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Introduction BAY 81–8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials. Aim To assess BAY 81–8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs). Methods In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs ( Results Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0–1.8) among patients without inhibitors (n = 20) and 0.0 (0.0–2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [n = 5], low titer [n = 1]) achieved a negative inhibitor titer. Conclusion BAY 81–8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81–8973 benefit–risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81–8973.

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

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

BACKGROUND: Inversions involving intron 22 (Inv22) of F8 are detected in approximately 45% of all severe hemophilia A patients. Diagnosis is complicated by the large size of the ~9.5 kb int22h repeated sequence which generates the inversions. Methods such as long-range PCR and inverse-shifting PCR are currently used diagnostically, but suffer from low PCR efficiencies and are difficult to standardize.OBJECTIVES: To design and validate a sensitive and robust assay for the detection of F8 int22h inversions.METHODS: Digital droplet PCR using mile-post assays was used to investigate archival DNA samples.RESULTS: The detection of linkage as a function of physical distance between loci was investigated using an anchor locus and mile-post loci located at 1, 6, 12 and 15 kb distances from the anchor locus. The proportion of linked molecules decreased with increasing distance between loci and showed 30-40% linked molecules for loci 12-15 kb apart. Mile-post assays specific for wild type and Inv22 type 1 and 2 chromosomes were then designed and optimized. All three assays showed high specificities and sensitivities, with coefficients of variation < 5% for all assays. Analysis of 106 patients and 20 carrier mothers showed complete concordance with previously known mutation status. The analysis demonstrated the robustness of the assays versus input DNA concentration (6 ng and higher) and level of fragmentation.CONCLUSIONS: Digital droplet PCR and mile-post assays can be used to detect F8 int22h inversions. The assay systems are technically simple to perform, highly efficient and robust. (Less)

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 (

One of the challenges of genetic testing in patients with hemophilia A is the interpretation of sequence variants. Here we report a silent variant found in exon 2 in the F8 gene in a 47‐year‐old patient with a previous von Willebrand disease (VWD) type 1 diagnosis. Clinically he had mild bleeding symptoms restricted to prolonged bleeding from minor wounds. Sanger sequencing of F8 gene using genomic DNA showed a hemizygous silent variant in exon 2: c.222G>T, p.Thr74Thr. When applying ACMG criteria, the variant was predicted to be “likely benign” in the analyzing software or VUS after curating. Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. These findings explain the patient's low FVIII:C level and led to the diagnosis of mild hemophilia A instead of VWD type 1. This case illustrates that mRNA work‐up may be needed to clarify a patient's phenotype–genotype., A patient with low FVIII levels was first misdiagnosed as von Willebrand disease. Genetic analysis revealed a silent variant in F8:c.222G>T.Sanger sequencing of the patient's cDNA after nested polymerase chain reaction showed that the patient had both a normal transcript containing exons 1–4 and a defect transcript lacking exon 2. The patient could be diagnosed with mild hemophilia A due to partial exon skipping.

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.

Background F8 int1h inversions (Inv1) are detected in 1-2% of severe hemophilia A (HA) patients. Long-range polymerase chain reaction (PCR) and inverse-shifting PCR have been used to diagnose these inversions. Objectives To design and validate a sensitive and robust assay for detection of F8 Inv1 inversions. Methods Archival DNA samples were investigated using mile-post assays and droplet digital PCR. Results Mile-post assays for Inv1 showing high specificities and sensitivities were designed and optimized. Analysis of four patients, two carrier mothers and 40 healthy controls showed concordance with known mutation status with one exception. One patient had a duplication involving exons 2-22 of the F8 gene instead of an Inv1 mutation. DNA mixtures with different proportions of wild type and Inv1 DNA correlated well with the observed relative linkage for both wild type and Inv1 assays and estimated the limit of detection of these assays to 2% of the rare chromosome. Conclusions The mile-post strategy has several inherent control systems. The absolute counting of target molecules by both assays enables determination of template quantity, detection of copy number variants and rare variants occurring in primer and probe annealing sites and estimation of DNA integrity through the observed linkage. The presented Inv1 mile-post analysis offers sensitive and robust detection and quantification of the F8 int1h inversions and other rearrangements involving intron 1 in patients and their mothers.

