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IntroductionSweden has been a pioneer in the prophylactic treatment of haemophilia. Magnetic resonance imaging (MRI) can detect small changes in joints and can therefore give an indication of a risk of developing arthropathy. AimTo use MRI to evaluate the outcome of the Swedish high-dose regimen and correlate the findings to age, bleeds, joint score and physical activity. MethodsThe study group comprised 48 Swedish male patients, mean age 25 years (range 12-33 years), with severe or moderate haemophilia A or B. Data on the Haemophilia Joint Health Score (HJHS) were available and physical activity was evaluated by a self-reported questionnaire. ResultsMRI score was recorded in 188 joints. Twenty out of 48 patients had a score of >= 1 (range 1-13) in 31 joints of which 3/31 scores were in the knees and 28/31 in the ankles. No correlation was found between the number of recorded bleeds and the MRI score or between HJHS and MRI score. There was no correlation between the physical activity and the number of joint bleeds per se, but a trend (OR 3.0) that those most physically active (19/48; 39.6%), more frequently had an MRI score of >= 1 with an overweight for the right ankle. ConclusionThe Swedish prophylactic model offers protection against haemophilia joint arthropathy but will still not prevent osteochondral changes in some patients at young age. MRI of the ankles can signal risk of future arthropathy and indicate need to modify the prophylactic regimen. Funding Agencies|Baxter Sweden AB (now part of Takeda)

Objectives To report the final results of the 2-year TAURUS study, assessing weekly prophylaxis dosing regimens of octocog alfa (Kovaltry (R)/BAY 81-8973) used in standard clinical practice in patients with moderate-to-severe haemophilia A. Methods TAURUS (NCT02830477) is a phase 4, multinational, prospective, non-interventional, single-arm study in patients of any age with moderate or severe haemophilia A (= 1

Introduction: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors.Aim: To report the efficacy and safety results from the NuProtect study.Methods: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study.Results: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events.Conclusion: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

People with haemophilia A (PwHA) have a deficiency of coagulation factor VIII and experience recurrent bleeding. Currently, PwHA are treated effectively with drugs such as FVIII products or emicizumab. Measuring and monitoring these drugs is important to determine the dose, which needs to be effective but not unnecessarily high due to costs (i.e., ~€100.000‒€400.000 per person per year). Mass-spectrometry (MS) is a beneficial technique to measure drug concentrations in blood and is used in clinical laboratories worldwide. Prior to this thesis, MS analysis was not used in haemophilia A care. This thesis aimed to optimize drug monitoring of FVIII and emicizumab in PwHA in three parts. Firstly, the development of MS methods measuring drugs similar to FVIII and emicizumab was summarized in a simple six-step workflow. Subsequently, two MS methods measuring FVIII and emicizumab were set-up and validated. Secondly, the studies on the concentration–biomarker relationship of FVIII yielded more questions than answers, while studies on literature and in our clinic indicated that emicizumab concentrations on standard dosing were often two-times above the minimal effective concentration. Thirdly, this thesis formed the groundwork for the design of a study protocol where the emicizumab dose is adjusted individually by targeting the minimum effective concentration. Finally, future perspectives were shared by giving four new applications of MS analysis quantifying FVIII and a framework for cost-efficient dosing strategies for other drugs similar to emicizumab.

Haemorrhage in patients with haemophilia is common after minor trauma but may occur spontaneously. Despite the diversity of bleeding sites, spontaneous haemothorax, on a non-traumatic basis, is an exceedingly rare event and only a few cases had been reported. We present a case of a 43-year-old man with a history of haemophilia A who had pleuritic chest pain for 1 day without significant history of trauma. Diagnostic thoracentesis showed bloody pleural fluid in which neither abnormal cell nor organism was found. He was treated by cryoprecipitate replacement and therapeutic thoracentesis for releasing haemothorax. After discharge, the patient returned for follow-up with complete radiological resolution. Regarding the consequences of retained haemothorax from conservative approach and the procedure-related bleeding of given therapeutic intervention in haemothorax making its management in patients with haemophilia to be more challenging. Our case illustrates a conservative treatment of spontaneous haemothorax in patient with haemophilia resulting in a good clinical outcome.

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.

