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Introduction: Prophylaxis has become standard of care for all persons with haemophilia (PWH) with a severe phenotype. However, 'standard prophylaxis' with either factor or non-factor therapies (currently only emicizumab available) is prohibitively expensive for much of the world. We sought to address the question of 'How much prophylaxis is enough?' and 'Can it be individualized?' and specifically 'Can emicizumab be individualized?'., Methods: We reviewed the literature on prophylaxis in haemophilia since its inception in the 1950s to the present, the development of more and less intense factor prophylaxis regimens and their outcomes and additionally the published outcomes of prophylaxis with low dose emicizumab., Results: What these experiences collectively show is that low dose emicizumab does result in significant benefits to patients whilst being much less expensive than a "one size fits all" emicizumab prophylaxis approach. We also took note that some non-factor therapies still in development are individualized given that high doses of these can potentially put patients at risk., Conclusions: Prophylaxis is now clearly accepted as standard of care for PWH with a severe phenotype but now in a very short time a large assortment of different treatment options for prophylaxis have become/are becoming available and the haemophilia community will need to determine how to best use these recognizing that no 'one treatment fits all'., (© 2024 John Wiley & Sons Ltd.)

Introduction: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA., Aim: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH., Methods: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months., Results: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study., Conclusion: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Hemophilia is a congenital bleeding disorder resulting from a low level or deficiency of clotting factors. It is an x-linked recessive disease and happens almost exclusively in males whereas females are the carrier of the affected gene. The most common types of hemophilia are hemophilia A and Hemophilia B. Hemophilia is classified into mild, moderate and severe. Prophylaxis treatment has more advantages clinically compare to on-demand therapy. It may reduce the bleeding frequency, gives protection from joint damage, may lower the number of total bleeding episodes per year, and may reduce annualised spontaneous and trauma related bleeding events. However, prophylaxis treatment needs regular weekly infusions therefore it is painful to administer especially if the vein is difficult to access. It may cause pain at the site of injections and may lead to non-adherence to treatment. Non-adherence to a regimen will result in insufficient clotting factor levels in the body. The efficacy of the medication is reduced and may lead to a high bleeding tendency. Thus far, the study on adult haemophilic patient adherence tool is scarce and limited; and therefore this review is warranted. The study protocol is conducted as per the PRISMA-P guideline. There are 4 concepts in this systematic review which are Haemophilia, adult and adolescence, preventive treatment and adherence. Articles will be sought from electronic databases PUBMED, Ovid EMBASE, CINAHL, and SCOPUS using the MeSH term, synonym free-text word, truncation, and proximity operators as per each database. The proposed keywords within each concept will be joined using the Boolean operator "OR "and the 4 different concepts combined using the Boolean operator "AND". Search will be limited to Human, English language, and publication until 2022. Studies will be included if they meet the study inclusion criteria. The quality of the studies will be appraised using the Newcastle-Ottawa quality assessment scale (NOS) for observation-based studies. This systematic review does not require formal ethical approval as data will be extracted from selected published studies. The results will be disseminated through a peer-reviewed publication and relevant conference presentations.(PROSPERO registration CRD42021273813)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mokhtar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The real-world effectiveness of the efmoroctocog alfa (recombinant FVIII Fc fusion protein, a rFVIIIFc) has been investigated in numerous studies, however, currently, there exists no comprehensive collection of the existing real-world evidence (RWE) on the performance of prophylactic use of rFVIIIFc., Aim: The aims of this systematic literature study were to identify, review, evaluate and collate the RWE of prophylactic rFVIIIFc for patients with haemophilia A reported in Europe., Methods: We searched Medline and Embase from 2014 to February 2022 to identify publications reporting the effectiveness of rFVIIIFc in patients with haemophilia A. The outcomes of interest were annualised bleeding rates (ABR, AjBR, AsBR), injection frequency, factor consumption, adherence, development of inhibitors and quality-of-life measures., Results: 46 eligible publications (eight full-text articles) were included. rFVIIIFc showed a low ABR in patients with haemophilia A. Studies assessing treatment switching from a standard half-life (SHL) treatment to rFVIIIFc found that the ABR and consumption were reduced in most patients. Studies assessing rFVIIIFc effectiveness reported a median ABR between 0.0 and 2.0 with median injections per week ranging between 1.8 and 2.4 and median doses between 60 and 105 IU/kg/week. Of the studies assessing inhibitor development, only one study reported an incidence of a low titre inhibitor, and no patients developed clinically significant inhibitors., Conclusion: rFVIIIFc prophylaxis treatment results in a low ABR across studies in patients with haemophilia A in a European real-world setting, which correlates with findings from clinical trials assessing the efficacy of rFVIIIFc in patients with haemophilia A., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

