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INTRODUCTION: Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear.AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.METHODS: After informed consent, children (

Registries will enable cohort studies to be performed, which are usually considered to be the best quality of observational studies. The quality of data of registries can be increased if is it possible to merge results ('crosstalk') between registries. A prerequisite for that is an agreed uniform core set of data to be collected and uniform definitions on the items to be collected. This paper discusses problems and barriers with existing registries and provides recommendations from an EMA workshop (European Medicines Agency), for core common data sets and how to secure the quality of data collected. The PedNet registry including >2200 children with haemophilia is presented as an example of a registry/cohort study.

Objective To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management. Method These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists. Results The 10 proposed principles for AHA care are as follows: (a) Improving initial diagnosis of AHA; (b) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; (c) Effective communication between laboratories, physicians, and specialists; (d) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; (e) Comprehensive assessment of bleeding; (f) Appropriate use of bypassing agents; (g) Long‐term follow‐up and monitoring for efficacy and safety of immunosuppressive treatment; (h) Inpatient/outpatient settings; (i) Access to innovative and disruptive treatments; (j) Promotion of international collaborative research. Conclusion The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non‐specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts toward improving its practical, multidisciplinary management.

The incidence of factor IX (FIX) inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date have been small, including patients with different severities, and without prospective follow up for inhibitor incidence. The study objective was to investigate the inhibitor incidence in patients with SHB followed up for to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUP) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by the annual collection of the inhibitor status and allergic re-actions. The presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on FIX gene mutation was collected. One hundred and fifty-four PUP with SHB were included; 75% were followed up until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (seven high-titer). The median number of ED at inhibitor manifestation was 11 (interquartile range [IQR]: 6.5-36.5). The cumulative inhibitor incidence was 9.3% (95% Confidence Interval [CI]: 4.4-14.1) at 75 ED, and 10.2% (95% CI: 5.1-15.3) at 500 ED. Allergic reactions occurred in four (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 PUP with SHB, the 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.

New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.

Introduction BAY 81-8973 (Kovaltry®), a recombinant factor VIII (rFVIII) product, was efficacious and well tolerated in paediatric previously treated patients (PTPs) with severe haemophilia A for ≥50 exposure days (EDs) in the LEOPOLD Kids study. Because long-term prophylaxis (≥100 EDs) can provide substantial patient benefits, FVIII products should demonstrate long-term safety and efficacy. Aim To demonstrate long-term (≥100 EDs) efficacy and safety of BAY 81-8973 in paediatric PTPs. Methods PTPs aged ≤12 years with severe haemophilia A without inhibitors could continue in the ongoing open-label extension study after completing ≥50 EDs in the LEOPOLD Kids main study. Patients received BAY 81-8973 for prophylaxis (25–50 IU/kg ≥2×/week), bleed treatment, and surgery. Bleeds were documented in electronic patient diaries. Inhibitor development was monitored every 6 months. Results At the August 2017 interim data cutoff, 46 patients (median [range] age at enrolment, 6.0 [1.0–11.0] years) had spent a median (range) of 602.5 (148–1069) EDs and 4.6 (1.0–5.9) years in the main plus extension studies. Median (quartile [Q]1; Q3) annualised bleeding rate for bleeds within 48 h after a prophylaxis infusion and total bleeds was 1.0 (0.2; 1.9) and 2.0 (0.4; 3.6), respectively. Most (>94%) bleeds were mild or moderate; 71.8% were treated with ≤1 infusion. BAY 81-8973 was also well tolerated with only one treatment-related adverse event (transient, low-titre inhibitor which did not require treatment adjustment). Conclusion BAY 81-8973 was efficacious for prophylaxis and treatment of bleeds during >4.5 years in paediatric PTPs with severe haemophilia A.

Research has been lacking on the natural history, complications, and treatment of haemophilia B, which is less common than haemophilia A and was recognized as a distinct clinical entity in 1947. Although the two diseases share the same clinical manifestations, they differ in causative mutation, risk of inhibitor development, and patient quality of life. Frequently debated is whether haemophilia B is as clinically severe as haemophilia A, with much of the published data on overall and haemophilia-specific health outcomes suggesting that haemophilia B may have a less severe clinical phenotype. However, although fewer haemophilia B than haemophilia A patients appear to experience bleeding, bleeds are just as severe. We review distinguishing characteristics of haemophilia B and its treatment, including management strategies for neonates, therapeutic approaches for patients who develop inhibitors, pharmacokinetics of factor IX concentrates administered as replacement therapy, and potential future treatments.

Background: The role of inherited thrombophilia testing in predicting a recurrence of deep vein thrombosis (DVT) after an incident of the first DVT in children remains unclear Objectives: To investigate the association between inherited thrombophilia and DVT recurrence. Design/Method: We conducted a retrospective regional study of all consecutive ICD10 codes of venous thromboembolism (VTE) in children over 15 years (January 1, 2000, to December 31, 2015) in a regional catchment area of southern Sweden using an electronic diagnosis registry. Eligible subjects were children aged 1-18 years presenting with DVT diagnosed with imaging and having undergone complete inherited thrombophilia workup after the first DVT event. Of the 174 patients diagnosed with DVTs, 139 were eligible for inclusion. Data regarding subject demographics and medical history, location of DVT and imaging method, coagulation studies at primary investigation including at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C, and the genotypes FVG1691A and FIIG20210A. Also, plasma values for coagulation factors, VIII and XI, D-dimer, INR, and cardiolipin antibodies, were analyzed. Results: A total of 139 patients had inherited thrombophilia workup after the incident of the first DVT. Inherited thrombophilia was found in 30 % of patients, the prevalence of minor thrombophilia among these 139 patients was 23 % (n = 32), whereas major thrombophilia accounted for 7 % (n = 10) of abnormal results. Anticoagulants as treatment were administered in 92 % of the first DVT. The majority of the cohort treated with anticoagulation therapy for 12 weeks. Patients with minor inherited thrombophilia treated for at least 24 weeks, whereas the patients with major inherited thrombophilia were continued on anticoagulation therapy for the long term. The incidence rate of recurrent thromboembolic events was 6.5 % (n = 9) of patients after their incident of the first thrombotic event. Recurrent thrombosis in patients with spontaneous DVT and proven inherited thrombophilia found in only 1 %. Conclusion: Inherited thrombophilia was not predictive of recurrent DVT among our cohort patients. Our findings suggest that Inherited thrombophilia testing may not predict risk for the recurrence of DVT, although it may help for adjustment of the duration of the anticoagulation therapy. Figure Disclosures No relevant conflicts of interest to declare.