Haemophilia B (HB) is a rare inherited bleeding disorder caused by the deficiency of coagulation factor IX (FIX). The major clinical issues are bleedings, often targeting the joints, and the development of neutralising antibodies, i.e. inhibitors, to the FIX replacement therapy. Historically HB has been seen as identical to the more common haemophilia A (HA), i.e. deficiency of coagulation factor VIII (FVIII), but important differences between the two diseases exist. As a result of the rarity of HB, much of our knowledge of HB has been extrapolated from what is known about HA. To improve the care for persons with HB (PwHB), studies focusing on HB are of importance. The aim of this thesis was to characterise HB regarding its diagnostic challenges, treatment, clinical outcomes, and the quality of life of PwHB, and to compare some of these aspects to those of HA.Paper I describes the comparison of the one-stage and the chromogenic assays in measuring the FIX activity level. In HA, a discrepancy between the two methods in measuring FVIII has been reported in approximately one-third of persons with non-severe HA; however, this has not previously been evaluated in HB. We found that 25% of persons with non-severe HB had discrepant results between the two methods, with higher values recorded when the chromogenic method was used. All but one of these persons had the same FIX gene (F9) mutated amino acid. This was the first study to show that assay discrepancy occurs in HB and we concluded that both the one-stage and the chromogenic assays are needed for the correct diagnosis and classification of HB.Papers II-IV describe a cohort of 79 persons with severe HB from the Nordic countries, and 79 matched controls with HA. In Paper II, joint assessment using ultrasound and haemophilia joint health score (HJHS) was conducted and showed that despite the fact that 95% of PwHB were treated with prophylaxis, 37% reported joint bleedings during the prior year. Ultrasound scores were overall low and HJHS scores were significantly lower among PwHB compared with persons with HA (PwHA), indicative of a milder arthropathy in patients with severe HB than in PwHA. Treatment adherence was evaluated using Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS) questionnaires and showed overall good adherence.Paper III presents information on F9 variants, inhibitors, and immune tolerance induction (ITI) therapy in PwHB. We found a high proportion of severe F9 gene defects and a relatively high prevalence of inhibitors of 15%. Of inhibitor patients, 92% had experienced allergic manifestations and 25% nephrotic syndrome. ITI success was independent of the F9 variant and was attained despite allergic reactions and previous ITI failures. Immunosuppression included in the ITI regimen showed a high beneficial rate and may enhance the chances of success. Analyses of noninhibitory anti-FIX antibodies (NNAs) with a multi analyte profiling-based fluorescence immunoassay (xFLI) and an enzyme-linked immunosorbent assay (ELISA) were conducted, but no NNAs were identified. In Paper IV, health-related quality of life (HRQoL) was assessed using the EQ 5D 3L questionnaire and showed a high frequency of pain, mobility problems and anxiety/depression in PwHB, indicating that areas of insufficient care exist. No significant differences in HRQoL between PwHB and PwHA were found, and impaired joint health assessed by the HJHS was found to have a significant negative impact on HRQoL.

Haemophilia A and B are congenital bleeding disorders characterized by missing or defective factor VIII or factor IX, respectively. Factor replacement therapy has been the gold standard for prophylaxis and treatment of bleeding complications. However, the inconvenience of regular intravenous administration, along with progression of arthropathy and development of inhibitors has driven the need for alternative treatment options, such as extended half-life products, non-factor coagulation products, such as subcutaneous emicizumab, blocking natural anticoagulants (rebalancing haemostatic agents) and gene therapy, which have been useful to control bleeding or are currently under late-phase clinical investigation.

Hemofilija A je prirojena motnja koagulacije krvi zaradi pomanjkanja oz. zmanjšane aktivnosti faktorja VIII (FVIII). Za bolezen so značilne krvavitve v mišice in sklepe. V primeru neustreznega zdravljenja se bolniki soočajo s krvavitvami, poškodbami hrustanca, vnetjih v kosteh in mišicah. Za ustrezno obravnavo bolnika sta bistvena pravilna diagnoza, ki jo zagotovimo s specifičnimi testi določanja aktivnosti faktorjev strjevanja krvi, in zdravljenje. Razvoj emicizumaba (Hemlibra Hoffman – La Roche Basel, Švica) je razširil možnosti zdravljenja za bolnike s hemofilijo A, z in brez inhibitorjev proti FVIII, in predstavlja alternativo nadomestnemu zdravljenju s FVIII za bolnike s hudo hemofilijo A. Po strukturi je emicizumab bispecifično protitelo, ki z enim krakom prepozna aktivni FX, z drugim pa aktivni FIX, in tako posnema delovanje FVIII. V Specializiranem hematološkem laboratoriju Kliničnega oddelka za hematologijo Univerzitetnega kliničnega centra v Ljubljani (SHL KOH UKCL) smo v okviru magistrske naloge uvedli novo metodo, R2EMI20, za določitev plazemske koncentracije emicizumaba. Metoda R2EMI20 je prilagojena enostopenjska metoda za določitev aktivnosti FVIII. Meritve koncentracij smo izvedli na koagulacijskem aparatu ACL TOP 500, in sicer je bilo vključenih več arhivskih vzorcih plazme bolnikov, ki bodisi prejemajo bodisi ne prejemajo emicizumaba. Dokazali smo, da je terapevtski interval tistih, ki prejemajo zdravilo, 30–80 µg/ml. Potrdili smo tudi ugotovitve študij, ki pravijo, da je pri bolnikih, ki ne prejemajo emicizumaba, imajo pa v plazmi prisoten rFVIII oz. imajo višjo aktivnost FVIII, rezultat meritev lažno povišana koncentracija emicizumaba. Novo vpeljana metoda R2EMI20 je primerna za klinično uporabo, saj smo poleg že zgoraj naštetih trditev dokazali, da je metoda ponovljiva v in med serijami pri različnih koncentracijah. Metoda bo v pomoč zdravnikom pri lažjem vodenju bolnikov, ki prejemajo to zdravilo. Spremljali bomo lahko, ali je bolnik razvil protitelesa na zdravilo in ali ga redno prejema. Haemophilia A is a congenital disorder of blood coagulation due to a deficiency or lack of activity of factor VIII (FVIII). The disease is characterised by bleeding in the muscles and joints. In case of inadequate treatment, patients experience bleeding, cartilage damage, inflammation in bones and muscles. A correct diagnosis, provided by specific tests to determine the activity of blood clotting factors, and treatment are essential for the proper management of the patient. The development of emicizumab (Hemlibra Hoffman – La Roche Basel, Switzerland) has expanded treatment options for patients with haemophilia A, with and without anti-FVIII inhibitors, and represents an alternative to FVIII replacement therapy for patients with severe haemophilia A. Structurally, emicizumab is a bispecific antibody that recognises active FX with one arm and active FIX with the other, thus mimicking the action of FVIII. In the Specialised Haematology Laboratory of the Clinical Department of Haematology, University Clinical Centre Ljubljana (SHL KOH UKCL), we have introduced a new method, R2EMI20, to determine the plasma concentration of emicizumab as part of the master thesis. The R2EMI20 method is a modified one-step method for the determination of FVIII activity. Concentration measurements were performed on an ACL TOP 500 coagulation device and included several archival plasma samples from patients either receiving or not receiving emicizumab. We have shown that the therapeutic range of those receiving the drug is between 30 - 80 µg/ ml. We have also confirmed the findings of studies suggesting that in patients who do not receive emicizumab but have rFVIII present in their plasma or have higher FVIII activity, the measurements may result in falsely elevated emicizumab concentrations. The newly introduced R2EMI20 method is suitable for clinical use because, in addition to the claims listed above, we have demonstrated that the method is reproducible within and between batches at different concentrations. The method will help physicians to facilitate the management of patients receiving this drug. We will be able to monitor whether the patient has developed antibodies to the drug and also if he/she is receiving it regularly.