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.

Background: The occurrence of mosaicism in hemophilia A (HA) has been investigated in several studies using different detection methods. Objectives: To characterize and compare the ability of AmpliSeq/Ion Torrent sequencing and droplet digital polymerase chain reaction (ddPCR) for mosaic detection in HA. Methods: Ion Torrent sequencing and ddPCR were used to analyze 20 healthy males and 16 mothers of sporadic HA patients. Results: An error-rate map over all coding positions and all positions reported as mutated in the F8-specific mutation database was produced. The sequencing produced a mean read depth of >1500X where >97% of positions were covered by >100 reads. Higher error frequencies were observed in positions with A or T as reference allele and in positions surrounded on both sides with C or G. Seventeen of 9319 positions had a mean substitution error frequency >1%. The ability to identify low-level mosaicism was determined primarily by read depth and error rate of each specific position. Limit of detection (LOD) was 1% require repeated testing and mononucleotide repeats with more than four repeat units need an alternative analysis strategy. Mosaicism was detected in 1 of 16 mothers and confirmed using ddPCR. Conclusions: Deep sequencing using an AmpliSeq/Ion Torrent strategy allows for simultaneous identification of disease-causing mutations in patients and mosaicism in mothers. ddPCR has high sensitivity but is hampered by the need for mutationspecific design.

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.

Mutations are not identified in ~5% of hemophilia A and 10-35% of type 1 VWD patients. The bleeding tendency also varies among patients carrying the same causative mutation, potentially indicating variants in additional genes modifying the phenotype that cannot be identified by routine single-gene analysis. The F8, F9 and VWF genes were analyzed in parallel using an AmpliSeq strategy and Ion Torrent sequencing. Targeting all exonic positions showed an average read depth of >2000X and coverage close to 100% in 24 male patients with known disease-causing mutations. Discrimination between reference alleles and alternative/indel alleles was adequate at a 25% frequency threshold. In F8, F9 and VWF there was an absolute majority of all reference alleles at allele frequencies >95% and the average alternative allele and indel frequencies never reached above 10% and 15%, respectively. In VWF, 4-5 regions showed lower reference allele frequencies; in two regions covered by the pseudogene close to the 25% cut-off for reference alleles. All known mutations, including indels, gross deletions and substitutions, were identified. Additional VWF variants were identified in three hemophilia patients. The presence of additional mutations in 2 out of 16 (12%) randomly selected hemophilia patients indicates a potential mutational contribution that may affect the disease phenotype and counseling in these patients. Parallel identification of disease-causing mutations in all three genes not only confirms the deficiency, but differentiates phenotypic overlaps and allows for correct genetic counseling.

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)

Many newly diagnosed Swedish severe haemophilia A (HA) patients are sporadic cases. Some genotypically non-carrier mothers have gone on to have two descendants with the same mutation, presumably due to mosaicism.

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.

Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds. Major issues associated with mild haemophilia are that it may not present for many years after birth, and that awareness, even within families, may be low. Methodological problems exist in diagnosis, such as inconsistencies in results obtained from different assays used to measure factor levels in mild haemophilia. Advances in genetic testing provide insight into diagnosis as well as the likelihood of inhibitor development, which is not uncommon in patients with mild or moderate haemophilia and can increase morbidity. The management of patients with mild haemophilia is a challenge. This review includes suggestions around formulating treatment plans for these patients, encompassing the full spectrum from clinical care of the newly diagnosed neonate to that of the ageing patient with multiple comorbidities. Management strategies consider not only the vast differences in these patients’ needs, but also risks of inhibitor development and approaches to optimally engage patients.

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.