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Background: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. Methods: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. Results: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P

Background Increasing survival among people with haemophilia means that more individuals are at risk of developing age-related morbidity. Little is known about morbidity and health-related quality of life (HRQoL) in different age groups within a single large population of people with haemophilia. Aim This study aimed to explore the association between increasing age and comorbidity among people with haemophilia and to compare their HRQoL with that of a sample of the general population in England. Methods The prevalence of comorbidity recorded in medical records and HRQoL assessed by EQ-5D were compared by age group in participants in the Cost of Haemophilia in Europe: A Socioeconomic Survey study (CHESS) in Europe. HRQoL was compared with that of a sample of the general population taken from the 2012 Health Survey for England (HSE). Results Younger adults in CHESS were more likely to have received prophylaxis from an early age. The mean number of affected joints in younger adults was 1.0; participants aged 41–50 (1.25) and 51–60 years (1.41) had the highest mean number of affected joints. The prevalence of comorbidity was 36% in patients aged 18–30, 61% in 31–60-year-olds and 68% in those aged 61+. HRQoL impairment in young adults with haemophilia was comparable with that in the HSE population aged over 60. Conclusions Older people with haemophilia have impaired quality of life compared with younger adults and an increasing prevalence of several age-related disorders affecting mental health and cardiovascular and bone health. Young adults with haemophilia report impaired HRQoL comparable with that in a general population aged 61+.

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

INTRODUCTION In good risk patients (historic inhibitor peak

We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in PTGS1 (the gene encoding cyclo-oxygenase 1, COX-1, the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COX-derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 (TXA2) formation by platelets, urinary TXA2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.

Aim: to examine healthcare professionals’ (HP) perceptions and experiences in relation to adherence to prophylactic treatment among young people living with haemophilia (YPH). Methods: All HPs in four haemophilia centres across England and Wales were invited to participate, and all HPs who agreed to take part (n = 6) were interviewed. Interviews were audio-recorded, transcribed and then analysed using Interpretative Phenomenological Analysis (IPA). Results: HPs estimate that generally young people with haemophilia keep to their treatment regimen well, although they also recognise that adherence may fluctuate with many patients going through shorter periods of non-adherence. The increasingly personalised or flexible approach to prophylaxis makes it harder to assess adherence. The main themes identified through IPA included (1) HPs’ suggest that adherence fluctuates (2) Non-adherence is mainly driven by lifestyle and developmental, social and family factors, and (3) Education, HPs’ sensitivity to individual needs, and psychological and peer support are key facilitators of good adherence. Conclusion: The increasingly flexible approach to prophylaxis requires a new way of thinking about, and assessment of, adherence. More personalised treatment regimen can be more complicated and may, therefore, lead to accidental non-adherence. The results of this study with HPs complement those of a previous qualitative study with patients but place greater emphasis on a broader perspective on understanding drivers of non-adherence as well as understanding strategies to improve adherence in the minority of patients who appear to struggle.

Introduction Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET). Aim and methods This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres. Results The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub-and-spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow-up patients for a long-term safety and efficacy surveillance. Conclusion We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.

Background Up to 30% of hemophilia A patients develop inhibitory antibodies against the infused factor VIII (FVIII). The development of a deimmunized FVIII is an unmet high medical need. Although improved recombinant FVIII (rFVIII) products evolved within the last years, the immunogenicity has not been solved. A deimmunized FVIII could reduce the probability of inhibitor development, providing safer therapy. Objective To develop a deimmunized FVIII molecule by modifying major histocompatibility complex (MHC) class II presentation, leading to a functional but less immunogenic molecule. Methods We performed (1) in silico prediction of potentially immunogenic T cell epitopes and their modification by amino acid substitutions in the FVIII sequence, (2) evaluation of functional and structural similarity of the modified rFVIII to unmodified FVIII and registered products, and (3) confirmation of the reduced immunogenicity by in vitro testing. Results A partially deimmunized fully functional FVIII molecule incorporating 19 amino acid substitutions was generated. The substitutions led to a reduction of the immunogenicity score, indicating a reduced immunogenicity based on in silico calculations. This was confirmed in an in vitro dendritic cell (DC)‐‐T cell assay. Using this assay, cells from healthy donors proved the significantly reduced immunogenicity of the modified FVIII variant by revealing less proliferation of T helper cells to this variant than to the unmodified FVIII. Conclusion In silico predictions resulted in a partially deimmunized FVIII. This FVIII is fully functional and was demonstrated to be less immunogenic in in vitro testing. This approach may result in a reduction of the inhibitor risk for patients with hemophilia A.