Introduction Assay discrepancy in factor VIII activity between the one-stage and the chromogenic assays has been described in approximately one third of patients with non-severe haemophilia A. Whether assay discrepancy may also occur in patients with haemophilia B remains unknown. Aim This study compared the results from the one-stage and the chromogenic assays in patients with haemophilia B. Methods Plasma samples from patients with haemophilia B attending the haemophilia centre in Malmo, Sweden, were collected after a wash-out period of more than 7 days and analysed with both assays. Results Fifty samples from 36 patients were analysed. No discrepancy was found in patients with severe haemophilia B. Among the 44 plasma samples from patients with non-severe disease, 15 showed a twofold or greater difference between the results of the two methods, with the chromogenic method presenting the higher value (mean FIX:Cone-stage 0.02 vs. FIX:Cchromo 0.06 IU mL−1). Of these 15 samples, 14 were from seven individuals from five families with the same mutated amino acid at the N-terminal cleaving site of the activation peptide (FIX: c.572G>A; p.Arg191His or FIX: c.571C>T; p.Arg191Cys). These mutations were not observed in any patients with non-discrepant results. The reported bleeding frequency for these patients was low and indicative of a mild bleeding phenotype. Conclusion Our findings imply that assay discrepancy occurs for factor IX activity and that both type of assays are needed for a correct diagnosis and classification of haemophilia B. The underlying mechanism by which the mutation influences the assays remains to be determined.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.

Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception. This can manifest as differences in patients’ experiences and response to pain, which require an individualized approach to pain management. Prophylaxis with factor replacement reduces the likelihood of bleeds and bleed-related pain, whereas on-demand therapy ensures rapid bleed resolution and pain relief. Although use of replacement or bypassing therapy is often the first intervention for pain, additional pain relief strategies may be required. There is an array of analgesic options, but consideration should be paid to the adverse effects of each class. Nevertheless, a combination of medications that act at different points in the pain pathway may be beneficial. Nonpharmacological measures may also help patients and include active coping strategies; rest, ice, compression, and elevation; complementary therapies; and physiotherapy. Joint aspiration may also reduce acute joint pain, and joint steroid injections may alleviate chronic pain. In the longer term, increasing use of prophylaxis or performing surgery may be necessary to reduce the burden of pain caused by the degenerative effects of repeated bleeds. Whichever treatment option is chosen, it is important to monitor pain and adjust patient management accordingly. Beyond specific pain management approaches, ongoing collaboration between multidisciplinary teams, which should include physiotherapists and pain specialists, may improve outcomes for patients.

TO THE EDITOR: Inhibitory antibodies (inhibitors) against factor VIII (FVIII) develop in 25% to 35% of previously untreated patients (PUPs) with severe hemophilia A (SHA). It is the most serious complication of classic hemophilia treatment.[1][1][⇓][2]-[3][3] Most inhibitors develop during the

Introduction: Pulmonary embolism (PE) is rare in childhood but a potentially fatal condition in the venous thromboembolism spectrum. However, the incidence of PE in children has been steadily increasing, which can be multifactorial. Adults data suggested that the finding of asymptomatic proximal DVT on routine ultrasonography is associated with increased mortality. Data on pulmonary embolism in children are scarce. Objective: To evaluate the relationship between asymptomatic proximal deep vein thrombosis detected in children presented with Pulmonary embolism. Methods: We conducted a retrospective chart review of all consecutive ICD 9 codes of Pulmonary Embolism (PE) in children over 10 years (January 1, 2000, to December 31, 2010) in Skåne university hospital in Sweden, using an electronic diagnosis hospital database. Eligible subjects were children aged 1-18 years presenting with PE diagnosed with imaging, and having undergone complete lower extremities radiological screening workup for DVT and lacking symptoms of acute lower extremity DVT. Data regarding subject demographics and medical history, risk stratification, low risk, massive or submissive PE, location of the proximal DVT, imaging method, presence of congenital vascular anomaly, time from symptom onset to diagnosis of the pulmonary embolism. Coagulation studies at primary investigation including at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C, and the genotypes FVG1691A and FIIG20210A. Also, plasma values for coagulation factors, VIII, cardiolipin antibodies, management, duration of anticoagulant, and the outcome were analyzed. Results: A total of 20 children enrolled. Age range 10-18 years (mean 15.8), 18 (90%) were female. Time from symptom onset to diagnosis of the PE: mean 4.8 days (range 1-28). All were low risk, and 6 (30%) associated with asymptomatic proximal DVT. The most common acquired risk factor was OCP/hormonal therapy was in 11 (55%). Minor thrombophilia in 5 (25%) of the cohort. All received anticoagulation therapy for 6 months, non-received pharmacologic thrombolysis. No bleeding, recurrence, nor thrombosis related mortality in 4 years follow uptime. Conclusion: PE is rare in children, and it is associated with asymptomatic proximal DVT is not uncommon. Our finding demonstrated the prevalence of PE associated with asymptomatic proximal DVT is 30%. This finding highlighted the importance of anticoagulant therapy for all patients with incidental proximal DVT. Figure Disclosures No relevant conflicts of interest to declare.

