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This guideline is intended to provide practical guidance for the diagnosis and treatment of haemophilia in Austria. Few randomized controlled interventional trials are available addressing the treatment of haemophilia, therefore recommendations are usually based on low level of evidence and represent expert consensus.This guideline is based on the WFH guideline, published in 2020, and adapted according to the national circumstances and experience.It includes recommendations and suggestions for diagnosis and follow-up visits and pharmacological therapies for treatment and prophylaxis. Further topics comprise special aspects in children and adults with severe haemophilia, outcome measurement, and management of trauma, special bleedings and interventions, including dental procedures, inhibitors, management of haemophilia carriers, and psychosocial aspects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The pathfinder6 (NCT02137850) international phase 3 trial examined immunogenicity, safety, and efficacy of the extended half-life factor VIII (FVIII) replacement product N8-GP (turoctocog alfa pegol; Esperoct) in previously untreated patients (PUPs) with hemophilia A., Objectives: We present end-of trial results for extended PUP N8-GP treatment for up to a median (range) 2.5 (0.0; 7.4) years., Patients/methods: Longer-term N8-GP treatment in PUPs with hemophilia A was examined. The prophylaxis regimen was ∼60 IU/kg N8-GP i.v. twice weekly, or every 3 or 7 days. The primary endpoint was the incidence of FVIII inhibitors., Results: Overall, 81 patients received N8-GP and were included in this analysis. The inhibitor incidence was 30.0% (15.7% high-titer [>5 BU]) for the extension phase. Patients had a median (range) 2.9 (0.1; 7.2) years of prophylaxis following the pre-prophylaxis period. During prophylaxis, the median annualized bleeding rate (ABR) (interquartile range) was 1.4 (0.6; 3.5), 13% of patients experienced no bleeding episodes, and 55.1% of patients experienced no spontaneous bleeds. The proportion of patients without any spontaneous bleeding episodes increased after the first year of prophylaxis. The hemostatic success rate in the treatment of bleeding episodes was 87.6%. No additional safety concerns were observed in patients with previously reported observation of temporarily decreased incremental recovery (IR)., Conclusion: Long-term end-of-trial PUP N8-GP prophylaxis data indicate that PUPs respond well to long-term N8-GP treatment. The inhibitor incidence was consistent with previous results. Median ABR during prophylaxis was 1.4. There were no lasting clinical impacts or safety concerns for patients with an observation of temporarily decreased IR., Competing Interests: Declaration of competing interests G.K. received grant and research support from Alnylam, Bayer, BPL, Opko Biologics, Pfizer, Roche, and Takeda, and participated in advisory boards and received honoraria for consultancy/lectures from Alnylam, Bayer, Biomarine, CSL, Novo Nordisk, Opko Biologics, Pfizer, Takeda, ROCHE, Sanofi, and Uniquore. A.C. participated in the advisory board of Novo Nordisk and received honoraria from Novo Nordisk, Grifols, Takeda, and Roche. Tadashi Matsushita participated in the advisory boards for Takeda, Bayer, Novo Nordisk, Chugai, and Pfizer; received educational and investigational support from Chugai and Novo Nordisk; received honoraria from Takeda, Bayer, Sanofi, Chugai, CSL, JB, KMB, Novo Nordisk, Fujimoto, Sysmex, and Guy Young; and received personal fees from Novo Nordisk during the conduct of the study. C.M. received consultancy or speaker fees from Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Roche, and Takeda; received travel support from Bayer, Biotest, CSL Behring, and Novo Nordisk; and received institutional research support from Bayer, Baxalta/Shire/Takeda, Biotest, CSL Behring, Novo Nordisk, and Sobi. V.Y. and M.Z. are employees of Novo Nordisk., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres., Aim: We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia., Methods: An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors., Results: All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protocol., Conclusion: Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI., (© 2023 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Gene therapy has recently become a realistic treatment perspective for patients with hemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of hemophilia A and B gene therapy with vectors derived from adeno-associated virus, including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centers according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as a primary source of data for pharmacovigilance, postmarketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Accurate measurements of coagulation factor activity form an essential part of hemophilia management and are performed by the one-stage or chromogenic assay. Current literature suggests that approximately one-third of persons with nonsevere hemophilia A exhibit assay discrepancy, albeit with a high variability between studies. Such data are scarce in nonsevere hemophilia B., Objectives: To investigate the extent of factor VIII/IX one-stage and chromogenic assay discrepancy in moderate and mild hemophilia A and B., Methods: Persons with previously diagnosed nonsevere hemophilia A and B with a factor level of 2 to 35 IU/dL were included from the international DYNAMO cohort study. Central measurements of the factor VIII and IX activity levels were performed by the one-stage and chromogenic assay. Relative and absolute discrepancy definitions were used, with the International Society on Thrombosis and Haemostasis-Scientific and Standardization Committee proposed ratio of >2.0 or <0.5 being the primary outcome. Discrepancy was also evaluated in a subgroup of 13 persons with mutations previously associated with discrepancy (≥3 cases reported in literature)., Results: A total of 220 persons were included, of whom 3 (1%) showed assay discrepancy: 2/175 hemophilia A and 1/45 hemophilia B. Six persons (3%) exhibited an absolute difference >10 IU/dL between the assay results. In addition, with more lenient definitions, over 90% of participants (n = 197) had no discrepant results. Only 1 out of 13 persons with a mutation previously associated with discrepancy had significant assay discrepancy., Conclusion: Little assay discrepancy was observed despite the presence of mutations previously associated with discrepancy, suggesting that the presence and magnitude of assay discrepancy are largely determined by laboratory variables., Competing Interests: Declaration of competing interest This work was supported by a grant from Novo Nordisk. S.C.G. has received an unrestricted research grant from Sobi. S.B. received research support from Sangamo Therapeutics and honoraria from CSL Behring. M.H.C. has received investigator-initiated research and travel grants as well as speaker fees over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars”, Baxter/Baxalta/Shire/Takeda, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma, and has served as a steering board member for Roche, Bayer, and Novartis. All grants, awards, and fees go to the Erasmus MC. P.W.C. had received research support from CSL Behring, and consultancy fees from CSL Behring, Novo Nordisk, Sobi, and Roche. J.E. received research support from CSL Behring and he has been a teacher on educational activities of Roche. S.J. has received financial support for research from Sanofi Genzyme and honoraria from Bayer, Takeda, Thrombosis Canada, Roche, Octapharma, and Hemalytic. The institution of M.J.H.A.K. has received unrestricted research grants from Sobi, and her institution received speakers’ fees from Sobi, Roche, and BMS. C.M. was a consultant or speaker for Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Roche, and Takeda. He has received travel support from Bayer, Biotest, CSL Behring, and Novo Nordisk; his institution has received research support from Bayer, Takeda, Biotest, CSL Behring, Novo Nordisk, Roche, and Sobi. S.S. has received conference support, educational speaker fees, and/or advisory board fees from Pfizer, Bayer, Shire, Takeda, Sobi, Roche, and CSL Behring. K.F.’s institution has received unrestricted research grants from Sobi, Pfizer, CSL Behring, and Novo Nordisk, and also consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. M.C. reports research funding from Bayer, CSL Behring, Daiichi Saknyo, Novo Nordisk, Portola/Alexion, Roche, Sanquin Blood Supply, and UniQure and consultancy or lecturing fees from Bayer, CSL Behring, Novo Nordisk, Pfizer, and Sobi. A.Z., F.R.K., P.B., C.H., R.C.C.H., C.A.M.K.T., B.L.G., and L.N. have no potential conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