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

Contains fulltext : 244121.pdf (Publisher’s version ) (Open Access) AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL(-1) . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h(-1) 68 kg(-1) , 2930 mL 68 kg(-1) , 1810 mL 68 kg(-1) , and 172 mL h(-1) 68 kg(-1) , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL(-1) . CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real-life data.

We read with interest the recent publication by Rauche et al. and congratulate them on highlighting the potentially significant role VWF may play in the progression and prognosis of COVID19. Since SARS-Cov2 first presented there has been an increasing recognition that the disease may trigger a widespread endotheliopathy. This fact could help to explain the highly varied presentation of patients with COVID19 from bowel ischaemia to large vessel occlusion causing strokes in addition to the more common presentation of respiratory symptoms.

BACKGROUND: COVID-19 infection is characterised, among other features, by a prothrombotic state with high rate of venous thromboembolism (VTE), D-dimer, and fibrinogen levels. Clinical observations have also highlighted that these patients have elevated von Willebrand factor (vWF) and factor VIIIc. METHODS: 24 consecutive COVID-19 positive patients were selected from the intensive care unit (ICU) or the high acuity ward of Brighton and Sussex University Hospitals NHS Trust. RESULTS: The rate of VTE was 25% and mortality rate was 16.7%. Fibrinogen and D-Dimers were elevated, 7.9 (1.6) g/L and 2.4 (2.02) ug/ml respectively. Factor VIIIc and von vWF antigen levels were both extremely elevated at 279 (148) u/dL and 350 (131) % respectively, which are comparable to levels seen in ICU patients with severe sepsis. vWF levels were significantly higher in patients that died (p=0.017) and showed a positive correlation with age. There was a statistically significant association between COVID-19 disease and non-O blood group (p=0.02); 80% (4/5) of COVID-19 patients with VTE were blood group A. CONCLUSION: Very high levels of vWF and factor VIIIc are common in COVID-19 patients, comparable to levels in severely septic non-COVID ICU patients. This could contribute to the hypercoagulable state and increased VTE rate in COVID-19. Further studies are needed to evaluate the use of vWF for stratifying thrombotic risk in COVID-19 and to determine if elevated vWF is contributing to disease pathogenesis.

Introduction Inhibitor formation is the greatest challenge facing persons with haemophilia treated with factor concentrates. The gold standard testing methodologies are the Nijmegen-Bethesda assay (NBA) for FVIII and Bethesda assay (BA) for FIX inhibitors, which are affected by pre-analytical and inter-laboratory variability. Aims To evaluate inhibitor testing methodology and assess correlation between self-reported and actual methodology. Methods Methodology was evaluated using a survey distributed alongside a UK National External Quality Assessment Service Blood Coagulation external quality assurance (EQA) exercise for FVIII and FIX inhibitor testing. Results Seventy four survey and EQA exercise responses were received (response rate 63.2%), with 50 paired survey/EQA results. 47.1% (33/70) reported using the NBA and 42.9% (30/70) the BA for FVIII inhibitor testing. Review of FVIII inhibitor assay methodology demonstrated discrepancy (self-reported to actual) in 64.3% (BA reporting) and 27.6% (NBA reporting). Pre-analytical heat treatment was used by 32.4%, most commonly 56°C for 30 minutes. Assay cut-offs of 0.1-1.0 BU/mL were reported. EQA samples (acquired FVIII and congenital FIX) demonstrated titres and coefficients of variation (CV) of 3.1 BU/mL (0.7-15.4 BU/mL; CV = 43%) and 18.0 BU/mL (0-117 BU/mL; CV = 33%), respectively. No significant assay or laboratory factors were found to explain this variance, which could have resulted in change in management for 6 patients (5 misclassified high-titre FVIII inhibitors and 1 false negative for a FIX inhibitor). Conclusions Heterogeneity was seen at each stage of assay methodology. No assay-related factors were found to explain variation in inhibitor titres. Further standardization is required to improve inhibitor quantification to guide patient care.