The purpose of prophylaxis in hemophilic patients is to prevent bleeding. The latest guidelines of the World Hemophilia Federation recommend that all patients with a severe hemorrhagic phenotype should receive prophylactic treatment, defined as the regular administration of therapeutic products (either factor concentrates or nonfactor replacement treatments). These products are aimed at preserving hemostasis and preventing bleeding, especially into joints. The guidelines also stipulate that prophylaxis should allow patients with hemophilia to lead healthy and active lives, participating in most physical and social activities, similar to the nonhemophilic population., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The prophylactic regimen in children with severe haemophilia is suggested in various publications and guidelines. Few data exist on its implementation in clinical practice., Aim: To investigate the implementation of primary prophylaxis based on real-life data from PedNet during the last 20 years., Methods: All children from the PedNet cohort (n = 1260) with severe haemophilia A (SHA) or severe haemophilia B (SHB), FVIII/IX < .01 IU/mL, born between 2000 and 2009 (Cohort I; SHA n = 662; SHB n = 88) and 2010-2019 (Cohort II; SHA n = 598; SHB n = 94) were included., Results: In SHA, the median age at start of prophylaxis was 17.3 months (IQR; 12.5-26.1) in Cohort I which decreased to 13.1 months (IQR; 10.4-19.1) in Cohort II (p < .000). "Once-a-week" prophylaxis at start increased from 49% to 68% (SHA) and 38% to 70% (SHB). FVIII doses were reduced from median 43.5 (IQR; 34.6-49.0) to 30.9 IU/kg (IQR; 26.3-46.3), while dosing with FIX did not change. After 2010 approximately 60% of the patients with SHA and SHB started prophylaxis before any joint bleed. The number of CVADs needed in both cohorts was around 30%. Incidences of inhibitors were unchanged: SHA (∼31%) and SHB (∼10%). Sporadic cases were diagnosed significantly later (median 8.3 months; IQR; 3.7-11.9) and they had more joint bleeds before start of prophylaxis., Conclusion: Primary prophylaxis nowadays starts at an earlier age: before any joint bleed (60% of patients with SHA and SHB). Approximately 70% started on a once-weekly schedule with significantly reduced doses in SHA but unchanged in SHB., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: People with non-severe haemophilia appear to be under-treated in many countries, and this may lead to joint damage and worsen quality of life., Aim: To review literature for clotting factor replacement prophylaxis in people with non-severe haemophilia A and B (HA/HB) in relation to long-term outcomes to support clinical decision-making., Methods: A targeted literature search was performed to identify studies published between 2000 and 2021 that included prophylaxis in people with non-severe HA/HB and long-term outcomes, including annualized bleeding rates, joint health and quality of life., Results: Although eligible articles included 2737 and 2272 people with mild or moderate HA, respectively, only 22% (n = 609) and 29% (n = 668) reported treatment regimens. A total of 549 people with moderate HA were treated with factor replacement prophylaxis and were from high-income countries. On the contrary, nearly all people with mild HA received desmopressin (n = 599). Details of treatment regimens for women with haemophilia and people with HB were sparse. Three studies provided long-term outcomes for people with moderate haemophilia who received prophylaxis with factor concentrate, supporting early prophylaxis in people with a frequent bleeding phenotype regardless of their endogenous clotting factor level to preserve joint health., Conclusion: There remain large knowledge gaps when considering how to provide optimal treatment for people with non-severe haemophilia. Nonetheless, there is a strong rationale that prophylaxis should be considered early in life according to similar strategies as for severe haemophilia for those with a frequent severe bleeding phenotype., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: As standard care of severe haemophilia A (SHA), prophylaxis should be individualised., Aim: This study aimed to investigate the effectiveness of this new-proposed individualised prophylaxis protocol., Methods: Boys with SHA were enrolled and followed a PK-guided, trough-level escalating protocol of prophylaxis after a six-month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS-Hemo., Results: Fifty-eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were: < 1 IU/dl, 17.2% (10/58); 1-3 IU/dl, 53.5% (31/58); 3-5 IU/dl, 15.5% (9/58); > 5 IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p < .0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p < .0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%-69.0%) and zero joint bleeding proportion (46.5%-81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p = .04) and HJHS (p = .02) were also reported at study exit., Conclusion: Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Hemophilia A is a genetically conditioned disease leading to hemostatic disorders due to factor VIII (FVIII) deficiency. The treatment of hemophilia has evolved throughout the past years and has significantly changed. One of the newest drugs for prophylactic treatment is the humanized bispecific IgG antibody - emicizumab, which binds with factor IXa and factor X, bridging those factors and thus mimicking the activity of factor VIII., Areas Covered: The literature search was done via the PubMed database, with the emphasis on clinical trials and case reports, describing the off-label emicizumab use. This review presents an extensive summary and considers the advantages and disadvantages (side-effects) of emicizumab, describing additional clinical situations, where emicizumab has been successfully used. In our review, we cover information about the mechanisms of action, indications, and efficacy and discuss some chosen case reports about off-label emicizumab use., Expert Opinion: Its convenient administration method (subcutaneous) and frequency of injections (from once a week to once a month) makes it a more comfortable treatment, limiting injection-site reactions, hospital stays, costs of prophylaxis, and significantly increasing patients' quality of life. Adverse effects are scarce and rarely serious - the most common ones are reactions at the injection-site and upper respiratory tract infections.

Introduction: Immunogenicity causing development of anti-drug antibodies (ADAs) are major challenges in the treatment of haemophilia, as well as other diseases where proteins are used for treatment. Furthermore, it is a complication for preclinical testing of such therapies in animal models., Aim: To investigate if the immunosuppressive drug CTLA4 immunoglobulin (CTLA4-Ig) can induce tolerance in haemophilia A (HA) rats receiving recombinant human coagulation factor VIII (rhFVIII) treatment., Methods: Two different prophylactic rhFVIII compounds were given intravenously to HA rats for 4 weeks. Both rhFVIII compounds were co-administered with commercially available CTLA4-Ig or human IgG subclass 4 (hIgG4) as control, and blood samples were collected. To functionally test if pharmacological efficacy was retained, rats were subjected to a bleeding experiment under anaesthesia at end of study., Results: The mean inhibitory level after 4 weeks in rats receiving rhFVIII and hIgG4 was 85.7 BU for octocog alfa and 37.4 BU for rurioctocog alfa pegol. In contrast, co-administration with CTLA4-Ig during rhFVIII therapy prevented the formation of ADAs (both binding and inhibitory) in 14/14 rats receiving octocog alfa and in 7/7 rats receiving rurioctocog alfa pegol. Moreover, we were able to show that the pharmacological efficacy of rhFVIII was preserved., Conclusion: In a rat model with spontaneous bleeding, co-administration of CTLA4-Ig with rhFVIII prevented antibody formation. No FVIII antibodies were detected, demonstrating that CTLA4-Ig co-administration can be applicable as a method to prevent immunogenicity, when evaluating human proteins in preclinical systems permitting continuous pharmacokinetic and pharmacodynamic assessment., (© 2022 John Wiley & Sons Ltd.)