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.

INTRODUCTION Oral health is an important component of care at haemophilia treatment centres (HTCs). Correlations between oral health and inflammation suggest that proper oral health may improve joint health. AIM To evaluate the dental habits, needs, and oral health status of paediatric patients with bleeding disorders, and identify predicters of poor oral health. METHODS From May 2016 to October 2017, consecutive paediatric HTC patients completed a 14-question survey and were examined by dental professionals. Descriptive analyses, chi-square tests and logistic regression models identified characteristics associated with four main dental outcomes. RESULTS Evaluations from 226 consecutive patients (age 1-20 years) were included. Diagnoses included haemophilia A and B (64%), von Willebrand disease (25%) and other bleeding disorders (13%). Nearly half of patients reported not brushing their teeth twice a day (44%). One-quarter of patients did not currently have a dentist (27%), and 15% reported specific challenges with access to dental care. Oral screening demonstrated significant pathology: 89% of patients had plaque accumulation, 37% had gingivitis and 8% had lesions suggestive of dental caries. Multivariate analysis revealed that having a primary caregiver with active decay was associated with significantly higher rates of suspicious lesions (OR 4.34, CI 1.41-13.35) and gingival erythema (OR 3.44, CI 1.63-7.25) and lower rates of twice daily teeth brushing (OR .17, CI .08-.37). CONCLUSION Children with bleeding disorders commonly have significant dental pathology and report obstacles to dental care, posing the potential risk for morbidity. Primary caregiver dental health is strongly associated with dental pathology in children.

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.

Background: There are only a few studies in patients with haemophilia (PWH) that examined both quality of life and depressive symptoms, with only few studies examining their association. Aim of this study was to examine the association between depressive symptoms and health-related quality of life (HRQoL) in PWH from Croatia and Slovenia. Subjects and methods: A total of 112 adult PWH on prophylactic (73%) or on-demand (27%) treatment were included in the study (median age 46 years, range 18-73 years). Depressive symptoms were assessed with BDI-II, HRQoL with SF-36v2, demographic and socioeconomic data were collected using a questionnaire, and clinical data were obtained from medical records. Results: All HRQoL scores were significantly negatively correlated with BDI-II in the -0.42 to -0.70 range (all p

Introduction Treatment of patients with Haemophilia A has improved significantly in recent years since the advent of novel therapeutic agents such as emicizumab. The low annualised bleeding rates associated with emicizumab have liberated many patients from the need for central venous access devices (CVAD). Optimal peri-operative management of CVAD removal is not currently known and there are no specific formal recommendations available. Aim We reviewed outcomes in a paediatric cohort in our centre undergoing CVAD removal without pre-operative factor or bypassing agent and reviewed the literature regarding port removal in patients on Emicizumab. Methods Ten male patients with severe Haemophilia A underwent CVAD removal without planned administration of factor concentrate or bypassing agent. Patients were monitored in hospital for 24 h with routine laboratory testing pre- and post-operatively. Results No significant bleeding episodes occurred in any patient, no patient required factor concentrate or bypassing agent and no patients were readmitted due to bleeding within 7 days of surgery. Conclusion We propose that, in the era of emicizumab, prophylactic factor administration pre-operatively for elective CVAD removal is not required in the majority of cases.