N8-GP (turoctocog alfa pegol) is a recombinant, glycoPEGylated, extended half-life, factor VIII replacement product. Here, we examined the immunogenicity, safety, and efficacy of N8-GP in previously untreated patients (PUPs). pathfinder6 is an ongoing, open-label, phase 3 trial that enrolled PUPs with severe hemophilia A and were aged <6 years. The primary end point was the incidence of factor VIII inhibitors (≥0.6 Bethesda units [BU]). Eighty patients received ≥1 N8-GP dose and were included in this analysis; ≥50 patients had ≥50 exposure days to N8-GP. The inhibitor incidence was 29.9% (14.9% high-titer [>5 BU]). Sixty-five patients received N8-GP prophylaxis for an average of 2.17 years with a median annualized bleeding rate (interquartile range) of 1.42 (0.76; 3.13) and a 90.5% hemostatic success rate. Temporarily decreased incremental recovery (IR), defined as ≥2 consecutive measurements of IR <0.6 (IU/dL)/(IU/kg) but no inhibitors, was observed in 17 patients within 5 exposure days to N8-GP and had a strong temporal correlation with anti-polyethylene glycol immunoglobulin G antibody titers. IR returned within the expected range with continued N8-GP dosing. During the period of decreased IR, hemostatic response was similar to that of the overall trial population, and no hypersensitivity related to N8-GP or unexpected new adverse events were reported. N8-GP prophylaxis was efficacious for the prevention and treatment of bleeding episodes in PUPs with severe hemophilia A. The inhibitor incidence was 29.9%. All patients with temporarily decreased IR continuing on N8-GP dosing returned within the expected range and had no evident lack of efficacy. This trial was registered at www.clinicaltrials.gov as #NCT02137850., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Detailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Gene therapy (GT) is becoming a realistic treatment option for patients with haemophilia. Outside clinical trials, the complexity and potential complications of GT will pose unprecedented challenges to haemophilia care centres., Aim: To explore the potential use of electronic tools to improve the delivery of GT under real-world conditions., Methods: Considering the hub-and-spoke model, the GTH working group on GT considered the entire patient pathway and reached consensus on requirements for an integrative software tool to secure documenting and sharing information between treaters, pharmacies and patients., Results: Six steps of the gene therapy process were identified, each requiring completion of the previous step as a prerequisite for entry. The responsibilities of GT dosing and follow-up treatment centres, read/write access rules, and the minimum data set were outlined. Data contributed by patients through mobile devices was also considered., Conclusion: Important information needs to be shared between patients and treatment centres in a real-world GT hub-and-spoke model. Collecting and sharing this information in well-organised electronic applications will not only improve patient care but also enable national and international data collection in clinical registries., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab., Aim: To review key factors that determine the choice of prophylaxis in young children., Methods: Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis., Results: The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen., Conclusions: In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration., (© 2021 John Wiley & Sons Ltd.)