Introduction: Low dose factor VIII prophylactic therapy in hemophilia has not been well established till date. This randomized controlled trial compared the efficacy of twice vs. thrice weekly schedule of low dose prophylactic factor VIII in children with hemophilia A as evaluated by the bleeding rate and clinico-radiological evaluation., Methods: Thirty-three children with severe hemophilia A (≤18 years) were randomized into two groups. Baseline evaluation included detailed history, clinical (HJHS 2.1 score and FISH score) and radiological examination (Pettersson score and ultrasound score). Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose being 10 U/kg in both groups. All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at the end of follow up were recorded., Results: We analyzed 14 children in twice weekly prophylaxis group and 16 children in thrice weekly prophylaxis group. Statistically insignificant difference was found between the bleeding rates in both the groups after prophylaxis with the median values of monthly bleeding rate being 0.17 and p-value of 0.79. The differences between the initial and final clinical and radiological scores within each group were found to be statistically significant. There was no significant difference in the clinical and radiological scores in between the groups., Conclusion: Twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A. Lay summaryHemophilia A is one of the most common congenital coagulation factor deficiencies. Low dose factor VIII prophylaxis is recommended for hemophilia in resource-poor settings to reduce the bleeding episodes and improve the quality of life, although the optimal schedule for the same has not been well established. A randomized controlled trial on 33 children with hemophilia A (≤18 years) was done to compare the efficacy of twice versus thrice weekly schedule of prophylactic factor VIII. Group 1 received twice weekly factor VIII prophylaxis while group 2 received thrice weekly factor VIII prophylaxis, the dose in both groups being 10 U/kg. They were evaluated by the bleeding rate and clinical (HJHS 2.1 score and FISH score) and radiological scores (Pettersson score and ultrasound score). All participants were followed up over next 6 months to one year. Data regarding acute bleeding episodes and repeat clinico-radiological assessment at end of follow up were recorded. When analyzed, statistically insignificant difference was found between the bleeding rates after the two prophylaxis regimes. There was a significant improvement between initial and final clinical and radiological scores in both the groups and no difference was recorded in between the groups. To conclude, twice weekly FVIII therapy is effective, easily administered prophylactic schedule to prevent long-term complications of hemophilia A., (© The Author(s) [2022]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30-50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved ( i.e. , more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients., (©2022 JOURNAL of MEDICINE and LIFE.)

Background: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose., Methods: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5  × 10 11 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 10 12 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII., Results: The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration)., Conclusions: Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.)., (Copyright © 2021 Massachusetts Medical Society.)

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Emicizumab reduces bleeding in hemophilia A patients with inhibitor (HA-inh). A combination of immune tolerance induction therapy (ITI) and emicizumab prophylaxis may provide additional benefits, but coagulation potential during this treatment remains unknown. We assessed coagulation potentials in simulated ITI models in vitro using modified-clot waveform analysis. Factor (F)VIII-deficient plasma preincubated with anti-A2 and anti-C2 monoclonal antibodies was reacted with emicizumab (50 µg/mL) (emicizumab-HA-plasma), then spiking bypassing agents (BPAs): activated prothrombin complex concentrates (aPCC 1.3 IU/mL; 50 IU/kg), recombinant factor (rF)VIIa (2.2 µg/mL; 90 µg/kg), and FVIIa/FX (1.5 µg/mL; 60 µg/kg), and/or FVIII (100, 200 IU/dL). Coagulation potentials in emicizumab-HA-plasma (10 BU/mL) remained within the normal range when BPA and FVIII were both present. In emicizumab-HA-plasma (1 BU/mL) with BPA and FVIII (200 IU/dL), they were near or beyond the normal range, but those with a half concentration of rFVIIa based on the half-life in blood were within the normal range. In samples without inhibitor, coagulation potentials with combined BPA and FVIII were far beyond the normal range but with FVIII (100 IU/dL) and rFVIIa at half concentration they remained within the normal range. These results may provide information on the feasibility of concurrent ITI under emicizumab prophylaxis.

Objective: This study aimed to observe the preventive effect of prophylactic treatment on joint health in people with hemophilia (PwH) and to investigate the importance of integration of ultrasonographic examination into clinical and radiological evaluation of the joints., Materials and Methods: This national, multicenter, prospective, observational study included male patients aged ≥6 years with the diagnosis of moderate or severe hemophilia A or B from 8 centers across Turkey between January 2017 and March 2019. Patients were followed for 1 year with 5 visits (baseline and 3 th , 6 th , 9 th , and 12 th month visits). The Hemophilia Joint Health Score (HJHS) was used for physical examination of joints, the Pettersson scoring system was used for radiological assessment, point-of-care (POC) ultrasonography was used for bilateral examinations of joints, and the Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score was used for evaluation of ultrasonography results., Results: Seventy-three PwH, of whom 62 had hemophilia A and 11 had hemophilia B, were included and 24.7% had target joints at baseline. The HJHS and HEAD-US scores were significantly increased at the 12 th month in all patients. These scores were also higher in the hemophilia A subgroup than the hemophilia B subgroup. However, in the childhood group, the increment of scores was not significant. The HEAD-US total score was significantly correlated with both the HJHS total score and Pettersson total score at baseline and at the 12 th month., Conclusion: The HEAD-US and HJHS scoring systems are valuable tools during follow-up examinations of PwH and they complement each other. We suggest that POC ultrasonographic evaluation and the HEAD-US scoring system may be integrated into differential diagnosis of bleeding and long-term monitoring for joint health as a routine procedure.

Introduction: The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations., Aim: To describe the development, methodology and achievements of the WFH AGS over the past 20 years., Methods: The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues., Results: Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry., Conclusion: The AGS has provided evidence to support research, programme planning and development activities of the WFH., (© 2020 John Wiley & Sons Ltd.)

Introduction: Adherence to a prophylactic therapy is obligatory to prevent bleeding in patients with haemophilia. It has already been recognized that depression is associated with treatment adherence., Aim: The aim of this study was to examine the prevalence of depressive symptoms in adults with haemophilia using an instrument designed or validated for diagnosing or screening for depression and to investigate the association of symptoms of depression with nonadherence to prophylactic therapy in patients from two East European countries., Methods: Adult patients with severe or moderate haemophilia receiving prophylaxis were eligible for the study. Depressive symptoms were assessed with BDI-II, adherence with VERITAS-Pro, demographic and socioeconomic data were collected using a questionnaire, and clinical data were obtained from medical records., Results: Final sample included 81 participants (median age was 45 years, range 18-73 years). There were 9 (11%) participants with scores on BDI-II above 14 points, the cut-off score for depressive symptomatology. In general, participants were adherent. However, there were 14 (17%) participants who had scores above 57 points, the cut-off score for nonadherence. There was an association between having depressive symptoms and being nonadherent, and depressive symptoms explained additional variance in adherence after controlling for sociodemographic, psychosocial and clinical characteristics., Conclusion: Since there is an association between depressive symptoms and nonadherence, it would be beneficial for both patients and the public health system for screening for depressive symptoms to be included as a part of the treatment protocol., (© 2020 John Wiley & Sons Ltd.)