INTRODUCTION Haemophilic arthropathy is a serious complication of haemophilia often requiring surgical intervention. It is unclear whether advances in comprehensive care are associated with a reduction in orthopaedic interventions and peri-procedural resource utilization. AIM To determine temporal patterns of orthopaedic interventions in persons with haemophilia (PWH), and evaluate changes in healthcare utilization and outcomes. METHODS In this Canadian multicentre retrospective cohort study, adult PWH from Northern Alberta and British Columbia who underwent orthopaedic procedures (1990-2018) were included. Temporal changes in the type of procedures, length of stay (LOS), factor utilization and outcomes were examined. RESULTS Sixty-five patients (78% haemophilia A) underwent 102 surgeries at a median age of 46.3. Of the 46 severe PWH, 28 (61%) were on prophylaxis at time of surgery. The proportion of total knee arthroplasties (TKA) declined over time (56% 1990-1999, 51% 2000-2009, 27% 2010-2018), with a concomitant rise in ankle arthrodesis (0% 1990-1999, 18% 2000-2009, 27% 2010-2018). Over time, PWH underwent orthopaedic procedures at an older age (P = .02). There was a significant reduction in perioperative factor VIII utilization (P = .003) and median LOS (P

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.

Introduction Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. Aim To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. Methods Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. Results Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. Conclusion Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.

Introduction Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. Aim To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. Methods Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. Results Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. Conclusion Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.

Introduction The Haemophilia Activities List (HAL) was developed to measure activities and participation in persons with haemophilia (PWH). Shortening the questionnaire may facilitate use of the HAL. Aim The aim of this study was to determine which items of the HAL are redundant, to construct a shorter version of the HAL, and to determine the construct validity of the HALshort . Methods A secondary analysis was performed on pooled data of two published studies using the HAL (seven domains, 42 items, optimum score: 100) in adults with haemophilia A/B. Data were divided into a derivation (62%) and a validation set (38%). Redundant items were identified by evaluation of: floor and ceiling effects, proportions of missing and 'not applicable' responses, inter-item correlations, component loadings in an exploratory factor analysis, internal consistency, and item-total correlations. Correlations with the SF-36 and EQ-5D-5L were used to determine construct validity of the HALshort . Results Data on 680 PWH were evaluated. In the derivation dataset (n = 420), median age was 30 years (range 18-80), 43% had severe haemophilia and 61% received prophylaxis. Median (IQR) HAL sum score was 65.0 (55.7-88.8). The stepwise procedure resulted in a HALshort of 18 items with a median sum score of 63.3 (54.4-86.7). Construct validity was similar for the HAL and HALshort in the validation dataset (n = 260). Conclusion This clinimetric study resulted in a >50% shortening of the HAL. The 18-item HALshort reduces patient burden and is expected to capture the information on activities and participation. The HALshort needs further validation.

The development of inhibitors against factor VIII (FVIII) concentrates is a severe complication of treatment for patients with haemophilia. We investigated annualized bleeding rates (ABRs) in patients in Argentina with haemophilia A with inhibitors and analysed potential differences between treatment strategies. This multicentre, retrospective, real-world data, cohort design study comprised ambulatory paediatric and adult patients with congenital haemophilia A and FVIII inhibitors treated according to standard clinical practice, with 12-months follow-up. Of 69 included patients, 39 (56.5%) received on-demand treatment, 13 (18.8%) received prophylactic treatment, and 17 (24.6%) received immune tolerance induction (ITI) therapy. The mean overall ABR was 7.68 ± 8.18, with similar rates for on-demand (8.59 ± 9.69), prophylaxis (5.54 ± 4.71), and ITI (7.24 ± 6.23) subgroups. In the negative binomial regression model, prophylactic treatment [incidence rate ratio (IRR) 0.41, 95% confidence interval (CI): 0.21-0.79, P

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.

Background Haemophilia A is an X-linked genetic condition which manifests itself mainly in male children in the first 2 years of life, during gross motor skill development. This disorder is rare in females. The clinical manifestation of severe haemophilia in preterm infants poses a great challenge to the therapeutic team. As extreme prematurity is linked to an increased risk of central nervous system or gastrointestinal bleeding, a well-informed and balanced treatment from the first days of life is crucial to prevent long-term damage. Haemophilia is most commonly caused by inheriting defective genes, and can also be linked to skewed X inactivation and Turner syndrome. The coincidental occurrence of haemophilia A and Turner syndrome is extremely rare, with only isolated cases described to date. Hence, a multidisciplinary approach is needed. Case presentation The authors report on a preterm girl (gestational age 28 weeks) diagnosed with haemophilia and Turner syndrome. The first manifestation of haemophilia was prolonged bleeding from injection sites on the second day of life. Indeterminate aPTT and factor VIII level Conclusions Haemophilia should always be considered in the differential diagnosis of prolonged bleeding, even in patients with a negative family history. In the case of coinciding atypical phenotypic features, further diagnostics for another genetic disease are recommended. Infant care should follow current care standards, while considering certain individual features.