Introduction: Currently the most serious treatment complication of haemophilia is the inhibitor development (ID), i.e. neutralizing antibody development. Aim: This nationwide multicentre study in Finland evaluated the incidence and risk factors of ID in previously untreated patients (PUPs) with severe haemophilia A (FVIII:C < 0.01 IU mL−1). Methods: We enrolled all PUPs (N = 62) born between June 1994 and May 2013 with at least 75 exposure days (EDs) to screen ID during follow-up extending to September 2013. Results: Thirteen ID (21% of 62) occurred; 10 (16% of 62) with high titre. Fifty-one patients (82%) were on primary prophylaxis (regular prophylaxis before the age of 2 and before the first joint bleed) from the median age of 11.4 months, 90% via a central venous access device. The initial product was rFVIII in 63% and pd-FVIII in 37%, moreover in 24% pd-FVIII was switched to rFVIII concentrate during the 75 EDs. Non-transient inhibitors developed in 9/51 (17.6%; 13.7% high titre) children with primary and in 4/11 (36.4%; 27.3% high titre) patients with secondary prophylaxis (P = 0.24). Overall, 74% had a high-risk genotype similarly distributed among the prophylaxis groups. The history of a major bleed enhanced ID (aHR, 4.0; 95% CI, 1.2–13.7), whereas FVIII treatment intensity or source and early implantation of ports did not increase ID risk. Conclusion: The cumulative incidence of ID was low notwithstanding prevalent high-risk mutations. Despite patient-related risk factors, our management involving early intensive primary prophylaxis via ports helps to prevent bleeds and lower the incidence of inhibitors. (Less)

SummaryCurrent therapy for haemophilia A is guided by severity of the disease, which in turn is best reflected in patients' endogenous factor VIII activity levels. For patients with severe haemophilia (particularly children), prophylaxis with continuous routine factor replacement has become standard of care in developed countries and is gradually becoming the standard of care in developing countries. The question arises then: what is an appropriate prophylaxis regimen to prevent bleeding events and arthropathy, while also maximizing patient quality of life and taking into consideration the costs of prophylaxis? Should all patients be treated with one standard, fixed prophylaxis regimen, or should prophylaxis be individualised for each patient? If so, what factors need to be considered in choosing the appropriate dose and frequency of factor administration? If prophylaxis is tailored to the individual patient, then patient-related factors (bleeding phenotype, activity profiles, age, joint status) and product-specific factors (half-life of the replacement factor in the individual patient) will determine the choice of regimen, whether it be a fixed-regimen prophylaxis or prophylaxis that is tailored to patient activity and bleeding risk. Regardless of the choice of prophylaxis regimen, for any regimen to be effective, adherence to therapy is key to optimising outcomes.

Owing to the heterogeneity in the clinical phenotype of haemophilia A and B, it is now recognized that disease severity (based on factor VIII/IX activity) may no longer be the most appropriate guide for treatment and that a 'one-size-fits-all' approach is unlikely to achieve optimal therapy. Based on the present literature and consensus views of a group of experts in the field, this article highlights key gaps in the understanding of the diverse relationships between bleeding phenotype and factors such as joint health, genetic susceptibility, laboratory parameters, quality of life and management of pain. Early prophylaxis is a potential 'gold standard' therapy and issues surrounding inhibitor development, variations in its clinical use and long-term outcomes are discussed. Comprehensive treatment should be individualized for all patients (including those with mild or moderate haemophilia and carriers). Wherever possible all patients should be given prophylaxis. However, adult patients with a milder haemophilia phenotype may be candidates for ceasing prophylaxis and switching to on-demand treatment. Regardless, all treatment (on-demand and prophylaxis) should be tailored towards both the patient's personal needs and their clinical profile. In addition, as the associations between risk factors (psychosocial, condition-related and treatment-related) and clinical features are unique to each patient, an individualized approach is required to enable patients to alter their behaviour in response to them. The practical methodologies needed to reach this goal of individualized haemophilia care, and the health economic implications of this strategy, are ongoing topics for discussion.

Haemophilia B is caused by a heterogeneous spectrum of mutations. Mutation characterization is important in genetic counselling, prenatal diagnosis and to predict risk of inhibitor development.To study the mutation spectrum, frequency of unique recurrent mutations, genotype-phenotype association and inhibitor development in a population-based study of the complete Swedish haemophilia B population.The study included, facilitated by centralized DNA diagnostics, the complete registered Swedish haemophilia B population (113 families: 47 severe, 22 moderate and 44 mild), each represented by a single patient. Mutation characterization was performed by conventional sequencing of all exons and haplotyping by genotyping of single nucleotide variants and microsatellites.A mutation was found in every family: eight had large deletions, three had small deletions (10 base pair) and 102 had single base pair substitutions (69 missense, 26 nonsense, four splice site and three promoter). Ten novel mutations were found and were predicted to be deleterious. Sixteen mutations (one total gene deletion, 14 substitutions and one acceptor splice site) were present in more than one family. Of the single nucleotide mutations (37/102), 36% arose at CpG sites. Haplotyping of families with identical mutations and present analyses showed that the frequency of unique mutations was at least 65%. Inhibitors developed in 9/47 (19%) patients with severe haemophilia B.The spectrum of haemophilia B mutations reveals at least 65% of the families carry a unique mutation, but with more inhibitor patients than reported internationally, probably as a result of many 'null' mutations.