Background: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs)., Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development., Patients/methods: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression., Results: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases., Conclusions: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Introduction: Patients with haemophilia (PWH) have traditionally been discouraged from engaging in sports and strenuous exercise activities, due to the perceived risk of bleeding complications. This puts PWH at an increased risk to become overweight or obese. However, the benefits of many forms of physical activity seem to outweigh their risks, although activities with significant trauma risk should be avoided., Aim: To evaluate physical activity patterns and body composition of adult PWH., Methods: This cross-sectional study compared data on physical activity from tri-axial accelerometers and body composition of 18 male adult PWH (aged 18-49 years) on prophylactic replacement therapy and without acute joint bleedings to those of 24 healthy age-matched controls, by means of Mann-Whitney-U-Tests., Results: Median moderate-to-vigorous physical activity was significantly (p = .000) lower in PWH (34.6 min/day) than in healthy controls (65.2 min/day). Body mass index was almost similar between PWH and controls (25.1 vs 24.2 kg/m 2 , p = .431). Yet, we found a consistent trend towards less desirable outcomes across body composition parameters, such as median body fat rate (23.5 vs 17.0%, p = .055) in PWH, compared with controls., Conclusion: Although physical activity has been recommended for PWH since the mid-1970s, the physical activity engagement of adult PWH was still severely limited, possibly due to over-cautiousness but presumably also in consequence of chronic pain. Poor physical activity engagement may well be expected to contribute to the increased body fat and decreased leg muscle mass. Consequently, policies should focus on improving the knowledge and motivation of PWH to engage in health-enhancing physical activity., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119.