Introduction: The management of haemophilia is critical to minimize the risk of disability and reduce the burden on China's healthcare system., Aim: This study was based on a single centre in China and was conducted to understand the evolution of real-world haemophilia care over the past 15 years., Methods: We retrospectively analysed clinical characteristics, diagnosis, treatment and medical expenditures of 428 patients with haemophilia from January 2004 to December 2018 from the Institute of Hematology & Blood Diseases Hospital in Tianjin, China., Results: The delayed diagnosis time significantly decreased from 13.3 ± 5.1 years before 2004 to 0.4 ± 0.4 year in 2014-2018 (P < .05). Among children and adults receiving prophylactic treatment, the annual factor consumption increased from 2004-2008 (168.8 IU/kg in children and 120.7 IU/kg in adults) to 2009-2013 (389.2 IU/kg in children and 316.2 IU/kg in adults) and 2014-2018 (1328.0 IU/kg in children and 878.8 IU/kg in adults, P < .001). The annual medical insurance expenditure for haemophilia had increased steadily over the past 10 years. The number of patients tested regularly for inhibitors increased from 2004 (1.9% [2/105]) to 2018 (21.5% [59/275]). The seroprevalence of hepatitis C virus (HCV) was 33.8% during the years examined, while the incidence rates of HCV among patients significantly decreased (7.3% in 2008 to 0.4% in 2018)., Conclusion: Significant improvements in the management of haemophilia were observed from 2004 to 2018. These results highlight the joint effort of the reimbursement policy and drug regulatory management paving the way for a better future for patients with haemophilia in China., (© 2020 John Wiley & Sons Ltd.)

Introduction: The clinical benefits of administering low-dose prophylaxis in children with haemophilia are well established. Qualitative research describing the impact of prophylaxis on quality of life is comparatively rare in this area., Aim: The aim of this study was to investigate in children the experiences of living and becoming adjusted to haemophilia before prophylaxis, by collecting information directly from children and their parents or guardians. A further goal was to evaluate whether and how the use of low-dose prophylaxis impacts the disease experience., Methods: A grounded theory design according to Strauss and Corbin was chosen for this study. The study was conducted in the Haemophilia Treatment Centre at Aluva, Kerala, India and involved nineteen participants (children, mothers, father and grandmothers) who were selected by theoretical sampling. Data were collected through audiotaped interviews, which included demographic and semi-structured interview questions. Data were coded and evolved into concepts and categories that lead to the emergence of theory., Results: The study resulted in the construction of 'Theory of Therapeutic Metamorphosis'. It comprised two stages: stage of bondage (enduring hardships), experienced during the absence of prophylaxis or on-demand treatment and stage of freedom (deliverance/reductions, energized life/improvements and behaviour to seek prophylaxis) experienced during low-dose prophylaxis., Conclusion: This study illustrates the challenges faced by children with haemophilia and their families and the positive impact of low-dose prophylaxis. Further prospective research studies are required to add to the growing knowledge in this area., (© 2020 John Wiley & Sons Ltd.)

Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC's anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC's cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC's anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.

Objectives: To investigate the effectiveness of low dose secondary/tertiary prophylaxis in severe Hemophilia A children and determine improvements in their daily life., Methods: Thirty Hemophilia A children (≤ 12 y) with factor VIII <2% and less than two joint bleeds without inhibitors, were given prophylaxis with recombinant Fc fusion long acting factor VIII (ELOCTATE) at 10 IU.kg -1 twice weekly for 1 y. Earlier, patients received on-demand FVIII for a minimum of six months. Outcome was measured in terms of annual bleeding rate, Hemophilia Joint Health Score (HJHS) and child activity/participation was measured in terms of school absenteeism, School Activity Participation Score and Daily Activity Score according to Beijing Children Hospital assessment scale., Results: A total of 30 children were included in the study. There was reduction in annual joint bleeds by 85.76% (14.5 to 2.2) and school absenteeism (days/month) by 86% (17.38 to 2.42) before and after prophylaxis respectively. Majority (43%) showed moderate improvement in daily activity score. Mean HJHS score was 8.3. There was mild improvement in School Activity Participation Score in 57%. Mean annual hospitalization rate reduced from 8.7 to 1.1 with improvement in joint scores. Mean annual factor consumption decreased from 1944.2 IU.kg -1 to 1560.3 IU.kg -1 ., Conclusions: With low dose secondary/tertiary prophylaxis, there is significant reduction in the annual joint bleed rate with improvement in joint health and child activity. As factor consumption is reduced, this has a positive effect on cost benefit; and is a very feasible option in developing countries.

Emicizumab has been approved in several countries for regular prophylaxis in patients with congenital haemophilia A and FVIII inhibitors because it substantially reduces their bleeding risk and improves quality of life. However, although significantly less frequent, some breakthrough bleeds may still occur while on emicizumab, requiring treatment with bypassing or other haemostatic agents. Thrombotic complications have been reported with the associated use of activated prothrombin complex concentrates. In addition, when surgery/invasive procedures are needed while on emicizumab, their management requires multidisciplinary competences and direct supervision by experts in the use of this agent. Given this, and in order to expand the current knowledge on the use of emicizumab and concomitant haemostatic agents, and reduce the risk of complications in this setting, the Italian Association of Haemophilia Centres (AICE) here provides guidance on the management of breakthrough bleeds and surgery in emergency situations in patients with haemophilia A and inhibitors on emicizumab prophylaxis. This paper has been shared with other National Scientific Societies involved in the field.

Introduction : Primary prophylaxis with FVIII is the therapeutic regimen of choice in severe hemophilia A; it reduces joint bleeding and associated chronic damage and helps prevent fatal bleeds. However, the high frequency of intravenous injections is a significant challenge for the optimal implementation of prophylaxis, particularly in children and adolescents. Novel therapeutic approaches have been developed to overcome this challenge. FVIII products with an extended plasma half-life can reduce the number of intravenous injections in the frame of prophylaxis regimens and can yield higher trough plasma levels of FVIII. The goal is to avoid all spontaneous bleeding episodes (zero events). Areas covered : This article reviews the benefits offered by the currently licensed extended half-life products and examines limitations, unmet needs, and knowledge gaps. Expert opinion : FVIII replacement remains the standard of care in patients with hemophilia A; however, there have been advances in novel treatment approaches. Non-factor products such as emicizumab offer a promising alternative that warrants more real-life experience and a direct comparison with FVIII replacement.

