear., Aim: This study aimed to investigate the efficacy and safety of emicizumab especially in those on reduced dose regimens in a real-world setting., Methods: We carried out a multicentre study from 28 hospitals between June 2019 and June 2023 in China and retrospectively analysed the characteristics including demographics, diagnosis, treatment, bleeding episodes, and surgical procedures., Results: In total, 127 patients with haemophilia A, including 42 with inhibitors, were followed for a median duration of 16.0 (IQR: 9.0-30.0) months. Median age at emicizumab initiation was 2.0 (IQR: 1.0-4.0) years. Median (IQR) consumption for loading and maintenance was 12.0 (8.0-12.0) and 4.2 (3.0-6.0) mg/kg/4 weeks, respectively. While on emicizumab, 67 (52.8%) patients had no bleeds, whereas 60 (47.2%) patients had any bleeds, including 26 with treated bleeds. Compared to previous treatments, patients on emicizumab had significantly decreased annualized bleeding rate, annualized joint bleeding rate, target joints and intracerebral haemorrhage. Different dosages had similar efficacy except the proportion of patients with treated spontaneous bleeds and target joints. Adverse events were reported in 12 (9.4%) patients. Postoperative excessive bleeding occurred following two of nine procedures., Conclusion: This is the largest study describing patients with HA receiving emicizumab prophylaxis on variant dose regimens in China. We confirmed that nonstandard dose is efficacious and can be considered where full-dose emicizumab is ill affordable., (© 2024 John Wiley & Sons Ltd.)

Aims: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. Methods: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03–15.2) and body weight of 14 kg (4–57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. Results: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL−1. Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03–77.6) and body weight of 30 kg (4–111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h−1 68 kg−1, 2930 mL 68 kg−1, 1810 mL 68 kg−1, and 172 mL h−1 68 kg−1, respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL−1. Conclusions: This study emphasizes the importance of external validation of population PK models using real‐life data. [ABSTRACT FROM AUTHOR]

Background: Patients with severe haemophilia have impaired haemostatic response, delayed clot formation and fibrin clots that are vulnerable to fibrinolysis. Emicizumab is a bispecific antibody that mimics activity of activated factor VIII (FVIII) and increases haemostatic capacity to the level of moderate‐to‐mild haemophilia, thereby used for prophylaxis. Regardless of the impressive clinical performance of emicizumab, breakthrough bleeds may still occur. We aimed to study, in FVIII knockout mice (FVIII‐KO), whether haemostasis is improved with the addition of tranexamic acid (TxAc) to emicizumab. Methods: FVIII‐KO mice received prophylaxis with emicizumab or emicizumab+TxAc before trauma. FVIII‐KO mice were given emicizumab 1.5 mg/kg via IV injection. A second retro‐orbital IV injection containing human FIX and FX (both 100U/kg) was given 24 h later and 5 min before the tail amputation or knee trauma. After trauma‐induced knee joint bleeding, magnetic resonance imaging (MRI), and histological analysis were used to compare haemostatic efficacy of the two prophylactic strategies. Thrombin generation (TG) was measured and clots obtained with TG experiment were analysed by scanning electron microscopy. Results: In FVIII‐KO mice, blood loss after tail clip was lower after prophylaxis with emicizumab+TxAc compared to emicizumab. MRI results and histological analysis of knee joints showed that the addition of TxAc significantly decreased joint bleeding. Fibrin fibre diameters of mice treated with emicizumab only was thicker than those who received combined prophylaxis with emicizumab+TxAc. Conclusion: Our results suggest a potential benefit of TxAc when used in combination with emicizumab in prophylactic settings, especially in patients presenting breakthrough bleeds. [ABSTRACT FROM AUTHOR]

Introduction: Improvements in haemophilia treatment over the last decades resulted in increased life expectancy in persons with haemophilia (PWH). Aim: We conducted a systematic review and meta‐analysis to examine all‐cause mortality and causes of death among PWH. Methods: We systematically searched EMBASE, MEDLINE, Web of Science, CINAHL and Cochrane central register of controlled trials from inception through March 15, 2021. Studies that reported a mortality estimate of PWH compared with the general population and/or reported causes of death were included. Random‐effects meta‐analysis with inverse variance method was used to obtain pooled estimates. We stratified the analysis by the year of cohort entry (before 2000 vs after 2000). Result: Of the 4769 studies identified, 52 met the eligibility criteria. The pooled all‐cause standardized mortality ratio (SMR) from 9 studies in PWH was 1.93 (95% CI 1.38–2.70; I2 = 97%). The pooled SMRs before and after the year 2000 were 2.40 (95% CI 1.92–3.00; I2 = 87%) and 1.20 (95% CI 1.03–1.40; I2 = 62%), respectively. Before the year 2000, 31.2% deaths occurred due to HIV followed by haemorrhage (26.0%), cardiovascular disease (18.2%), liver disease (9.0%), and cancer (8.9%). Fewer (13.9%) deaths were attributable to HIV after the year 2000 with the proportion of deaths due to haemorrhage remaining unchanged. Conclusion: With treatment advances, mortality in PWH has declined over the last few decades approaching that of the general population. However, haemorrhage remains a leading cause of death requiring further attention. [ABSTRACT FROM AUTHOR]