Background: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies., Objective: To assess the FVIII treatment history in patients with non-severe hemophilia A., Methods: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR)., Results: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively., Conclusion: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur., (© 2020 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary., Competing Interests: K.H. received honoraria for advisory boards, travel grants and/or speaker fees from Bayer, Biotest, Chugai, CSL Behring, NovoNordisk, Pfizer, Roche, Shire/Takeda and Sobi, and unrestricted research grants from Bayer, CSL Behring and Pfizer. M.A. received honoraria for advisory boards, travel grants, speaker fees and/or research funding from Biogen, Biotest, Novo Nordisk, Roche, Shire and Sobi. C.B. received honoraria for advisory boards, travel grants, research funding and/or speaker fees from Bayer, Biotest, CSL Behring, NovoNordisk, Pfizer, Roche, Shire/Takeda and Sobi. C.B. is investigator in the STASEY Trial (Roche). C.B. and C.K. are principal investigators of the German Pediatric Haemophilia Research Database (GEPHARD). GEPHARD is funded by manufacturers of haemophilia drugs. S.Ha. received honoraria for advisory boards or speaker's fees from Bayer, Baxalta/Shire/Takeda, Biotest, CSL Behring, Novartis, Novo Nordisk, Octapharma and Pfizer, and research grants from Bayer, Shire/Takeda, Biotest, CSL Behring, Novo Nordisk, Octapharma and Pfizer. S.He. received honoraria for advisory boards or speaker's fees from Bayer, Shire/Takeda, CSL Behring, Biotest, NovoNordisk, Pfizer, Roche and Sobi. R.K. has acted as a consultant, received speaker's fees and/or research funding from Bayer Healthcare, Biomarin, Biotest, CSL Behring, Grifols, Octapharma, Pfizer, NovoNordisk, Sanofi, Shire/Takeda, Sobiand Roche/Chugai. C.K. received honoraria for advisory boards, travel grants and/or speaker fees from Bayer, BFSH, Biotest, Bioverativ, CSL Behring, MSD, NovoNordisk, Pfizer, Roche, Shire and Sobi, and unrestricted research grants from the European Union, FP7 IMI, DFG, BMBF, FSKK-Foundation, Abbvie, Bayer, Biotest, Bioverativ, CSL Behring, Gilead, Intersero, Jansen, NovoNordisk, PENTA Foundation, Pfizer, Roche/Chugai, Shire and Sobi. K.K. received grants, travel support and/or lecture fees from Bayer, Biotest, CSL Behring, NovoNordisk, Roche, Sobi, Shire/Takeda and honoraria for advisory board from Shire/Takeda. C.M. has received personal honoraria (consultancy, speaker, chair) from Bayer, Biotest, CSL Behring, NovoNordisk, Roche; fees to the institution for study participation from Bayer, Shire/Takeda, Biotest, CSL Behring, NovoNordisk, Sobi; unrestricted grants to institution from Biotest, CSL Behring; travel support from Bayer, Biotest, CSL Behring, NovoNordisk. J.O. received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL-Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, Swedish Orphan Biovitrum and Takeda. W.S. has received honoraria and research funding from Biotest, Octapharma, Pfizer, Sobiand Shire/Takeda. W.S. has been a member of expert panels and advisory committees from NovoNordisk, Roche, Sobi and Shire/Takeda. C.W. is an employee at Werlhof-Institut, received honoraria from Bayer, Biotest, CSL-Behring, LFB, Novo Nordisk, Pfizer, Shire and Sobi, and acted as a consultant in advisory boards for Bayer, CSL-Behring, Novo Nordisk, Pfizer, Shire and Sobi. C.E.E has acted as a consultant, received speaker's fees and/or research funding from Bayer Healthcare, Biotest, CSL Behring, Grifols, Octapharma, NovoNordisk, Shire/Takeda, Sobi, Roche/Chugai, Alnylam and Kedrion., (Thieme. All rights reserved.)

Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development., (© 2020 by The American Society of Hematology.)

Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF , CLEC4M , and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non- VWF and non- ABO variants that modify FVIII PK in pediatric hemophilia A patients., (© 2019 by The American Society of Hematology.)

The Austrian Haemophilia Registry collects epidemiological data on patients with haemophilia, on treatment modalities and potential side effects. The Registry covers more than 85% of the assumed total number of haemophilia patients in Austria. This report summarizes data on 753 patients: 84.3% (635) have haemophilia A and 15.7% (118) have haemophilia B. Patients' median age is 34 years (range: 1-93 years). Of the total cohort, 39.0% (294) patients have severe haemophilia, 11.3% (85) moderate haemophilia, and 49.4% (372) mild haemophilia. Of the patients with severe haemophilia, 38.4% (113) have been infected with hepatitis C virus (HCV) and 12.6% (37) are human immunodeficiency virus (HIV) positive. Overall, 10.6% (67) of patients with haemophilia A and 1.7% (2) of those with haemophilia B have had an inhibitor in their history. Among patients with severe haemophilia, 68.4% (201) receive prophylaxis and 28.6% (84) receive on-demand therapy. There are 65.0% (191) patients with severe haemophilia who are treated with recombinant products. In conclusion, most patients with severe haemophilia receive prophylactic treatment. HCV and HIV infections are still important issues in the Austrian haemophilia population., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Venous access is essential in patients with haemophilia for administration of factor concentrates. Peripheral venipuncture may be challenging, particularly in young children or during immune tolerance induction (ITI). Central venous access devices (CVADs) carry a significant risk for complications. An alternative for venous access is peripheral arteriovenous shunts (AVSs), but there is sparse documentation in the literature. The aim of this study was to document our experience with AVS over 12 years in 27 boys with severe haemophilia., Methods: For AVS creation, a subcutaneous vein is connected end-to-side with an artery at the wrist (Cimino) or at the forearm (Gracz shunt). Factor concentrates were substituted as for intermediate size surgery. To prevent shunt occlusion, heparin (5 units/kg/h) was given during the first 3 days., Results: Indications for AVS creation were prophylaxis start (n = 20) and ITI (n = 7). Age at shunt insertion was median 1.5 years (minimum 8 months; maximum 11.7 years). Shunt maturation was achieved within a median of 3 weeks after surgery (1.5 weeks; 18 weeks). Age when home treatment was established was median 2.1 years (9 months; 11.7 years). Four patients required AVS revisions due to stenosis, but 26 of 27 patients (96%) achieved good long-term shunt function. There were few other complications., Conclusion: Arteriovenous shunts provide a good alternative to CVAD and carry a lower risk of complications. AVSs allow earlier start of prophylaxis and home therapy with an improved quality of life for patients and families., (© 2018 John Wiley & Sons Ltd.)