Background: Physical activity in people with haemophilia (PWH) reduces the development of severe arthropathy, but it must be performed after regular, proper prophylaxis. Strict adherence to treatment is crucial to achieving effectiveness and established outcomes. The primary aim of this study was to collect prospective data on adherence to prophylaxis for over 36 months. A secondary aim was to verify whether adherence correlates with physical activity., Materials and Methods: Italian patients with severe haemophilia A treated on prophylaxis with octocog alfa were included in the study. Physical findings were assessed by the Haemophilia and Exercise Project (HEP)-Test-Q and the Early Prophylaxis Immunologic Challenge (EPIC)-Norfolk Physical Activity Questionnaire; orthopaedic status was assessed by the Hemophilia Joint Health Score (HJHS). Adherence was measured as percentage of empty vials returned with respect to the prescribed amount., Results: Forty-two PWH were enrolled: 31% children, 21.4% adolescents, and 47.6% adults. Type, frequency and impact of physical activities differed among the three groups. The HEP-Test-Q showed the highest impairments in the domains "endurance" and "strength/co-ordination". Eight percent of patients were classified as adherent to prophylaxis. Among them, 50% had at least one bleeding episode in the year before enrolment; this percentage dropped during the three years of the study. While remaining stable in the "non-adherent" group, the HJHS score decreased in the "adherent" patients. The mean number of school/work days lost was lower in adherent patients (from 3.4±6.8 to 0.2±0.9) than in non-adherent ones., Discussion: PWH with better orthopaedic scores reported better physical performance. Adherence to long-term prophylaxis proved to be high and correlated with a reduction in bleeds, target joints, school/work days lost, and with a performance improvement in endurance sports activities over time.

Introduction . Medical improvements have allowed hemophilia patients to anticipate an increased quality of life and life expectancy similar to that of the general population. Analysis of the potential disease symptoms of hemophilia patients based on a survey of Sasang Constitutional Medicine (SCM) is important for optimal preventive care and adjunctive therapy to avoid life-threating complications., Aim: To predict potential disease symptoms from the viewpoint of SCM as a preventive care strategy for hemophilia patients., Methods: Sixty-one hemophilia patients responded to a survey on Sasang constitutional classification, hemophilia disease pattern, and original symptoms., Results: In terms of SCM type, the 61 of hemophilia patients included 37 Tae-Eum (60.7%), 18 So-Yang (29.5%), and 6 So-Eum (12.5%). Hemophilia was found to be higher in Tae-Eum type and lower in So-Yang and So-Eum types, while considering the distributional rate of Korean Sasang types. Most of the patients with Tae-Eum type had Joyeol or Ganyeol. Furthermore, the incidences of diabetes and high blood pressure were greater in Tae-Eum type than in those of other types., Conclusion: In order to increase the quality of life and overall life expectancy, hemophilia patients with Tae-Eum type should be treated through management according to SCM along with medicine against hemophilia as long-term preventive care. Diabetes and high blood pressure should be regularly monitored in patients with Tae-Eum type., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Mi Kyung Lee et al.)

There have been numerous advances in the field of hemophilia management in the past decade, including long acting factor products, non-factor products, and potentially curative interventions such as gene therapy. Each of these interventions introduces exciting treatment modalities to patients with both hemophilia A and B, however they also pose a daunting array of possible management options. Adverse reactions to novel agents are being reported as more patients are treated and long-term sustainability of interventions such as gene therapy is yet to be determined. The practicing hematologist should be aware of the intricacies involved in customizing care for their individual patients and be aware of the monitoring strategies for each interventional strategy to avoid adverse events. Upfront cost vs. long term benefit should be considered as choices of treatment strategies are made, especially in resource poor countries. The goal of the newer agents is to decrease annualized bleed rates and avoid debilitating arthropathy. This article looks at current treatment models for prophylaxis and management of inhibitors, reviews the recent advances in the field (with bioengineered factor products, non-factor products and gene therapy) and summarizes the incorporation of these new interventions in the treatment plan for patients with hemophilia.

Introduction: Emicizumab is a bispecific monoclonal antibody that mimics factor VIII (FVIII) by binding to factors IXa and X to promote hemostasis in haemophilia A (HA) and HA with inhibitors (HA-I). As emicizumab differs biochemically from FVIII, there is interest in its real-world haemostatic efficacy., Aim: To describe real-world patient experience with emicizumab by retrospective chart review., Methods: We reviewed medical records of patients cared for at the Hemophilia Center of Western PA, who initiated emicizumab following its licensure, and on whom bleeding events and factor use were available. Comparisons between groups were done by Student's t test for continuous data and by chi-square or Fisher's exact test for discrete data., Results: A total of 42 patients whose charts were reviewed included 18 (42.9%) with HA and 24 (52.1%) with HA-I. Groups were similar in age, 17 (40.5%) <18 years, race, and haemophilia severity, and initiated weekly subcutaneous emicizumab 1.5 mg/kg, following 4-week induction. Fourteen (33.3%) experienced at least one breakthrough bleed, of which 11 (44.0%) were joint bleeds, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, P = .251. Surgical procedures were performed in 10 (23.8%), of whom 4 (40.0%) had postoperative bleeding and one developed postoperative thrombosis in association with FEIBA despite emicizumab discontinuation 1 month preoperatively. Local skin reactions occurred in three and headache in one. Overall, 85.0% of those who rated their health indicated it was improved., Discussion: Despite breakthrough bleeds and postoperative thrombosis associated with emicizumab, most HA and HA-I experienced improved health., (© 2019 John Wiley & Sons Ltd.)