INTRODUCTION: Standard treatment of congenital haemophilia A is based on replacement therapy with coagulation factor VIII (FVIII) products. A major complication of FVIII therapy is the occurrence of IgG alloantibodies (inhibitors) that neutralize FVIII activity.AIM: The aim of the analysis was estimating the risk of high-titre inhibitor associated with the second-generation full-length product compared to third-generation full-length product and other recombinant FVIII (rFVIII).METHODS: We conducted a combined analysis of individual patient data from three large studies in previously untreated patients (PUPs) with severe haemophilia A.RESULTS: A total of 1109 PUPs were treated from 1993 to 2013 including 787 PUPs treated from 2004 onwards (primary analysis cohort). A total of 322 patients (29.0%) developed an inhibitor, of which 192 (17.3%) a high-titre inhibitor. In the primary analysis set, 29.9% of patients developed an inhibitor and 17.2% a high-titre inhibitor. The combined analysis indicated a lower risk of high-titre inhibitor development for the third-generation rFVIII product compared to the second-generation rFVIII product (primary analysis: adjusted hazard ratio (HR) = 0.72, 95% CI: 0.49 to 1.06). Adjusted HR for all inhibitor development was significantly lower for the third-generation product compared to the second-generation product.CONCLUSION: The trend of an increased risk of inhibitor development in PUPs for one recombinant product illustrates that extrapolation from one recombinant factor VIII product to other products might not be justified. (Less)

The standard therapy for patients with haemophilia is prophylactic treatment with replacement factor VIII (FVIII) or factor IX (FIX). Patients who develop inhibitors against FVIII/FIX face an increased risk of bleeding, and the likelihood of early development of progressive arthropathy, alongside higher treatment‐related costs. Bypassing agents can be used to prevent and control bleeding, as well as the recently licensed prophylaxis, emicizumab, but their efficacy is less predictable than that of factor replacement therapy. Antibody eradication, by way of immune tolerance induction (ITI), is still the preferred management strategy for treating patients with inhibitors. This approach is successful in most patients, but some are difficult to tolerise and/or are unresponsive to ITI, and they represent the most complicated patients to treat. However, there are limited clinical data and guidelines available to help guide physicians in formulating the next treatment steps in these patients. This review summarises currently available treatment options for patients with inhibitors, focussing on ITI regimens and those ITI strategies that may be used in difficult‐to‐treat patients. Some alternative, non‐ITI approaches for inhibitor management, are also proposed, Supported by a grant from Novo Nordisk Health Care AG, in compliance with international guidelines for good publication practice.

Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients’ quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5–1.8 times that of standard products for FVIII and 3–5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.

Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. 'Bypassing agents' may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at 'good' or 'bad risk' for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities.

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Initiating prophylactic treatment at an early age is considered to be the optimal form of therapy for a child with haemophilia A or B. The pioneering long term experiences of prophylactic treatment from Sweden and The Netherlands demonstrated the benefit of prophylaxis in retrospective and observational studies. Decades later, these benefits were confirmed in a randomized controlled study in USA. We review the current status of prophylactic replacement therapy of haemophilia in children, adolescents, adults and the elderly. Prophylaxis should begin at an early age and there are arguments for continuing it into adulthood. The dose of prophylaxis is dependent on the goal of treatment, economic resources and venous access and should be tailored individually. Starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels.

To facilitate early prophylaxis, step-up regimens starting prophylaxis with infusions 1xweek(-1) were introduced. Choice of initial regimen may affect outcome. This study aims to classify initial prophylactic regimens and compare them on short-term outcome. From the European Paediatric Network for Haemophilia Management' (PedNet) registry, patients with severe haemophilia A without inhibitors, born 2000-2012, receiving prophylaxis were included. Treatment centres were classified according to the initial frequency of prophylactic infusions and the age at reaching infusions >= 3 x week(-1). Bleeding, and central venous access device (CVAD) use were compared at age 4 years. In 21 centres with 363 patients, three regimens were identified: (i) start prophylaxis with >= 3 x week(-1) infusions before age three (full: 19% of centres, 18% of patients); (ii) start 1-2 x week(-1), increasing frequency as soon as possible (asap), reaching >= 3 x week(-1) before age three (43% of centres, 36% of patients); (iii) start 1-2 x week(-1), increasing frequency according to bleeding (phenotype), reaching >= 3 x week(-1) after age three (38% of centres, 46% of patients). Prophylaxis was started at median 1.2 years on the full and asap regimen vs 1.8 years on the phenotype regimen. Complete prevention of joint bleeds was most effective on the full regimen (32% full vs. 27% asap and 8% phenotype), though at the cost of using most CVADs (88% full vs. 34% asap and 22% phenotype). The three prophylaxis regimens identified had different effects on early bleeding and CVAD use. This classification provides the first step towards establishing the optimum prophylactic regimen. (Less)

The aims of the study were to define the frequency, outcome and reasons for prenatal diagnosis (PND) in Sweden during a 30-year period in order to study trends and changes. The study population, from the Swedish nationwide registry of PND of haemophilia, consisted of 54 women, compromising >95% of all, who underwent PND (n = 90) of haemophilia during 1977-2013. PND was performed by amniocentesis (n = 10), chorionic villus sampling (n = 64) or by analysis of foetal blood (n = 16). A total of 27/90 foetuses were found to have haemophilia. Sixteen went to termination and the remaining 11 were born during the end of the study period (2000-2013). Three of 90 pregnancies were terminated due to findings other than haemophilia and 3/90 PNDs led to miscarriage. In the 30 families with known haemophilia, PNDs (n = 55) were used in 27/55 cases for 'psychological preparation' and in 23/55 cases with the aim to terminate the pregnancy. A subgroup of women (n = 17) who consecutively underwent PND in the years 1997-2010 were further interviewed. For 11/17, being a carrier had a negative effect on the decision to become pregnant, and in 11 cases PND had influenced their decision to conceive. Our study show that PND of haemophilia is stable over time but increasingly used during the last decade as a psychological preparation for having a child with haemophilia as compared to earlier where more terminations of pregnancies were conducted.

Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long-term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15th Zurich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population. A framework for outcome assessment in inhibitor patients incorporates traditional hemophilia outcome measures, such as bleed frequency and mortality, alongside measures of health, functioning, disability, social participation, quality of life, and economic considerations. It is important to remember that inhibitor patients differ in their clinical needs, perspectives, and priorities according to age, inhibitor status, degree of joint disease, and activity levels; as a result, the relative importance of different outcome measures will change throughout an inhibitor patient's life. Challenges inherent in measuring long-term outcomes in inhibitor patients include the small number of known patients, the subjective nature of many outcome assessment tools, and the risk of overburdening patients with repeated requests to complete questionnaires or participate in studies. Therefore, there is an urgent need to reach consensus on the most important and appropriate assessment tools for measuring outcomes in this population. These tools should ideally be standardized, easily applied, and internationally applicable in order to collect and generate quality outcome data.

Patients with haemophilia A (and their physicians) may be reluctant to switch factor VIII (FVIII) concentrates, often due to concerns about increasing the risk of inhibitors; this reluctance to switch may contribute to patients missing the clinical benefits provided by the arrival of new factor VIII products. This topic was explored at the Eleventh Zurich Haemophilia Forum. Clinical scenarios for which product switching may be cause for concern were discussed; when there is a clinical need, there are no absolute contraindications to switching, but some patients (e.g. previously untreated patients and those undergoing elective surgery) may require more careful consideration. Both patient and physician surveys indicate that the reluctance to switch, and the fear of inhibitor development, does not appear to be evidence based. The evaluation of more recent data did not support previous studies suggesting that particular products (e.g. recombinant vs. plasma-derived and full length vs. B-domain modified) may be associated with increased risk. In addition, data from three national product switches showed that switching was not associated with increased inhibitor risk, but highlighted the need for regular inhibitor testing and for a centralised, unbiased database of inhibitor incidence. To conclude, current evidence does not suggest that switching products significantly influences inhibitor development.

Haemophilia is an X-linked recessive genetic disease of haemostasis. Women carriers may present with a bleeding tendency similar to milder forms of the disease. Haemophilic newborns present risk factors and patterns of bleeding that are challenging. Identification of carriers and genetic counselling before conception is considered optimal to help decide on available conception options and during pregnancy to help minimise bleeding risks for both carrier mother and affected baby. Preimplantation genetic diagnosis is attractive to many couples at risk of having a child with haemophilia and relevant technology is becoming more available although it has both practical and ethical limitations. Pregnancy in carriers should be managed by a multidisciplinary team in a comprehensive treatment centre. The optimal mode of delivery for carriers expecting a baby known to have or being at risk of haemophilia is an issue of great debate. The general consensus among authors is avoidance of instrumental delivery, foetal scalp electrodes and blood sampling in pregnancies at risk of carrying an affected foetus, as well as early recourse to Caesarean section as guided by obstetric indications. Intracranial haemorrhage, although infrequent, is one the most devastating types of bleeding in haemophilic newborns and can occur regardless of the mode of delivery or the severity of haemophilia. Early screening is proposed for all infants with severe or moderate haemophilia who have had traumatic delivery and/or have evidence of extracranial haemorrhage. Women with postpartum haemorrhage should have a bleeding work-up.

Although effective therapies for haemophilia have been available for decades, the prevention and treatment of joint disease remain major clinical concerns for all haemophilia patients. Early identification of joint disease is vital to initiate or modify treatment, and prevent arthropathy. However, there remains a need for more sensitive and accurate methods, which may also detect improvement in patient outcome with new therapies or different prophylaxis regimens. These topics were explored at the Ninth Zürich Haemophilia Forum. A summary of our shared views on the limitations of current assessment methods, and the potential advantages of more recently developed tools, is provided. Ultrasonography enables more frequent routine monitoring and the early detection of joint disease. In addition, serological markers may provide suitable biomarkers of early arthropathy. To prevent arthropathy, in our opinion, prophylaxis is key to prevent joint bleeds and subsequent initiation of the 'vicious circle of joint disease'. However, issues remain, including when prophylaxis should be started, stopped, and if it is efficacious for inhibitor patients. Once joint bleeding has occurred, enhanced on-demand treatment should be considered. For more advanced stages of joint disease, the issues regarding the treatment options available are explored. Radiosynovectomy should be performed to treat chronic synovitis, and may prevent the need for elective orthopaedic surgery (EOS). Ultimately, however, EOS can be considered once all other treatment options have been explored. While, bypassing agents have facilitated the use of EOS in inhibitor patients, a multidisciplinary approach and careful surveillance is required for good patient outcome.

Hemophilia A is a congenital, recessive, X-linked bleeding disorder that is managed with infusions of plasma-derived or recombinant factor (F) VIII. The primary considerations in FVIII replacement therapy today are the: 1) immunogenicity of FVIII concentrates, 2) role of longer-acting FVIII products, 3) prophylactic use of FVIII in children and adults with severe hemophilia A, and 4) affordability and availability of FVIII products. Improving patient outcomes by increasing the use of FVIII prophylaxis, preventing or eliminating FVIII inhibitors, and expanding access to FVIII concentrates in developing countries are the major challenges confronting clinicians who care for patients with hemophilia A.