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically., Summary: Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg -1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically., (© 2017 International Society on Thrombosis and Haemostasis.)

Background: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy., Methods: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites., Results: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00)., Conclusions: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

This guideline which is endorsed by the Austrian Society of Haemophilia, the Austrian Society of Paediatrics, and the Austrian Society of Haematology & Medical Oncology is intended to give a clear and practical guidance for diagnosing and treating haemophilia in Austria. In the treatment of haemophilia there are few controlled interventional trials, and recommendations usually have a rather low level of evidence.The main basis for this paper are the new international guidelines by the World Federation of Hemophilia, published in 2013. These were adapted according to the local situation and experience.Covered topics are diagnostics, control visits, pharmacological treatment options, prophylaxis and treatment in children and adults, possible problems arising in haemophilia carriers and special aspects like home therapy, options for venous catheters, management of various traumas, bleedings and interventions, including dental procedures, and last not least inhibitors and their treatment.

Recently, we reported that distinct immunoglobulin (Ig) isotypes and IgG subclasses of factor VIII (FVIII)-specific antibodies are found in different cohorts of patients with hemophilia A and in healthy individuals. Prompted by these findings, we further investigated the distinguishing properties among the different populations of FVIII-specific antibodies. We hypothesized that the affinity of antibodies would discriminate between the neutralizing and nonneutralizing antibodies found in different study cohorts. To test this idea, we established a competition-based enzyme-linked immunosorbent assay technology to assess the apparent affinities for each isotype and IgG subclass of FVIII-specific antibodies without the need for antibody purification. We present a unique data set of apparent affinities of FVIII-specific antibodies found in healthy individuals, patients with congenital hemophilia A with and without FVIII inhibitors, and patients with acquired hemophilia A. Our data indicate that FVIII-specific antibodies found in patients with FVIII inhibitors have an up to 100-fold higher apparent affinity than that of antibodies found in patients without inhibitors and in healthy individuals. High-affinity FVIII-specific antibodies could be retrospectively detected in longitudinal samples of an individual patient with FVIII inhibitors 543 days before the first positive Bethesda assay. This finding suggests that these antibodies might serve as potential biomarkers for evolving FVIII inhibitor responses., (© 2015 by The American Society of Hematology.)

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Neutralizing antibodies against factor VIII (FVIII) remain the major complication in the replacement therapy of hemophilia A patients. To better understand the evolution of these antibodies it is important to generate comprehensive datasets which include both neutralizing and nonneutralizing antibodies, their isotypes, and IgG subclasses. We developed sensitive ELISAs to analyze FVIII-binding antibodies in different cohorts of hemophilia A patients and in healthy individuals. Our data reveal the prevalence of FVIII-binding antibodies among healthy individuals (n = 600) to be as high as 19%, with a prevalence of antibody titers > or =1:80 of 2%. The prevalence of FVIII-binding antibodies was 34% (5% for titers > or =1:80) in patients without FVIII inhibitors (n = 77), 39% (4% for titers > 1:80) in patients after successful immune tolerance induction therapy (n = 23), and 100% (n = 20, all titers > or =1:80) in patients with FVIII inhibitors. We found significant differences for IgG subclasses of FVIII-binding antibodies between the different study cohorts. IgG4 and IgG1 were the most abundant IgG subclasses in patients with FVIII inhibitors. Strikingly, IgG4 was completely absent in patients without FVIII inhibitors and in healthy subjects. These findings point toward a distinct immune regulatory pathway responsible for the development of FVIII-specific IgG4 associated with FVIII inhibitors.