Continuous replacement therapy with clotting factor products can lead to serious complications in haemophilia A patients. One of potential reasons of such complications is an undesirable immune response to a blood clotting factor VIII (FVIII) product, which undermines the treatment effectiveness. The aim of the study was to systematise and summarise data on undesirable immunogenicity of plasma-derived and recombinant FVIII products, formation of immunological tolerance, and modern approaches to the development of clinical trial programmes for such products. The analysis was based on scientific literature, as well as Russian and international guidelines, including the updated document of the European Medicines Agency. The paper presents clinical trial data on pharmacokinetics, efficacy, and safety of FVIII products, including data on manifestations of unwanted immunogenicity. It highlights molecular mechanisms of interaction between inhibitors and FVIII, and analyses the main factors (genetic characteristics, immune status of patients, dosage regimen, etc.) affecting the frequency and intensity of the immune response to the product. The authors summarised approaches to the clinical trial design, including selection of patients and studied parameters. They substantiate the need for post-authorisation studies to collect additional clinical data on both efficacy and safety of the routine use of the product, including additional assessment of immunogenicity and other adverse reactions. It is concluded that the successful use of high-quality FVIII products ensures by harmonisation of requirements of Russian and international regulatory documents.

Contains fulltext : 237493.pdf (Publisher’s version ) (Closed access) BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of

Background Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. Case presentation We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. Conclusions Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

Introduction Severe haemophilia A (HA) has a major impact on health‐related quality of life (HRQoL). Aim Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. Methods This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia‐Specific Quality of Life Questionnaire for Adults (Haem‐A‐QoL) and EuroQoL 5‐Dimensions 5‐levels (EQ‐5D‐5L). In particular, changes from baseline in Haem‐A‐QoL ‘Physical Health’ (PH) domain and ‘Total Score’ (TS) are evaluated. Results Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem‐A‐QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) –12.0 (21.26)‐ and –8.6 (12.57)‐point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty‐four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ‐5D‐5L questionnaire. Conclusions Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem‐A‐QoL PH and less work disruption than previous treatment.

Emicizumab is a bispecific antibody exerting cofactor function of FVIIIa irrespective of the presence of FVIII inhibitors. Long-term data of phase 1/2 and phase 3 studies have been accumulated. Various questions such as indicated patients, ITI, application to PUPs, hemostatic treatment including surgeries, and emicizumab-related morbidity remain to be solved.The review describes the mode of action, data from pre-/post-marketing and ongoing clinical studies according to PubMed search and our own works.For patients with a persistent inhibitor, emicizumab is a definite therapeutic option, although the possibility of BPAs-associated thromboembolic/TMA events raises concerns. The use of ITI together with emicizumab prophylaxis is being examined in clinical trials. For non-inhibitor, especially pediatric patients, emicizumab prophylaxis can be an option. Outcome assessment 'beyond ABR' such as joint health, physical/mental activity, QOL is required. Furthermore, continuous data collection for emicizumab-related adverse events and morbidity would be recommended.

INTRODUCTION Published guidelines are available to assist in the management of patients with inherited bleeding disorders in the elective surgical setting however good quality outcome data is lacking. AIM - Evaluate the outcomes of adult patients with inherited bleeding disorders, who received factor replacement for elective surgery in NSW/ACT, Australia. - Assess adherence to relevant guidelines including Haemophilia Treatment Centre (HTC) utilisation and appropriate factor replacement. METHOD A retrospective analysis was performed between 2000 and 2018 to describe patient characteristics, surgical details, factor provision and outcomes. Univariate analysis was used to determine variables associated with guideline adherence. Covariates with p

Introduction Emicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with haemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to predict the approximate FVIII level in severe haemophilia A patients with inhibitors on emicizumab using global haemostasis assays. Materials and methods Patients with moderate and mild HA in the non-bleeding state and healthy controls had FVIII levels and thrombin generation assessed. Linear regression was utilized to model the FVIII levels as a function of the thrombin generation assay parameters and to make a calibration curve of FVIII levels versus peak thrombin and endogenous thrombin potential. Patients with severe haemophilia A with inhibitors on emicizumab had thrombin generation performed in the same manner and their peak thrombin and endogenous thrombin potential results were placed on the calibration curve to calculate their FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT). Results All patients with severe HA with inhibitors on emicizumab had F8EmT >10%, suggesting they had been converted to a mild haemophilia phenotype. The patient's weight was inversely correlated to their F8EmT. Conclusion The results from this study suggest that the F8EmT in patients with severe HA on emicizumab falls within the range of mild haemophilia which is consistent with the data noted in the emicizumab clinical trials and in vivo studies in animals.

Introduction SCT800 is a recombinant human B-domain-deleted coagulation factor VIII (BDDrFVIII) developed in China. Aim To evaluate the repeat pharmacokinetics (PKs), efficacy, and safety of SCT800 in previously treated Chinese adolescent and adult patients with severe haemophilia A. Methods A phase III, multicentre, prospective, open-label, single-arm trial was conducted at 12 medical centres. Subjects received treatment for 24 weeks. PKs were assessed at the initial and repeated dosing 24 weeks later. The primary endpoint was annualized bleeding rate (ABR). Breakthrough bleeding episodes and inhibitor development were assessed. Results A total of 71 of 73 patients completed the study, and 18 were enrolled for the repeat PK investigation. Total exposure was 5643 exposure days. Overall, SCT800 showed comparable repeat PK profiles. The total ABR was 2.82 (95% confidence interval 2.01-3.96). During prophylaxis, 43.8% of patients had no bleeding episodes. The majority (89.4%) of bleeding episodes were controlled with 1-2 injections of SCT800, the success rate (defined as 'excellent' or 'good' haemostatic response) for the treatment of bleeding episodes was 92.6%. The incidence of treatment-related adverse events was 53.4%. Drug-related AE incidence was 4.1%. The observed AEs were similar to those of other coagulation factor VIII, but lower in frequency. No subject developed an inhibitor, and no other safety concerns were identified. Conclusions SCT800 has robust PK characteristics, and is safe and efficacious for the prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult patients with severe haemophilia A.