Background For communities of people living with hemophilia and other genetic conditions, gene therapy could represent a paradigm shift in treatment strategies. As investigational therapeutic modalities such as gene therapy become more widely used and discussed, there is a critical need for all stakeholders to communicate using a lexicon that is intelligible, accurate, consistent, and representative of novel treatments. In doing so, expectations can be more carefully managed and potential risks, benefits, and limitations better understood. In recognition of this need, a first-ever study of gene therapy lexicon was conducted using established methods of market research and linguistic analysis. Methods Ninety-four participants representing hematologists, nurses, caregivers, and people with hemophilia A, in six countries (US, UK, Spain, Germany, France, Italy) took part in a series of in-depth interviews, face-to-face focus groups, an advisory board meeting, and online group interviews to develop, refine, and test verbal, written, and pictorial language concepts through a three-phase iterative process. Sessions were conducted in local languages using detailed discussion guides. Feedback from participants was captured using real-time instant-response dial testing to measure moment-by-moment emotional responses to language stimuli. Semiquantitative analysis of the responses informed selection of preferred language concepts for final testing, and qualitative discussion explored preference rationale. Participants also completed polling and forced rank and choice written exercises. Results Study feedback showed that the hemophilia community has preferences around consistent lexicon to describe hemophilia and its management. Expert linguistic analysis of feedback from the three phases enabled agreement of a consensus lexicon of vocabulary and an optimized summary narrative for talking about gene therapy amongst people affected by hemophilia A. Preferences were largely consistent across audiences and countries, although some country-specific recommendations were made. A representative summary phrase was agreed: “Gene therapy is being studied in clinical trials with the aim to allow the body to produce factor VIII protein on its own”. Conclusions The use of preferred language across different stakeholders increases understanding and comfort during discussions of novel and complex therapeutic modalities such as gene therapy. Consistent use of community-informed lexicon minimizes miscommunication and facilitates informed decision-making regarding potential future treatment opportunities.

Prolonged aPTT in Patients with Covid-19 In this study, 20% of patients with Covid-19 had a prolonged activated partial-thromboplastin time. In 90% of these cases, the cause was lupus anticoagulant...

Gray platelet syndrome (GPS) is a rare recessive disorder caused by variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet ɑ-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macro-thrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4-lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease. ispartof: BLOOD vol:136 issue:17 pages:1956-1967 ispartof: location:United States status: published

Single missense mutations in the F8 gene encoding the coagulation protein factor VIII give rise predominantly to non-severe hemophilia A. Despite only a single amino acid sequence difference between the replacement, therapeutic factor VIII and the patient’s endogenous factor VIII, therapeutic factor VIII may still be perceived as foreign by the recipient’s immune system and trigger an immune response (inhibitor). Inhibitor formation is a life-long risk for patients with non-severe hemophilia A treated with therapeutic factor VIII, but remains difficult to predict. The aim of this study was to understand whether fortuitous, primary sequence cross-matches between therapeutic factor VIII and proteins in the human proteome are the reason why certain F8 mutations are not associated with inhibitor formation. We predicted which therapeutic factor VIII differences are potentially perceived as foreign by helper T cells – a necessary precursor to inhibitor development – and then scanned potentially immunogenic peptides against more than 100,000 proteins in the proteome. As there are hundreds of disease-causing F8 missense mutations and the human leukocyte antigen gene complex governing peptide presentation to helper T cells is highly polymorphic, these calculations pose a huge combinatorial challenge that we addressed computationally. We found that cross-matches between therapeutic factor VIII and the human proteome are commonplace and have a profound impact on the predicted risk of inhibitor development. Our results emphasize the importance of knowing both the F8 missense mutation and the human leukocyte antigen alleles of a patient with missense mutation hemophilia A if his underlying risk of inhibitor development is to be estimated.

Emicizumab is a bispecific antibody that activates FX to FXa in the absence of FVIII. It has been shown to reduce bleeding episodes in people with haemophilia A complicated by a FVIII inhibitor. Despite the protection against bleeds, some breakthrough bleeds are inevitable and these may require additional haemostatic treatment. Emicizumab has been associated with severe adverse events when co-administered with activated prothrombin complex concentrate. To minimize the risk of adverse events, the UK Haemophilia Centre Doctors' Organisation issues the following updated interim guidance to its Inhibitor Guidelines for managing patients receiving Emicizumab based on the limit published information available in February 2018.