Background: Tissue factor pathway inhibitor (TFPI) is the major inhibitor of tissue factor-initiated coagulation, making it an interesting and novel therapeutic target in hemophilia treatment. The aptamer BAX499 (formerly ARC19499) is designed to improve hemostasis by specifically inhibiting TFPI., Objectives: The aim of the study was to examine the concentration-dependent augmentation of clotting by BAX499., Methods: Whole blood clot formation was quantified by rotational thromboelastometry and thromboelastography, and thrombin generation in platelet-poor plasma was assessed with the calibrated automated thrombogram, in samples from patients with congenital hemophilia A (N=55) and B (N=11), patients with acquired hemophilia A (N=1), and healthy controls (N=37)., Results: BAX499 significantly improved clotting of samples from hemophilic patients in a concentration-dependent manner, resulting in clotting profiles in samples from patients with severe hemophilia that were similar to those of healthy controls., Conclusion: BAX499 improved ex vivo clotting parameters in blood and plasma from patients with hemophilia A and B with different severity of disease, and also in a patient with acquired hemophilia. These results further support the contention that anti TFPI strategies may be an effective treatment for hemophilic patients., (© 2012 International Society on Thrombosis and Haemostasis.)

In patients with haemophilia A knowledge of the pathogenetic mutation is important i) as basis for carrier diagnosis and ii) for risk estimation of inhibitor formation. The pathogenetic mutations were identified by testing inversions in intron 1 and 22 (IVS22 and IVS1) and sequencing part of the promoter, the coding region and the exon/intron boundaries in a cohort of Austrian haemophilia A patients. A total of 239 patients from nine participating centres, who had consented to genetic testing and of whom clinical information was available were included in the study. First, IVS22 and IVS1 were tested; in case of absence of either inversion patients were subjected to sequencing. Mutations within the FVIII gene were identified in 234 patients. Notably, 53 mutations had not previously been described in HAMSTeRS. Of our patient cohort, 72.5 % had either an IVS22 or a missense mutation. Interestingly, in three brothers with severe haemophilia, we found a double mutation in exon 14 (missense + small deletion). The spectrum of mutations in Austrian haemophilia A patients was comparable to that found in the German and Italian population; however, it differed from the spectrum reported in the UK. In conclusion, 53 not previously published mutations were identified in Austrian haemophilia A patients. The occurrence of double mutations in the factor VIII gene could be confirmed and their low frequency was corroborated. We speculate that the differences between mutations in Austria and other European countries are due to ethnic diversity. Detailed investigations of the association of ethnicity and the mutation spectrum are planned.

Factor VIII (FVIII) levels show a considerable variability in female carriers of haemophilia A. Presently, the reasons for this are poorly understood. The aim of the study was to elucidate the influence of genetic and non-genetic parameters on FVIII plasma levels in carriers (n = 42). Results were compared with age-matched healthy women without carriership of haemophilia A (n = 42). Each carrier was tested for the family-specific mutation, ABO blood group, FVIII level, von Willebrand factor (VWF) antigen and activity and C-reactive protein (CRP). FVIII levels were lower in carriers compared to non-carriers [74% (51-103) vs. 142% (109-169), P < 0.001]. No statistically significant differences were observed between the two groups with respect to VWF activity, prothrombin-time, hs-CRP, fibrinogen, body mass index (BMI), age and smoking status as well as the distribution of ABO blood groups. In non-carriers, FVIII was statistically significantly correlated with BMI, activated partial thromboplastin time (APTT), VWF antigen, hs-CRP and fibrinogen. In carriers, significant correlations between FVIII and APTT, VWF antigen and activity were found, whereas BMI, hs-CRP or fibrinogen did not correlate with FVIII. In non-carriers, the association of FVIII with ABO blood groups was statistically significant (P = 0.006), but not in carriers of haemophilia A (P = 0.234). The type of FVIII gene mutation did not influence FVIII levels. Carrier status is the major determinant of a carrier;s FVIII plasma level. Factors known to influence FVIII levels in the general population do not significantly affect FVIII activity in carriers, neither does the type of mutation influence FVIII levels.