Having a child with a chronic disease often increases the burden in the family with more hospital visits, treatment administration, and increased worries for the ill child. A cross-sectional, international, multi-centre study in caregivers of children

Introduction Development of an inhibitor to Factor IX is a potentially life-threatening complication that occurs in 2-4% of severe hemophilia B patients. Attempt to eradicate these neutralizing alloantibodies with immune tolerance induction (ITI) regimens using prolonged repeated exposure to FIX fails to induce tolerance in ~70% of cases, and is limited by severe complications including FIX hypersensitivity and nephrotic syndrome. Cases of FIX ITI with immunosuppressive drugs have been reported infrequently. In light of increased understanding of the role of active T lymphocyte regulation of clotting factor-directed B lymphocyte-mediated humoral immunity, an approach combining immune modulating agents and frequent FIX infusions was reported by Beutel, et al (Haemostaseologie, 2009; 2014). We report a multi-institutional retrospective experience with combination immune modulation therapy (CIT), including B cell suppression with anti-CD20 monoclonal antibody Rituximab and T cell modulation using mycophenylate mofetil (MMF) with FIX ITI in 11 males with severe congenital hemophilia B. Methods The originally published regimen of Beutel, et al involves a 50 day course including FIX 100 IU/kg twice daily, rituximab 375 mg/m2 x 4 doses, mycophenolate (MMF) 300 mg/m2/dose daily, dexamethasone 6 mg/m2/dose pulses and IVIG 1 g/kg x 6 doses. Following individual Institutional Review Board approval, data on 11 patients was contributed by the INPH investigators and via outreach internationally and collected retrospectively using a uniform data collection form. Cases were included in the CIT series if the combination of FIX, rituximab and MMF was used. Approaches varied in the concomitant use of IVIG and pulse corticosteroids (dexamethasone or prednisone). Results CIT was the first immune tolerance therapy for 9/11 patients. Patients were 14-222 months of age at time of CIT, with a median time from inhibitor diagnosis to CIT 20 (range 0-207) months. Median historical peak inhibitor titer prior to initiation of CIT was 3.2 (range 1-42) BU/ml. Inhibitor titers at the initiation of CIT ranged from undetectable to 7 BU/ml. Eighty-onepercent of patients had a history of FIX hypersensitivity reaction. Prior to initiation of therapy, 27% of the patients underwent FIX desensitization during the initial course. The patients received FIX BID (9/11 patients) or QD (2/11 patients), 4 doses of rituximab 375 mg/m2, MMF for a minimum of 49 days (varying duration from 49-1247 days). IVIG was infused in 10/11 patients, with most receiving 3-7 doses during each course of CIT. 6/11 patients received between 2-10 courses of pulse corticosteroids during a CIT course. Each course of CIT achieved disappearance of the titer of FIX inhibitor at a median time of 1 month (range 1-41 months) Hypersensitivity reactions did not limit the courses of CIT, but did recur with inhibitor recurrence in 1 patient. Recurrence occurred in 6/11 patients at a median time of 11 months from time of CIT, in some cases soon after documented B cell recovery with a median inhibitor titer of 1.8 (range 0.7-7) BU/ml. In cases of recurrence, a negative inhibitor titer was achieved again in 1 patient by increasing FIX dose and in 4 patients who received additional courses of CIT. Repeat recurrence was seen in these patients following repeat CIT, although at low titer with a median of 1 BU/ml (range 1-4), allowing ongoing management with FIX in 3 of the 4. Overall, patients have had a median follow-up of 61 months following CIT, 9/11 patients are currently managed with factor IX for prophylaxis and bleeding, while 2/11 use bypassing agents. The most common complication was hospitalization for central venous catheter-related bacterial infection that occurred from < 1 to > 12 months after the use of rituximab in 3/11 patients. Nephrotic syndrome occurred in 3/11 patients. In each case, nephrotic syndrome responded to corticosteroids or re-initiation of CIT and FIX could be resumed. Conclusions FIX ITI with CIT targeting both B and T cells in hemophilia B is an effective means of achieving a negative inhibitor titer with tolerable safety in this series, allowing return to use of FIX for hemostasis and prophylaxis in most patients. Although recurrence is common and longer follow up is needed, when compared to the experience with using FIX alone, outcomes appear to be improved using CIT with FIX ITI as an initial approach. Disclosures Abajas: Bayer: Honoraria; CSL Limited: Honoraria. Allen:Shire: Employment, Equity Ownership. Oldenburg:Pfizer: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Shire: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding.