Introduction: Turoctocog alfa is a recombinant, B domain-truncated factor VIII (FVIII) approved for patients with haemophilia A., Aim: To evaluate the safety and efficacy of turoctocog alfa in previously untreated patients (PUPs) with severe haemophilia A., Methods: Guardian 4 was a multicentre, multinational, non-randomized, open-label phase 3 trial comprising a main and extension phase. The former concluded once ≥ 50 patients had received treatment for ≥ 50 exposure days (EDs) or developed inhibitors. Patients received turoctocog alfa intravenously for prevention and treatment of bleeds. The primary endpoint was the incidence rate of FVIII inhibitors (≥0.6 Bethesda Units) reported during the first 50 EDs., Results: Of the 58 patients who completed the main phase, 25 (43.1%) patients developed inhibitors (detected within 6-24 [mean: 14.2] EDs from treatment start). High-risk mutations were identified in 60% of patients who developed inhibitors in the main phase and were a significant predictor of inhibitor development (P = .003). Of the 21 patients who started immune tolerance induction therapy, 85.7% completed treatment with a negative inhibitor test (note that data on the last 3 patients completing ITI are based on information collated from sites prior to the final database lock). Haemostatic response (including missing values as failure) was rated as 'excellent' or 'good' for 86.1% of bleeds occurring during prophylaxis. The estimated mean annualized bleeding rate for patients on prophylaxis was 4.26 bleeds/patient/year (95% CI: 3.34 - 5.44)., Conclusions: Turoctocog alfa was effective at preventing and stopping bleeds and was well tolerated. Inhibitor development was within the expected range for this PUP population., (© 2019 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Monitoring of clinical effectiveness of bypassing agents in haemophilia patients is hampered by the lack of validated laboratory assays. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been evaluated for predicting clinical effectiveness of bypassing agents, however, with limited success., Aim: Application of a longitudinal model-based approach may allow for a quantitative characterization of the link between ROTEM parameters and the probability of bleeding events., Methods: We analyse longitudinal data from haemophilia A rats receiving gene-based FVIIa prophylaxis in terms of total circulatory levels of FVII/FVIIa, clotting time (CT) measured using ROTEM and the probability of bleeding events., Results: Using population pharmacokinetic-pharmacodynamic (PKPD) modelling, a PK-CT-repeated time-to-event (RTTE) model was developed composed of three submodels (a) a FVII/FVIIa PK model, (b) a PK-CT model describing the relationship between predicted FVIIa expression and CT and (c) a RTTE model describing the probability of bleeding events as a function of CT. The developed PK-CT-RTTE model accurately described the vector dose-dependent plasma concentration-time profile of total FVII/FVIIa and the exposure-response relationship between AAV-derived FVIIa expression and CT. Importantly, the developed model accurately described the occurrence of bleeding events over time in a quantitative manner, revealing a linear relationship between predicted change from baseline CT and the probability of bleeding events., Conclusion: Using PK-CT-RTTE modelling, we demonstrated that ROTEM parameters can accurately predict the probability of bleeding events in a translational animal model of haemophilia A., (© 2019 John Wiley & Sons Ltd.)

Bayesian forecasting for dose individualization of prophylactic factor VIII replacement therapy using pharmacokinetic samples is challenged by large interindividual variability in the bleeding risk. A pharmacokinetic-repeated time-to-event model-based forecasting approach was developed to contrast the ability to predict the future occurrence of bleeds based on individual (i) pharmacokinetic, (ii) bleeding, and (iii) pharmacokinetic, bleeding and covariate information using observed data from the Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease (LEOPOLD) clinical trials (172 severe hemophilia A patients taking prophylactic treatment). The predictive performance assessed by the area under receiver operating characteristic (ROC) curves was 0.67 (95% confidence interval (CI), 0.65-0.69), 0.78 (95% CI, 0.76-0.80), and 0.79 (95% CI, 0.77-0.81) for patients ≥ 12 years when using pharmacokinetics, bleeds, and all data, respectively, suggesting that individual bleed information adds value to the optimization of prophylactic dosing regimens in severe hemophilia A. Further steps to optimize the proposed tool for factor VIII dose adaptation in the clinic are required., (© 2019 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Aim: To assess effect of low dose prophylaxis in hemophilics in terms of bleeding, joint function, QoL and cost-effectiveness., Methods: Analytic study done during one year among 70 adult hemophilics. In observation period (12 weeks), on-demand factor and during prophylaxis (12 weeks), low dose factor was given (Factor VIII 10 IU/KgBW biweekly for haemophilia A and Factor IX 20 IU/KgBW weekly for haemophilia B). Clinical joint assessment was done by Gilbert score and improvement by WFH definitions., Results: Bleed reduced by 68.99% in moderate hemophilics (40 v/s 129) and 64.86% in severe hemophilics (26 v/s74) (p<0.05). During observation in moderate hemophilics, joint, soft tissue and mucosal bleeds occurred in frequency of 120, 1 and 8. This was reduced to 39 joint bleeds, 1 soft tissue bleed and no mucosal bleed during prophylaxis. In severe hemophilics, 70 joint, 2 soft tissue bleeds and 2 mucosal bleeds occurred during observation which reduced to 26 joint bleeds without soft tissue/mucosal bleed in prophylaxis. Bleeding episodes decreased by 65.79% in joints, 66.67% in soft tissues, 100% mucosal bleeds. After prophylaxis one joints (0.61 %) showed good improvement in joint function, thirty (18.18 %) joints showed moderate improvement and ninety two joints (55.76 %) showed mild improvement in joint function. Hospitalization reduced by 60.34% (163 v/s 411) and absenteeism by 53.73% (279 v/s 603). Factors consumption reduced by 12.33 % during prophylaxis period., Conclusion: The low dose prophylaxis strategy significantly decreased the subsequent episodes of total bleeds including joint bleeds and improved the joint function as well as quality of life., (© Journal of the Association of Physicians of India 2011.)

: Prophylaxis has helped improve patients' perception of their quality of life, enabling them to lead a more normal life. For these reasons prophylactic treatment is nowadays considered a gold standard in the treatment of severe hemophilia A or B. Despite its benefits in terms of preventing bleeding and preserving patients' health, this intensive treatment is not always adhered to by patients with hemophilia - promotion of adherence should involve a multidisciplinary team which addresses not only the clinical aspects of a condition but also the different psychosocial aspects affecting patients and their (social, family and healthcare) environment.