The most serious complication of haemophilia A is development of a high-titre factor VIII (FVIII) inhibitor which renders the patient unresponsive to FVIII replacement. Bleeding complications can only be controlled using FVIII-inhibitor bypassing agents but their effect is less certain. The ultimate goal is to eliminate the inhibitor by immune tolerance induction therapy (ITI) using daily high doses of FVIII. The success rate of ITI using various protocols is between 56 and 79% (1, 2). If ITI is unsuccessful, the inhibitor usually persists throughout life. We report on a patient with a high titre FVIII inhibitor that persisted after ITI but spontaneously disappeared 15 years later.

Patient registries are databases essential for identifying and tracking individuals with a particular disease and for collecting epidemiological information. The data obtained are necessary for quality control and quality assurance in treatment and for studying the impact of new developments on prevention, diagnosis and treatment. The Austrian Hemophilia Registry is a joint initiative between Austrian hemophilia treaters, represented by the Austrian Hemophilia Society's scientific advisory board, and the Austrian Hemophilia Society (OHG). The registry's main objective is to record information on patients with hemophilia, such as severity of disease, types of treatment and general health status. The registry also aims to improve the planning of supply of factor concentrates and to provide an instrument for early detection of side effects, such as an increase in inhibitor development or certain infections. The registry consists of three parts: the first contains basic information on quality control, the second contains extended data for quality control collected annually, and the third, "study part", covers scientific data and is also updated annually. For the latter, written informed consent of each patient is a prerequisite. Data are stored centrally on a server of an independent, public institution (University for Health Sciences, Medical Informatics and Technology: UMIT). The server is situated in a data-processing center with sophisticated security measures including physical control of access. Participating institutions comprise the main hemophilia care centers in Austria. Statistical analysis is carried out on anonymized data only. The project was financed by a public-private partnership with financial resources provided by the Austrian Ministry of Health (BMGFJ) and the pharmaceutical industry. The entire project, which is planned to be long term, will be monitored, evaluated and adjusted by the scientific advisory board accordingly.

Unlabelled: It has been shown that HIV-positive haemophilic children develop growth retardation. As not only the HIV infection but also other disease-related factors might compromise growth in these children, growth data were analysed in a longitudinal cross-sectional manner in 84 HIV-negative haemophilic patients from two university clinics. A total of 2-24 height and weight measurements (median 6) were recorded in each patient resulting in 683 single values collected between 1977-1995. Height SDS of all haemophilic boys was -0.31 +/- 2.13 (mean +/- SD, NS versus 0) and body mass index SDS was 0.21 +/- 3.49 (mean SD, NS versus 0) at first measurement and remained unchanged throughout the observation period. Neither height nor body mass index differed with respect to the severity of haemophilia (mild/moderate/severe) or the study centre (Vienna/Prague)., Conclusion: Growth in HIV-negative patients with haemophilia is not affected in spite of the immunological abnormalities attributed to the substitution therapy or the bleeding episodes in the joints with the potential effect on the growth plate.

The purpose of this study was to determine the value of Gradient Echo imaging for the evaluation of cartilage (3D fatsat) and blood products (2D Hemoflash), and the use of contrast enhanced SE imaging for the evaluation of synovial changes, in comparison to the clinical evaluation of children with hemophilia A. We investigated 21 joints in 16 patients with evidence of hemophilia A (mean age 11.3+/-2.1 years). In all patients, clinical examination, plain film radiographs, and MR evaluation were performed magnetic resonance imaging (MRI) was performed by using sagittal T1 SE and T2 SE images, as well as 3D fatsat GE and 2D GE images. Axial and sagittal T1 weighted SE images were obtained before and after contrast application. Findings from the clinical examination and MR imaging, regarding the evaluation of blood, synovia, and cartilage were compared. Clinical examination revealed evidence of a bleeding episode in 12 joints (57.1%), whereas MRI revealed evidence of blood or blood products in 15 joints (71.4%). Clinical investigations, including bleeding scores, pain scores, and physical examination scores did not correlate with MR findings. Due to the MR findings in 6 of 16 patients, therapeutic management was changed from on demand to prophylactic therapy. MR imaging with gradient echo and contrast-enhanced sequences is more sensitive than clinical examination for the detection of blood products in children with hemophilia. Its ability to demonstrate potentially early stages of cartilage or synovial alterations might assist in therapy planning. Clinical scores might underestimate effects of hemophilia.