Introduction: Venous thromboembolism (VTE) is a rare complication in childhood. Pediatric VTE is an important and increasingly frequent clinical challenge likely due to increased detection and advanced medical interventions leading to improved survival of previously fatal conditions. Objective: The principal aim of this population based study was to describe the incidence, age distribution, type/location of VTE, and acquired and genetic pro-thrombotic risk factors of VTE and recurrence of VTE in children 0-18 years. Material and Methods: The Regional Ethical Review Board in Lund approved the study. We conducted a retrospective regional study of all consecutive ICD-10 codes of VTE in children 0-18 years over a 15-year period (January 1, 2000, to December 31, 2015) in a regional catchment area of southern Sweden using an electronic diagnosis registry. Eligible subjects were defined as children under the age of 18 who presented with VTE and had imaging evidence of thrombosis. Of the 174 patients diagnosed with VTEs, 164 fulfilled the study group criteria. Data regarding subject demographics and medical history (central venous catheter, cancer, congenital heart disease, history of VTE, current infection, etc.), location of VTE and imaging method (upper, lower extremities, pulmonary embolism, renal, cardiac, cerebral sinus venous thrombosis (CSVT), etc.), coagulation studies at primary investigation which included in all cases evaluation of at least plasma concentrations of protein C, protein S, antithrombin, resistance to activated protein C and the genotypes FV-G1691A and FII-G20210A. In addition, plasma values for coagulation factors VIII and XI, D-dimer, PK-INR, and cardiolipin antibodies were analyzed. Results: The incidence of VTE in children in the investigated region of Sweden was found to be 0.8 per 10,000 children. Of the study group with confirmed VTE (n=164), 73/164 (45%) were males and 91/164(55%) females, with bimodal age distribution at diagnosis, 25 (15%) < 1 month, 139 (85%) >1 month-18 years. Of the children, 143/164 (87%) had DVT (deep venous thrombosis), 21/164 (13%) had PE (pulmonary embolism) and 5/164 (3%) had both DVT and PE. Of 143 patients with DVT, 50 (30%) had lower extremity DVT, 46 (28%) had upper extremity DVT and 34 (20.7%) CSVT and the remaining 13 various locations. 79/164 (59%) had acquired potential risk factors, 11/164 (11%) had genetic risk factors, 34/164 (21%) had both genetic and acquired risk factors, and 22/164 (13%) had no identified risk factors. The most frequent acquired risk factors in the cohort were the use of hormonal therapy (34%), concomitant malignancy (21%), infection at the time of thrombosis (19%) or a CVL (central venous line) (15%). Genetic thrombophilia risk factors were found in 45/164 (27.5%), the most common were Factor V Leiden (FVL) in heterozygous form in 35 (21%), FII mutation (heterozygous) in 4 (2%) and double heterozygosity for FVL and FII mutation found in 2 (1%). Plasma deficiency of Protein S was found in 5, Protein C deficiency in 6 and Antithrombin deficiency in 1 patient (who had 3 episodes of VTE). Recurrent VTE was documented in 9 (5%), of which 5 had a congenital pro-thrombotic disorder (i.e. FVL mutation (n=3), antithrombin deficiency (n=1) and a protein S deficiency (n=1). Two out of the nine with recurrent VTE had neither a genetic nor an acquired identified risk factor. Six out of a total of 45 (13.3%) with genetic risk factors had a recurrent VTE. No common acquired pro-thrombotic risk factor was found in the group with recurrent VTE. Conclusion: The incidence, age-distribution, locations and underlying disorders agree with published findings in pediatric populations. In our study, 87% of the children with VTE had either an identifiable acquired or genetic risk factor or a combination of both. Of those with a genetic risk factor, 13% had a recurrent VTE during the study period which indicates an even higher cumulative risk during childhood which emphasizes the need to consider prophylaxis in situations with increased risk of VTE. However, of those with recurrent VTE, no frequent acquired risk factor was identified. Disclosures No relevant conflicts of interest to declare.

Introduction.In patients with hemophilia treated with factor VIII products, the development of inhibitory antibodies poses the largest safety risk. Especially during the first 50 exposure days (EDs), up to 37% of patients with severe hemophilia A have been reported to develop an inhibitor. To study neo-immunogenicity of products and new treatment strategies, patients have been distinguished into previously untreated (PUPs) and previously treated patients (PTPs); the latter defined as patients treated for more than 150 EDs. The number of 150 EDs was established in the eighties during a time when most patients received on-demand treatment and testing for inhibitors was not frequently performed. More recent studies on inhibitor incidence in PUPs with severe hemophilia A report that 50% of inhibitors develop within 14-15 EDs, however the cut-off number of EDs for a PUP to become a PTP is not well defined. The aim of this study was to define the number of EDs for PUPs to become PTPs based on long-term follow-up of patients with severe hemophilia A Methods.All patients with severe hemophilia A born after January 1, 2000, treated for at least 1 ED and followed prospectively until inhibitor development or the number of EDs at last follow-up, were included. The number of EDs at inhibitor development is the last exposure day before the first positive titer was reported. An inhibitor was defined as positive when at least two positive inhibitor titers were measured. Positivity was defined according to the cut-off level in each individual center's laboratory. Results.Of 1,038 PUPs with severe hemophilia A, 930 (89.6%) were followed until 75 EDs, 429 until 500 EDs and 212 until 1000 EDs. In total, 300 inhibitors developed, of which 298 (99.3%) within the first 75 EDs. Thereafter only two inhibitors developed, both low titer: after 249 and 264 EDs. Conclusion.Almost all inhibitors develop during the first 75 EDs. Patients with severe hemophilia A can be defined as PTP after 75 instead of 150 exposure days. A change of definition of PTP will increase the number of severe hemophilia A patients eligible for new therapies. Disclosures Santagostino: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Male:SOBI: Speakers Bureau; Shire: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liesner:Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Sobi: Speakers Bureau; Bayer: Consultancy, Research Funding; Roche: Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Carcao:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:CSL Behring: Research Funding; Sobi: Research Funding; Bayer: Research Funding. Álvarez-Roman:Shire: Consultancy; NovoNordisk: Consultancy; SOBI: Consultancy. Koenigs:Gilead: Research Funding; CSL Behring: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Intersero: Research Funding; Bioverativ: Consultancy; Roche/Chugai: Consultancy; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Jansen: Research Funding.

Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P.01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P.01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P.01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.

Clinical experience over decades and numerous retrospective and, recently, also prospective studies clearly demonstrate that prophylactic treatment, albeit much more expensive, is superior to on-demand treatment regardless of whether the outcome is number of joint- or life-threatening bleeds or arthropathy optimal prophylactic treatment should be started early (primary prophylaxis) but various opinions exist on the model. The optimal model should be to individualize prophylaxis taking into account the bleeding phenotype and the individual susceptibility to arthropathy and further develop monitoring by global coagulation assays and pharmacokinetic parameters. This review covers proof of concept of primary prophylaxis in children, comparisons between prophylaxis and on demand treatment, and future trends of prophylactic treatment of hemophilia.