Aim: Previous studies have reported inhibitor development (ID) risk in those patients who have hemophilia A (HA) with missense mutations to be 3-10%. We investigated the association between ID risk and various features of missense mutations; including the impact directly related to amino acid group change. Materials and Methods: Missense mutations in the F8 gene, clinical findings of the patients including severity of HA, and ID status were obtained from the F8 gene variant database (http://www.factorviii-db.org/). Twenty amino acids were then classified into groups according to their side chains. All information regarding each specific mutation, as well as any impact of the mutation on the amino acid group change, was recorded. Additionally, localization (at which domain) of any changed amino acid in the F8 protein was noted. Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), Mendelian Clinically Applicable Pathogenicity and Deleterious Annotation using Neural Networks scores were applied to identify a significant cut-off value indicative of ID. Results: Three variations were identified that could be considered as useful in the prediction of ID in mild HA. The first being that among mild HA patients, 7.9% (n=70/883) with mutations causing no amino acid group changes showed ID. This rate, however, was only 2.9% in patients with mutations leading to amino acid group changes. Secondly; in patients with mutations causing no amino acid group changes affecting A2, A3 and C2 domains, ID risk was found to be higher than in patients with mutations leading to amino acid group changes. Thirdly; an association between ID and CADD and REVEL scores was observed. Conclusion: In mild HA patients, the characteristics of missense mutations in terms of amino acid group changes, and CADD and REVEL scores could be of considerable utility in the prediction of ID risk.

Background: Patients with haemophilia experience recurring hemarthroses, mainly involving knees, elbows and ankles, which lead to haemophilic arthropathy, the major chronic complication of haemophilia. With new approaches to haemophilia treatment leading to fewer joint bleeds and, in some cases, no bleeding events, assessing whether current outcome assessment tools provide adequate sensitivity and specificity for management and care of patients with haemophilia is needed. Methods: An overview of current imaging tools for monitoring joint health, novel osteochondral damage and synovial proliferation biomarkers, and the relationship between assessments for functionality and imaging modalities is provided. Usefulness and sensitivity of point-of-care ultrasound (POCUS) to complement other assessments and use of ultrasound to monitor haemophilic arthropathy are also examined. Results: This review provides rationale for haemophilia teams to move beyond traditional outcomes in joint imaging, as well as guidance and evidence on assessment of joint health for potential new treatment modalities, such as gene therapy. The role of POCUS in the existing paradigm for haemophilia care and management along with the use of ultrasound as a complement to other outcome assessment tools are also discussed. Finally, the clinical effects of subclinical bleeding on joint function are described, to motivate screening for synovial proliferation. Conclusion: POCUS can facilitate the early detection of joint damage and can monitor disease progression while providing insights into the efficacy of treatment regimens, and should be considered as an essential assessment tool for managing the care of patients with haemophilia.

Background: To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance. Aim: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens. Methods: We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen. Results: In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration-time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose. Conclusion: It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.

International audience; Background Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life? Method MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number. Results A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis. Conclusion The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA.

Introduction The use of pharmacokinetic assessment for optimal prophylactic dosing of factor concentrates in haemophilia has gained increasing enthusiasm over the last decade. However, blood sampling on several occasions is burdensome and limited sampling using population-based PK is appealing. Aim To compare the pharmacokinetics and dosing recommendations for prophylaxis using six-point single subject versus population-based method (WAPPS-Hemo) for simoctocog alfa (Nuwiq® ). Methods Twelve adult patients with severe haemophilia A received a factor VIII (FVIII) dose of ≈50 IU/kg, and the activity was measured pre-infusion and at 30 min, 6, 9, 24 and 48 h post-infusion. Half-life (t1 /2 ), weight-normalized AUC and time to troughs of 5%, 3% and 1% were calculated. The correlation between the PK algorithms was assessed using intraclass correlations (ICC) and dosing estimations were provided. Results WAPPS-Hemo yielded a slightly longer mean t1 /2 , but the overall correlation between the methods was good (ICC ≥0.79) The time to troughs of 5%, 3% and 1% showed ICCs ≥0.86. For all variables, the most converging limited time point was 6+48 h. Additional time points did not improve the correlation. Despite similar pharmacokinetics, the mean estimated dose for a specific trough level varied from 60% less to 20% more using the population-based approach. The time to 1% and the corresponding dose was sensitive to the baseline assumption. Conclusion Our data support the use of population-based PK for patients on simoctocog alfa prophylaxis but also indicates differences, stressing the importance of the sampling scheme and monitoring actual FVIII levels achieved.