Over the past decades, haemophilia management has continually evolved, with prophylaxis now considered the treatment of choice. Prophylaxis primarily seeks to prevent bleeding and haemarthrosis episodes from occurring and avert the otherwise inevitable haemophilic arthropathy. Yet, numerous unanswered issues remain. These concern dose levels, dosing intervals, ways of integrating variability in bleeding phenotype, patient age, joint status, lifestyle, physical activity, treatment adherence and individual responses to FVIII or FIX concentrates. Individualized prophylaxis may thus be paramount. One crucial tool that may allow more accurate prophylaxis regimens to be implemented is the individual pharmacokinetic (PK) study. Therefore, physicians in charge of managing those living with haemophilia must be comfortable with PK profiling in order to be in a position to tailor patients' treatment, taking into account PK data, while minimizing patients' inconvenience, discomfort, as well as, possibly, treatment costs. For optimization of prophylaxis, recent development of recombinant molecules with more attractive PK properties, such as prolonged elimination half-life, increases the choice of dosing regimens, enabling decreased frequency of dosing for some, if deemed appropriate. For each patient, PK parameters can be determined, including trough levels, AUC, and time spent under a predefined threshold, with additional pharmacodynamic (PD) parameters possibly established by means of a global coagulation test like the thrombin generation test. Most importantly, target PK/PD parameters will need to consider clinical variables like patient age, body weight, joint status, treatment adherence, number of bleeding episodes, activity index or lifestyle.

Introduction: Reported levels of adherence to prophylaxis among young people with haemophilia (YPH) vary widely and are predominately based on estimations made by healthcare professionals and parents. Reasons for (non)adherence among YPH in particular have not been evidenced. Aim: to examine experiences in relation to prophylaxis with YPH themselves, and barriers and facilitators to their adherence. Methods: 11 Participants were recruited in five haemophilia centres across England and Wales. All patients who met the inclusion criteria (aged 12-25, diagnosed with haemophilia, on prophylaxis) were approached during a routine check-up appointment, and all participants who agreed to take part were interviewed. Interviews were audio recorded, transcribed and analysed using Interpretative Phenomenological Analysis. Results: Self-reported adherence to prophylaxis was good. Few participants admitted to intentionally skipping injections although they reported sometimes forgetting. However, due to the increasingly personalised and flexible approach to prophylaxis, adherence is not straightforward to define. Barriers to adherence included a busy lifestyle, dislike of the intravenous injection, venous access issues, anxiety or stress and being out of one’s normal routine. Support was an important facilitator to adherence, including support from health professionals at the haemophilia centre as well as friends. Parents appear to be very involved with their child’s haemophilia management, even after they leave home. Conclusion: What this study adds is that the increasingly flexible and personalised approach to managing prophylaxis in haemophilia may sometimes lead to confusion around treatment frequency and dosing. This may lead to accidental non-adherence, which is distinct from both skipping and forgetting. Advice from haemophilia teams may not always be consistent and is likely to be interpreted differently by different individuals. Some additional training and education of patients and their families to increase their knowledge and skills around prophylaxis may reduce this confusion and therefore is likely to improve adherence further.

Summary Inhibitor formation in non-severe haemophilia A is a life-long risk and associated with morbidity and mortality. There is a paucity of data to understand real-world inhibitor screening practice. We evaluated the treatment burden, haemostatic strategies, F8 genotyping and inhibitor screening practices in non-severe haemophilia A in seven London haemophilia centres. In the 2-year study period, 44% (377/853) patients received at least one haemostatic treatment. Seventy-nine percent of those treated (296/377) received factor VIII (FVIII) concentrate. F8 genotype was known in 88% (331/377) of individuals. Eighteen per cent (58/331) had ‘high-risk’ F8 genotypes. In patients with ‘standard-risk’ F8 genotypes treated on-demand with FVIII concentrate, 51·3% episodes (243/474) were screened within 1 year. However, poor screening compliance was observed after ‘high-risk’ treatment episodes. In patients with ‘standard-risk’ F8 genotypes, 12·3% (28/227) of treatment episodes were screened in the subsequent 6 weeks after surgery or a bleed requiring ≥5 exposure days. Similarly, in the context of ‘high-risk’ F8 genotypes after any FVIII exposure, only 13·6% (12/88) of episodes were screened within 6 weeks. Further study is required to assess optimal practice of inhibitor screening in non-severe haemophilia A to inform subsequent clinical decisions and provide more robust prevalence data to further understand the underlying immunological mechanism.

We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in prostaglandin endoperoxide synthase 1 (PTGS1) (the gene encoding cyclo-oxygenase 1 [COX-1], the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COXderived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 formation by platelets, urinary thromboxane A2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.