A demographic survey was made of all children (n= 137) born with severe or moderate haemophilia in Sweden during the period 1970-92. Bn addition, all prenatal diagnoses (n= 86) performing during the period were evaluated. The annual incidence of severe and moderate haemophilia, having remained constant for decades, increased from 0.78/10,000 males in the 1970s to 1.34 in the 1980s, levelling off at 1.31 in the 1990s. Although prenatal diagnosis did not affect the incidence of haemophilia in the 1970s and 1980s, it did so in the 1990s, because the incidence would have been 40% higher (1.83) had not prental diagnosis been available and 16 affected fetuses been aborted. The average proportion of sporadic cases, 62%, remained almost unchanged during the study period, suggesting mutation rates to be constant. There were fewere children in families with known haemophilia than in sporadic families, but no evidence was found to suggest that the frequency of female offspring (i.e. potential carriers) born in haemophilia families had increased since the option of prenatal diagnosis was introduced.

INTRODUCTION: Routine outcome assessment of prophylaxis should use validated tools, while balancing comprehensiveness and burden. Collecting overlapping information should be avoided. AIM: To assess correlations between different outcome assessment tools in haemophilia. METHODS: From an international cross-sectional study, data on objective outcome (Haemophilia Joint Health Score (HJHS 2.1, range 0-124), radiological Pettersson score) and self-reported joint bleeding, Haemophilia Activities List (HAL, range 100-0), health-related quality of life (SF-36, including five physical and five mental domain scores, range 100-0), and Utility (SF6D and EQ-5D, range 1.0-0) were extracted. Spearman's correlations were calculated: ≥0.8 very strong, 0.60-0.79 strong, 0.40-0.59 moderate. RESULTS: Ninety patients with severe haemophilia, on prophylaxis since median age 3.4 years, were evaluated at median 25.5 years (range 16.0-37.6). Objective outcome was favourable (median HJHS 2.1 6 points, Pettersson score 9 points). Self-reported outcome showed a median of 7 joint bleeds in 5 years, median HAL sum 96 points, high scores for physical domains of SF-36 (median 80-95) and high Utility values (median SF6D 0.87; EQ-5D 0.84). Physical examination (HJHS 2.1) showed strong correlation with radiological scores, moderate correlation with physical domains of the SF-36 and Utility, but no correlation with self-reported bleeding or limitations in activities (HAL). Bleeding was not associated with any other outcome parameter. The HAL was only correlated with the SF36 'Physical functioning' domain. CONCLUSION: For the evaluation of patients on early prophylaxis, information on bleeding should be complemented by objective joint assessment as well as self-reported limitations in activities and quality of life.

Progressive joint destruction resulting from intra-articular bleeding is the major morbidity affecting patients with haemophilia (PWH), particularly those with inhibitors. Advances in understanding the detrimental processes set in motion by the exposure of joints to bleeding have shaped current management methods. However, to achieve optimal joint health in PWH, in addition to achieving haemostasis at the bleeding vessel, it may be appropriate to explore experimentally other conceptual frameworks. These include the possibilities that markers might help to identify individuals at the risk of more rapid joint deterioration, that clotting factors may have additional local action within tissues, and that outcomes might be improved with therapies that directly address wound healing and inflammation. Joint assessment tools are important. Conventional radiography is frequently used, but given the possibility of subclinical joint bleeds, accurate non-invasive imaging tools are required to detect soft tissue and cartilage changes. Magnetic resonance imaging and ultrasonography can prove valuable here. New imaging techniques should help to increase understanding of the biological basis of early events in haemophilic arthropathy. The optimal way to measure outcomes in haemophilia is to use several methods - in addition to imaging methods, a 360° approach will use physical, functional and quality-of-life instruments. In PWH, inhibitor development complicates treatment of joint bleeds and increases the risk of developing arthropathy. A new therapeutic approach for joint bleeds in inhibitor patients divides treatment into two phases: bleed control, with bypassing agent therapy until bleeding has definitely ceased, followed by regular dosing to prevent rebleeds until synovial recovery is complete.

Regular replacement therapy (prophylaxis) for haemophilia has been shown to prevent development of disabling arthropathy and to provide a better quality of life compared to treatment on demand; however, at a substantially higher cost. Calculations based on pharmacokinetic principles have shown that shortening dose intervals may reduce cost. The aim of this prospective, randomized, crossover pilot study was to address whether daily dosing is feasible, if it reduces concentrate consumption and is as effective in preventing bleeding as the standard prophylactic dosing regimen. In a 12 + 12 month crossover study, 13 patients were randomized to start either their own previously prescribed standard dose, or daily dosing adjusted to maintain at least the same trough levels as obtained with the standard dose. Ten patients completed the study. A 30% reduction in cost of factor concentrates was achieved with daily prophylaxis. However, the number of bleeding events increased in some patients in the daily dosing arm and patients reported decreased quality of life during daily prophylaxis. Daily treatment had a greater impact on daily life, and the patients found it more stressful.Prophylaxis with daily dosing may be feasible and efficacious in some patients. A substantial reduction of factor consumption and costs can be realized, but larger studies are needed before the introduction of daily prophylaxis into clinical routine can be recommended.

For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zurich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤ 5 yr of inhibitor detection) when inhibitor titers are

To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.

A group of international physicians committed to the unique care of pediatric hemophilia patients form the International Network for Pediatric Hemophilia (INPH). The main objectives of the group center on scientific studies, educational presentations and networking. By joining together on an international level, large hemophilia centers with extensive experience in the clinical care of children with hemophilia perform and publish scientifically valid studies. Annual meetings of the group include invited speakers who present hot topics or new developments in this therapeutic area for the purpose of educating the group on cutting edge research. Furthermore, since members have experience in pediatric treatment from different parts of the world, current practices as well as new trends can be discussed and shared among the group. The Fifth Annual INPH meeting was held in Buenos Aires, Argentina, on July 8–9, 2010 and focused on the topics of prophylaxis treatment and immune tolerance induction in the clinical care of children with hemophilia. The meeting is structured around roundtable discussions on the members’ current research and clinical activities, project reports of INPH study initiatives, followed by invited educational presentations with interactive discussions.

Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.