Introduction: Recombinant coagulation factor VIII (FVIII) products are the standard of care for patients with haemophilia A. The development of modified FVIII products has provided benefit for patients but presented challenges for monitoring FVIII activity. Aim: This single‐centre study evaluated the Roche FVIII one‐stage clotting assay (OSA) in measuring FVIII activity in plasma samples spiked with seven FVIII products at clinically relevant concentrations. Methods: FVIII‐deficient plasma samples were spiked with two batches of recombinant FVIII products (octocog alfa, moroctocog alfa, simoctocog alfa, efmoroctocog alfa, damoctocog alfa pegol, rurioctocog alfa pegol, lonoctocog alfa) at 1–120 IU/dL FVIII activity, according to their labelled potency. Measurement was conducted on the cobas t 511/711 analysers using the Roche FVIII OSA and the Technoclone TECHNOCHROM FVIII:C chromogenic substrate assay (CSA). Results: Using the OSA, FVIII activity was close to labelled potency for most analysed FVIII products including a recombinant FVIII Fc fusion protein. PEGylated FVIII product, damoctocog alfa pegol, was marginally above and single‐chain product, lonoctocog alfa, below the predefined acceptance criteria: for FVIII activity < 25 IU/dL: ± 5 IU/dL; for FVIII activity ≥ 25 IU/dL: ± 20% (relative). The different principles of OSA and CSA led to discrepancies in the estimation of all analysed FVIII products. Additionally, in vitro recovery was increased at lower levels of FVIII activity using the OSA, whereas recovery was more consistent using the CSA. Conclusion: These data allow the interpretation of FVIII activity results for different FVIII products using the Roche FVIII OSA on the cobas t 511/711 analysers. [ABSTRACT FROM AUTHOR]

Introduction: Valoctocogene roxaparvovec is an investigational AAV5‐based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. Aim: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). Methods: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti‐AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 1013 vg/kg dose, n = 7) and 4 years (4 × 1013 vg/kg dose, n = 6). Results: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was ‐0.14 (95% confidence interval [CI]: ‐.32 to.03) IU/dl/wk in the 6 × 1013 vg/kg cohort in year 5 and ‐.06 (95% CI: ‐.14 to.01) IU/dl/wk in the 4 × 1013 vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 1013 vg/kg cohort; all six Haemo‐QOL‐A domain scores increased. For the 4 × 1013 vg/kg cohort, high baseline Haemo‐QOL‐A scores persisted. Conclusion: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A. [ABSTRACT FROM AUTHOR]

Introduction: Females may have haemophilia with the same factor VIII (FVIII) or factor IX (FIX) levels as affected males. Characterization of females with haemophilia would be useful for health care planning to meet their unique needs. Federally‐funded haemophilia treatment centres (HTCs) in the United States contribute data on all individuals with bleeding disorders receiving care to the Population Profile (HTC PP) component of the Community Counts Public Health Surveillance of Bleeding Disorders project. Aims: To estimate the number of females with haemophilia receiving care at HTCs in the United States and compare their characteristics with those of males with haemophilia. Methods: HTC PP data collected on people receiving care at an HTC from January 2012 through September 2020 with haemophilia A and B were evaluated by sex for demographic and clinical characteristics. Results: A factor level < 40% was reported for 23,196 males (97.8%) and 1667 females (47.6%) attending HTCs; 51 (.48%) severe, 79 (1.4%) moderate, and 1537 (17.9%) mild haemophilia patients were female. Females were older, more often White, and less often non‐Hispanic than males. Females were less likely to have history of HIV or HCV infection, even among those with severe disease, but twice as likely to have infection status unknown. Females with mild haemophilia were more often uninsured than males. Conclusions: Females with severe or moderate haemophilia are uncommon, even in specialized care centres; however, almost one in five patients with mild haemophilia was female, indicating needs for specialized care based on factor level and history for affected females. [ABSTRACT FROM AUTHOR]

Introduction: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight‐based dosing of Factor VIII (FVIII) does not account for inter‐individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. Aim: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. Methods: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. Results: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one‐compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. Conclusion: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice. [ABSTRACT FROM AUTHOR]