Although the use of clotting factor concentrates is the mainstay of haemophilia care, the development of inhibitors complicates disease management. Perioperative management of patients with inhibitors is therefore a challenge. A systematic literature review was performed to identify literature reporting on the perioperative monitoring and management of haemophilia. MEDLINE, Embase and Cochrane databases were searched from database inception to 26 March 2018. Recent congress proceedings were also searched. Titles and abstracts, then full texts, were screened for relevance by two reviewers. Quality of included studies was assessed using the Critical Appraisal Skills Programme checklist. Of the 2033 individual entries identified, 86 articles met the inclusion criteria. The identified studies were screened again to find articles reporting perioperative laboratory monitoring in patients with congenital haemophilia A or B, resulting in 24 articles undergoing data extraction. Routine perioperative assay monitoring practices were the most commonly reported (n = 20/24); thrombin generation assay was the least commonly reported (n = 2/24). Other monitoring practices described were factor VII and factor VIII coagulation activity (n = 8/24, n = 5/24, respectively), and thromboelastography or rotational thromboelastometry assessments (n = 3/24). The impact of monitoring on treatment decisions was, however, rarely reported. In conclusion, many methods of perioperative monitoring of haemophilia patients with inhibitors have been identified in this review, yet there is a lack of reporting in larger scale cohort studies. More detailed reporting on the impact of monitoring outcomes on treatment decisions is also needed to share best practice, particularly as new therapeutic agents emerge.

Introduction\ud \ud The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015.\ud \ud \ud Methods\ud \ud Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint‐bleed rate (ABR/AJBR) from Haemtrack (HT) in HT‐compliant patients.\ud \ud \ud Results\ud \ud We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n = 130/137) of HT‐compliant children

Tranexamic acid (TXA) is a synthetic antifibrinolytic drug used widely used to control bleeding complications in a wide variety of clinical situations. Soon after its development in the 1960s it found use in treatment of women with menorrhagia, and in inherited bleeding disorders. Subsequently it was used in surgery and with proven efficacy to reduce transfusion requirements and bleeding complications. Recent meta-analysis have provided further evidence of efficacy and safety. Tranexamic acid is now on the World Health Organization’s (WHO) list of essential drugs, and is the focus of ongoing worldwide trials. Similarly, there is increasing evidence base in both congenital and acquired bleeding disorders. We present a clinical narrative of the antifibrinolytic system and associated drugs to accompany the pharmacy review by Chaplin et al, with the aim of highlighting the evolution of TXA use in bleeding disorders over recent decades.

The 6th Haemophilia Global Summit was held in Prague, Czech Republic, in September 2015. The programme was designed by an independent Scientific Steering Committee of haemophilia experts and aimed to share optimal management strategies for haemophilia at all life stages, explore recent potential advances in the management of haemophilia A and B and discuss challenges in haemophilia care. In this supplement from the meeting, Dan Hart reviews the lessons that can be learnt from cost-constrained environments with regard to improving care for people with haemophilia globally. Sebastien Lobet discusses the importance of physical activity for optimising care and Roseline d'Oiron and Jan Blatný consider the role of real-world data in understanding the effect of treatment in a clinical setting over the long term and the true impact of treatment on the day-to-day life of the patient. Gili Kenet addresses the current challenges relating to the optimal management of prophylaxis, and Gerry Dolan and Cedric Hermans discuss the value of pharmacokinetic (PK) parameters in informing treatment decisions. Cedric Hermans and Valerie Libotte explore the importance of considering social and occupational development factors as an integral part of haemophilia care, and Jan Astermark reviews key strategies to predict and prevent inhibitor development.

Haemophilia remains a complex disorder to diagnose and manage, requiring close cooperation between multidisciplinary healthcare professionals. There are still many unmet challenges in haemophilia care. The first Team Haemophilia Education (THE) meeting, held on 7-8 May 2015 in Amsterdam, The Netherlands, aimed to promote the optimal care of haemophilia patients through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. Haemophilia treatment centres from several countries were asked to complete a premeeting online questionnaire to establish the biggest challenges that they face when managing patients. The concerns expressed were used to develop the agenda, which comprised a combination of formal presentations, case studies and informal workshops covering such topics as pharmacokinetics, laboratory assays and tailoring of treatment to individual patients. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE meeting 2015.