: Prophylaxis with factor VIII concentrates is the cornerstone of treatment for severe hemophilia A. In children, early onset of primary and secondary prophylaxis is the gold standard in most of countries with adequate financial resources. In adults, it is reasonable to continue the prophylactic treatment initiated during childhood to preserve joint functionality. Adults with advanced hemophilic arthropathy can also benefit from tertiary prophylaxis, showing reductions in bleeding episodes, target joints and missed days from work. The long-term evolution of hemophilic patients usually depends on how successfully prophylaxis can prevent bleeding in both children and adults. For prophylaxis to be efficient it is essential to consider the resources available (factor concentrate use and trough levels) and the patient's bleeding phenotype and clinical situation (levels of activity required, presence of chronic synovitis and arthropathy), and to define the annual number of bleeds (particularly into joints) acceptable for each patient.

: Prophylaxis entails long-term continuous intravenous administration of concentrates of the deficient factor with a view to preventing spontaneous bleeds and the development of hemophilic arthropathy. Initiation of prophylaxis at an early age and continuous uninterrupted factor administration in patients with hemophilia have been hailed as essential by such organizations.The most widely used prophylaxis regimens include the Swedish (Malmö), the Dutch and the Canadian protocols. Different international groups have hailed prophylaxis as the most effective treatment in patients with hemophilia.Prophylaxis is effectiveness in preventing bleeding and arthropathy in children with (particularly early-onset) hemophilia. Although some retrospective trials confirm the benefits of prophylaxis, others point to a lack of conclusive data to support switching adult patients with established hemophilic arthropathy who always received on-demand treatment to prophylactic treatment.The potential effects of prophylaxis on the patients' sex lives, renal status, prostate involvement and cataract must be analyzed before indicating prophylactic treatment in elderly patients.The high efficacy of prophylactic treatment in patients with hemophilia and inhibitors has been widely reported in the literature.

Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement., (© 2019 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: Prophylaxis has commonly become standard treatment for severe haemophilia patients. The World Federation of Hemophilia (WFH) recommends low-dose prophylaxis in countries with resource constraints., Objective: To determine efficacy and safety of low-dose factor VIII (FVIII) tertiary prophylaxis compared to on-demand treatment in severe haemophilia A children in Indonesia., Methods: Eligible patients were randomly assigned to prophylaxis and on-demand groups. Patients in the prophylaxis group received infusion of FVIII 10 IU/kg body weight, two times per week. Primary outcomes were the numbers of joint bleeding and total bleeding episodes; secondary outcomes were evidence of FVIII inhibitor, Hemophilia Joint Health Score (HJHS) and Hemophilia Early Arthropathy Detection Ultrasound (HEAD-US) score. Patients were monitored for 12 months., Results: Fifty patients, all with tertiary prophylaxis, 4-18 years of age, were randomized into prophylaxis (n = 25) and on-demand (n = 25) groups. The mean follow-up time was 12.8 ± 0.86 vs 12.3 ± 0.54 months, respectively. Numbers of total and joint bleeding episodes were significantly lower in the prophylaxis group (P < 0.001, 95% CI -24.6;-10.7 and P < 0.001, 95% CI -14;-3, respectively). The prophylaxis group showed improvement of joint function (P = 0.004; CI 95% -3;-0.5); on the contrary, we found deterioration in the on-demand group (P = 0.001; CI 95% 1;3). HEAD-US scores showed improvement at month 6 in the prophylaxis group, but there was no significant difference between groups at month 12., Conclusion: Low-dose FVIII tertiary prophylaxis was effective in reducing joint bleeding episodes and improvement of HJHS compared to on-demand FVIII treatment in severe haemophilia A children., (© 2019 John Wiley & Sons Ltd.)

Introduction: The optimal treatment modality for haemophilia A is lifelong prophylaxis which is expensive and may not be implementable everywhere where factor VIII (FVIII) availability is limited. A less costly alternative to prophylaxis is low-dose prophylaxis (LDP) which was compared to conventional prophylaxis in this model-based simulation study., Aim: To explore whether LDP is motivated where standard prophylaxis is not implementable, including evaluating LDP efficacy compared to high-dose prophylaxis and investigating the potential economic benefit of individualized dosing., Methods: For a virtual adult haemophilia A population, FVIII activity levels were simulated following alternative treatment regimens, based on a published population PK model. The regimens included very LDP, LDP and conventional prophylaxis twice and thrice weekly. The annual probability of bleeding was predicted based on the weekly time spent below 1 IU/dL, using a previously published relationship. Additionally, PK-based dose individualization was evaluated to determine FVIII savings using Bayesian forecasting., Results: A treatment regimen of 10 IU/kg administered thrice weekly cost 75% less than a standard high-dose regimen and was predicted to have a 5% higher median probability of annual bleeds. PK-based dose individualization may result in further cost-savings, but implementation needs benefit versus feasibility consideration., Conclusion: Based on simulations, a promising LDP regimen was identified that decreased treatment costs compared with standard high-dose prophylaxis at a small increase in bleeding risk. The results indicate that LDP is advocated where the standard-of-care is on-demand treatment; however, the results should be considered in the context of any limitations of the applied models., (© 2019 John Wiley & Sons Ltd.)