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.

Introduction: The phase 2/3 PROTECT VIII main study demonstrated efficacy and safety of BAY 94–9027 (damoctocog alfa pegol; Jivi®), a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life. Aim: To report the final efficacy and safety data for BAY 94–9027 from the PROTECT VIII extension. Methods: Previously treated males aged 12–65 years with severe haemophilia A (FVIII

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries. Several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of patients. These challenges are now being addressed by extended half‐life recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Here, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations from a regulatory perspective. The database on human medicines from the European Medicines Agency (EMA) was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon and has considerable potential. With regard to the benefit of the gene therapy medicinal products, more long‐term efficacy and safety data are awaited. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders, but issues remain about the affordability and accessibility to patients.

Inherited bleeding disorders (IBDs) encompass a large number of different but rare conditions that can lead to increased risk of bleeding. The most common IBDs are von Willebrand disease, haemophilia A and haemophilia B. The diagnosis of IBDs requires a detailed history of the bleeding and specialized coagulation testing. The management of bleeding episodes in patients with IBDs can include the use of coagulation factor concentrate, desmopressin and antifibrinolytics such as tranexamic acid. This brief review focuses on the more common IBDs.

Introduction: The standard treatment of hemophilia A consists of the prophylactic administration of a coagulation factor concentrate, to be administered intravenously several times a week. Newly ap...

Introduction Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). Aim To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. Methods PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). Results Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. Conclusion The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.

INTRODUCTION Obesity alters the pharmacokinetic (PK) properties of drugs making it difficult to determine the appropriate dose when administering weight-based medications. Alternative descriptors of body weight, such as lean body mass (LBM) and ideal body weight (IBW), are sometimes used in these situations. METHODS We performed a single-centre, randomized, controlled, open-label, 3 × 3 crossover trial to determine whether recombinant factor VIII (rFVIII) dosing based on LBM and IBW achieves a targeted FVIII recovery with better precision than based on total body weight (TBW) in overweight and obese, adult males with haemophilia A. Participants were randomized to 1 of 6 possible FVIII concentrate dosing sequence scenarios (TBW, LBM and IBW). Recombinant FVIII was administered on 3 separate weeks following a washout period of at least 72 hours. RESULTS A total of 19 participants were randomized and completed the study. FVIII recovery was lower at 30 minutes post-rFVIII infusion in LBM vs TBW and IBW vs TBW-based dosing, mean difference -0.38 (95% CI: -0.56, -0.20) and -0.28 (95% CI: -0.47, -0.10) IU/dL per IU/kg, respectively. In LBM vs TBW and IBW vs TBW-based dosing, there was a non-significant increase in the proportion of participants with a targeted FVIII recovery of 2.00 ± 0.20 IU/dl per IU/kg, OR = 1.93 (95% CI: 0.44, 8.55) and OR = 3.65 (0.80, 16.72), respectively. DISCUSSION Based on our study's findings, overweight and obese patients with haemophilia A may benefit from an individualized PK analysis using LBM and IBW to determine the most accurate, and potentially cost-effective, method of achieving targeted FVIII recovery.

Introduction Central venous access devices (CVAD) are used to facilitate intravenous treatment with coagulation factor concentrates (CFCs) in haemophilia A (HA). Guidelines for perioperative CFC replacement therapy are based on single centre experiences, and the length of replacement therapy varies. Aim The aim of this study was to evaluate whether haemostasis coverage under four days is as effective and safe as a longer period of haemostatic coverage. Methods We identified patients with severe HA without inhibitors or major bleeds within one month of the surgery who received their first CVAD. We compared the CFC consumption and bleeds between children with ≤4 and those who received 5-7 perioperative treatment days including the day of surgery. Bleeds were recorded up to 4 days after the end of perioperative haemostatic coverage. Results In total, 144 children met the eligibility criteria and were included in the study cohort: 34 had received haemostatic coverage for ≤4 days, while 110 had received 5-7 days of haemostatic coverage. One bleed related to the surgery occurred in both groups. Conclusion Overall, the bleeding complications were rare. Haemostatic coverage with CFCs under ≤4 days with elective CVAD insertions was as effective as coverage for ≥5 days.

Introduction BAY 94‐9027 (damoctocog alfa pegol; an extended half‐life PEGylated recombinant factor VIII [FVIII]) demonstrated efficacy and safety in previously treated paediatric patients (PTPs) aged

The authors analyse the course of aseptic necrosis of the femoral head in a 7-year-old boy with haemophilia A (factor VIII level - 0%) caused by massive haemarthrosis into the hip joint (joint tamponade). The patient’s clinical and radiological symptoms differed from those in classic LCP disease, and now, after 20 years, the consequences of necrosis do not confirm typical Perthes disease (LCP). Significant shortening (about 5 cm) of the limb and the X-ray image of the proximal end of the femur resemble the consequences of severe necrosis of the femoral head in the treatment of an infant with developmental dysplasia of the hip (DDH). The study presents necrosis of the femoral head in the course of haemophilia due to its extremely rare occurrence as opposed to haemophilic arthropathy typical for this disease. This description may also contribute to considerations on the etiopathology of LCP disease.