A 58-year-old morbidly obese male (body mass index: 38 kg/m 2 ) with severe haemophilia A underwent total knee replacement surgery. Perioperatively, factor VIII (FVIII) levels were measured daily and maximum a posteriori (MAP) Bayesian estimation was used to calculate the individual pharmacokinetic (PK) parameters and doses required to obtain prescribed FVIII target levels. In the MAP Bayesian procedure, a population PK model was used in which PK parameters were normalised using body weight. In this specific case, ideal body weight was used to scale the PK parameters instead of actual body weight. Except for the preoperative FVIII level, adequate FVIII levels were achieved during the 10-day perioperative period. During follow-up visits, the knee prosthesis was reported to function adequately., Competing Interests: Competing interests: BLvG has received unrestricted educational grants from Baxter and CSL Behring. MHC has received unrestricted research grants for investigator-initiated studies and educational as well as travel grants from Pfizer, Shire, Bayer, Novo Nordisk, CSL Behring, Novartis and Roche. RAAM has received travel grants from Shire and Bayer. The remaining authors declare no competing financial interests., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Standard prophylaxis dosing based on bodyweight may result in over- or under-dosing due to interpatient variability. Adopting individual pharmacokinetic (PK) based tailoring may improve adherence to treatment guideline, and consequently clinical outcomes. Here we report clinical observations performed across the adoption of individual PK based tailoring in a single center in Japan., Methods: An individual PK study on sparse samples was modeled on myPKFiT or WAPPS-Hemo, depending on concentrate, and used to optimize treatment regimens. Adherence to prophylaxis and bleeding rate were calculated from patient diaries. Radiological joint scores were used to assess arthropathy, and SPSS to perform all the analyses., Results: Thirty-nine patients underwent PK profiling, and 20 required and accepted a modification of their treatment (8 increases in dose, 5 reductions in frequency, 5 switches to extended half-life (EHL)). Adherence to prophylaxis remained the same in those increasing the dose, whilst increased in all the other groups. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AjBR) decreased in all the groups but reached statistical significance only in those switched to EHL and showed a larger reduction in those patients without baseline arthropathy. Longer time spent above a 1% or 5% threshold was associated with a decrease in the ABR/AjBR., Conclusions: Our study results suggest that PopPK based tailoring supported changing treatment regimen in nearly half of the patients, and may have contributed to an improvement in the adherence and a reduction in the ABR/AjBR., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Congenital hemophilia A, a relatively common and sometimes life-threatening bleeding disorder, is caused by inherited deficiency of clotting factor (F) VIII. The adoption of an appropriate medical and environmental prophylaxis is critical for long-term management of hemophilia because it will considerably reduce the number of both mild and severe bleeding episodes. Among the many therapeutic options that have become available over the past decades, ACE910 (also known as emicizumab) is a bispecific immunoglobulin G antibody characterized by its unique ability to bind FIX or FIXa on one arm and FX on the other, thus abrogating FVIII activity in vivo. Several phase I to III clinical trials have now been published, confirming the clinical efficacy and relative safety of this new agent for long-term prophylaxis of hemophilia A, especially those patients having FVIII inhibitors. The recent regulatory clearance of ACE910 in many countries will hence impose additional challenges to clinical laboratories because the panel of available tests will need to address the emerging issue of monitoring patients treated with this novel anti-hemophilic agent by using conventional as well as innovative approaches. Therefore, this article is aimed to provide an update on clinical background and challenges of laboratory assessment in hemophilia A patients undergoing ACE910 administration., (© 2019 Elsevier Inc. All rights reserved.)

Introduction : rFVIIIFC was the first extended half-life product to complete the phase 3 development program and be registered. It was developed to reduce the high treatment burden imposed by prophylaxis. It is now one of four extended half-life products available for a variety of indications in hemophilia A. This article focus on the efficacy use of rFVIIIFC in the prevention of bleeds in hemophilia A. Areas covered : This article provides an update on efficacy data from three clinical studies describing the use of rFVIIIFC in the treatment and prevention of bleeds in hemophilia A. The update includes the efficacy use of rFVIII in all age groups, in the perisurgical setting, in immune tolerance induction, and in improving the quality of life of patients. The role of rFVIIIFC prophylaxis in the face of rapidly evolving non-replacement therapy and gene therapy is summarized. Expert commentary : The role of rFVIIIFC in hemophilia A prophylaxis is uncertain in the light of development of newer prophylaxis agents with better route of administration, improved pharmacokinetic and superior efficacy profiles. While rFVIIIFC was primarily developed for prophylaxis in hemophilia A, this role may change in the face of competitive extended half-life products and non-replacement therapies.

Physical activity provides many benefits in patients with congenital bleeding disorders. Patients with hemophilia are encouraged to participate in exercise and sports, especially those patients receiving prophylaxis. Several publications and guidelines have explored this issue in hemophilia patients, evaluating in particular the impact of physical activity on patients' well-being and quality of life. The other rare congenital bleeding disorders are less studied; they are heterogeneous in terms of clinical bleeding phenotype, incidence of hemarthrosis, and arthropathy. Furthermore, prophylaxis in these patients is less common than in hemophilia patients, which must be considered when choosing the type of physical and sporting activity. In this review, the authors have analyzed the literature focusing their attention on those rare coagulation disorders that may be complicated by arthropathy and the role of exercise and sports in this context., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Regular prophylactic treatment with factor VIII (FVIII) and factor IX (FIX) concentrates in hemophilia A and B, respectively, is introduced in early infancy and has resulted in dramatic improvement of the conditions. Recombinant FVIII and FIX concentrates have been available for > 25 years and have been modified and refined through the years; however, unfortunately frequent intravenous administrations are still necessary. The half-lives of these products have now been extended (EHL) by fusion with albumin, the Fc-portion of IgG, or by being PEGylated. This has been very successful for EHL-FIX, with 3-5 times longer half-life, and to a lesser degree for EHL-FVIII with a half-life extension of only 1.5 times the conventional products. New treatment principles using FVIII mimetics or monoclonal antibodies that rebalance the pro- and anti-coagulation system by interfering with production of anti-thrombin or tissue factor pathway inhibitor have the benefits of long-lasting activity, subcutaneous administration, and being useful in patients both with and without neutralizing antibodies. As the ultimate treatment, recent progress has also been made with gene therapy of both hemophilia A and B.

Introduction: Early long-term prophylaxis is the standard of care to prevent joint bleeding and chronic arthropathy in patients with severe hemophilia. Areas covered: Despite the obvious prophylaxis advantages upon the clinical outcomes, there are still several drawbacks to be addressed for the optimal patients' compliance. Frequency of treatment due to short half-life of conventional FVIII and FIX concentrates, difficult venous access, adherence to the prescribed therapy and costs may represent significant critical issues. The development of inhibitors also makes replacement therapy ineffective, preventing patients from receiving long-term prophylaxis. This paper will review these drawbacks and the tools to overcome these limitations, mainly thanks to the use of extended half-life products and the development of novel non-conventional therapeutic approaches. Expert commentary: The use of extended half-life products may help in reducing the burden of the frequent intravenous administration and in better tailoring an individualized prophylaxis. The development of novel therapeutic approaches, like the bi-specific antibody mimicking the coagulation function of FVIII or inhibition of anticoagulant proteins may facilitate prophylaxis treatment not only in patients with inhibitors, but also in severe hemophilia patients without inhibitors. Exciting opportunities are emerging for improving prophylaxis in hemophilia.