Haemophilia it “philia” means love and “haemo” means blood it is a genetic disorder in which blood doesn’t clot which leads to excessive bleeding occurring to any injury or damage the bleeding is internal or external. Haemophilia is an X linked disorder. Females are carriers while males are sufferers. there are three types of haemophilia, haemophilia A, B and C out of this three type C is an autosomal recessive. The common symptoms present in haemophilia are pain, swelling, unexplained bleeding and blood in urine and stool. It is a rare condition 1 in million cases per year. Earlier haemophilia is treated by using Haemate P and Beriate P which dramatically improved the quality of life and life expectancy of haemophilia patients. The currently present treatment can help but cure is not yet found. Although physical therapy plays an important role in preventing joint bleeding and splinting to avoid further injury and a promptly designed programme to start weight bearing helps patient to gain back functionality. While recent advances like gene therapy, engineered clotting factors and an extensive pipeline of new approaches and modality. A 9 year old boy suffered a direct hit on his left knee there was no external bleeding at that time due to swelling the patient was taken to hospital where he was diagnose with haemophilia and was started with factors for Haemophila and then referred to physical therapy for pain, swelling, and improving strength. The patient responded very well to the physical therapy with significant improvement in the condition.

Emicizumab is a bispecific-humanized monoclonal antibody that improves hemostasis by bridging activated factor IX and factor X to substitute for the function of missing activated FVIII. It is an alternative to prophylaxis with factor VIII replacement and is associated with improved outcomes in individuals with hemophilia A with and without inhibitors.Emicizumab is efficacious in reducing bleeding events when compared to on-demand treatment and factor-based prophylaxis. Except for the few thrombotic microangiopathy and thrombotic event cases mainly seen in the HAVEN 1 trial, emicizumab has an overall excellent safety profile with minimal side effects.Knowledge gaps include the efficacy and safety of emicizumab in younger age groups and those with mild or moderate hemophilia A. Future directions for research include exploring the risk of inhibitor recurrence in patients with a history of high titer inhibitor who have been successfully tolerized, who switch from factor prophylaxis to emicizumab, as well as conducting 'real world studies' to evaluate the patient's perception of emicizumab in regard to ease and tolerability in order to optimize individualized treatment plans.

Patients with haemophilia A who have similar FVIII levels show clinical heterogeneity, and 10-15% of patients with severe haemophilia do not have a severe bleeding phenotype. The aim of this study was to assess whether global haemostasis tests, such as thrombin generation assay (TGA) and thromboelastography (TEG), can predict the bleeding pattern of severe haemophilia better than trough levels and pharmacokinetic profiles, particularly in the prophylactic setting. The study group consisted of 39 patients with haemophilia A and 75 healthy controls. The annual bleeding rate (ABR) and Hemophilia Joint Health Score 2.1 (HJHS) of the patients were determined. Basal factor FVIII, inhibitor levels, TEG and TGA of participants with prophylaxis were performed after a washout period. Then, a recombinant FVIII product was administered to patients. After factor replacement, the above tests were repeated at 30 min, 6 and 48 h. There was a significant difference in the ABR and HJHS between the groups according to the basal factor VIII activity of patients after wash-out. TEG and TGA parameters of patients with factor activity above 1% were significantly better than those of patients with factor activity below 1%. After factor concentrate administration, factor activities, TEG and TGA parameters at 30 min, 6 and 48 h were similar in the two groups. We showed that the 1% trough level but not for the 3% trough level is critical for both clinical phenotypes and thrombin generation for haemophilia patients in the prophylactic setting.

Introduction Emicizumab (Hemlibra™) is approved for prophylaxis of Haemophilia A (HA) patients with and without inhibitors. However, real-world data on emicizumab use in the elderly HA patients with concomitant cardiovascular risk factors are lacking. Aim To evaluate the safety and efficacy of emicizumab in a real-world cohort of elderly HA patients. Methods A prospective longitudinal observational study on HA patients over 50 years old treated, followed and monitored during emicizumab prophylaxis was conducted. We documented any bleeding or adverse events and collected plasma samples for emicizumab levels, aPTT and thrombin generation (TG). Results Seventeen HA patients (2 with inhibitor), whose median age was 62.4 years (range: 51.5-77.1) composed the cohort, including 9/17 with multiple cardiovascular risk factors (high risk group). Seven patients had chronic HIV infection. The median follow-up of our cohort was 400 days (range 89-805, IQR 211-479 days). The median annualized bleeding rate (ABR) significantly decreased for all patients. Among patients who displayed significant bleeding tendencies, emicizumab steady state levels as well as TG were lower as compared with the group. The ABR of four patients concomitantly treated by antiplatelet agents was significantly higher compared with the rest of the cohort. Neither thrombosis nor thrombotic microangiopathy (TMA) was encountered. Conclusions Emicizumab prophylaxis for HA patients older than 50 years including those with cardiovascular risk factors was well tolerated. As lower emicizumab and TG levels were observed among bleeding patients, we suggest that monitoring laboratory assays could be of value within this age group.