Essentials Chromogenic factor VIII and factor IX assays have not been widely adopted partly due to perceived cost. Chromogenic assays may be needed for monitoring therapy with some extended half-life concentrates. Efficient use of reagents makes the costs of chromogenic and one-stage factor IX assays similar. A similar approach for factor VIII delivers lower costs for chromogenic compared with one-stage assays. Summary Background Measurement of coagulation factor factor VIII (FVIII) and factor IX (FIX) activity can be associated with a high level of variability using one-stage assays based on activated partial thromboplastin time (APTT). Chromogenic assays show less variability, but are less commonly used in clinical laboratories. In addition, one-stage assay accuracy using certain reagent and instrument combinations is compromised by some modified recombinant factor concentrates. Reluctance among some in the hematology laboratory community to adopt the use of chromogenic assays may be partly attributable to lack of familiarity and perceived higher associated costs. Objectives To identify and characterize key cost parameters associated with one-stage APTT and chromogenic assays for FVIII and FIX activity using a computer-based cost analysis model. Methods A cost model for FVIII and FIX chromogenic assays relative to APTT assays was generated using assumptions derived from interviews with hematologists and laboratory scientists, common clinical laboratory practise, manufacturer list prices and assay kit configurations. Results Key factors that contribute to costs are factor-deficient plasma and kit reagents for one-stage and chromogenic assays, respectively. The stability of chromogenic assay kit reagents also limits the cost efficiency compared with APTT testing. Costs for chromogenic assays might be reduced by 50–75% using batch testing, aliquoting and freezing of kit reagents. Conclusions Both batch testing and aliquoting of chromogenic kit reagents might improve cost efficiency for FVIII and FIX chromogenic assays, but would require validation. Laboratory validation and regulatory approval as well as education and training in the use of chromogenic assays might facilitate wider adoption by clinical laboratories.

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)

WOS: 000451511200001, PubMed ID: 30073913, Objective: To identify ways that provision of hemophilia care can be maximized at the local level, irrespective of available resources or cultural or geographic challenges. Methods: The SHIELD group used its multinational experience to share examples of local initiatives that have been employed to deliver optimal hemophilia care. Results: The examples were reviewed and categorized into four key themes: guidelines and algorithms for delivery of care; collaboration with patients and allied groups for care and education; registries for the monitoring of treatment and outcomes and health care planning and delivery; and opportunities for personalization of care. These themes were then incorporated into a road map for collaborative care in hemophilia that reflected the contribution of best practice. Discussion: Differing healthcare reimbursement systems, budgetary constraints, and geographical and cultural factors make it difficult for any country to fully deliver ideal care for people with hemophilia. The SHIELD approach for collaborative care provides illustrative examples of how four key themes can be used to optimize hemophilia care in any setting., Bayer Pharma Plc, The authors are members of the SHIELD (Supporting Hemophilia through International Education, Learning and Development) group, an independent panel of physicians with expert interest in the treatment of haemophilia. Formation of the SHIELD group and its meetings were supported by Bayer Pharma Plc. Members received honoraria for attendance at meetings but no honoraria were paid for contributions to this manuscript. This publication and its content are solely the responsibility of the authors. Medical writing assistance was provided by Clark Health Communications under the direction of the authors and paid for by Bayer Pharma Plc.

Objectives\ud \ud In a separate document, we have provided specific guidance on performing individual pharmacokinetic (PK) studies using limited samples in persons with hemophilia with the goal to optimize prophylaxis with clotting factor concentrates. This paper, intended for clinicians, aims to describe how to interpret and apply PK properties obtained in persons with hemophilia. \ud \ud \ud Methods\ud \ud The members of the Working Party on population PK (PopPK) of the ISTH SSC Subcommittee on Factor VIII and IX and rare bleeding disorders, together with additional hemophilia and PK experts, completed a survey and ranking exercise whereby key areas of interest in the field were identified. The group had regular web conferences to refine the manuscript’s scope and structure, taking into account comments from the external feedback to the earlier document. \ud \ud \ud Results\ud \ud Many clinical decisions in hemophilia are based on some form of explicit or implicit PK assessment. Individual patient PK profiles can be analyzed through traditional or PopPK methods, with the latter providing the advantage of fewer samples needing to be collected on any prophylaxis regimen, and without the need the for a washout period. The most useful presentation of PK results for clinical decision making are a curve of the factor activity level over time, the time to achieve a certain activity level, or related parameters like half‐life or exposure (AUC). Software platforms have been developed to deliver this information to clinicians at the point of care. Key characteristics of studies measuring average PK parameters were reviewed, outlining what makes a credible head‐to‐head comparison among different concentrates. Large data collections of PK and treatment outcomes currently ongoing will advance care in the future. \ud \ud \ud Conclusions\ud \ud Traditionally used to compare different concentrates, PK can support tailoring of hemophilia treatment by individual profiling, which is greatly simplified by adopting a PopPK/Bayesian method and limited sampling protocol.

INTRODUCTION Factor VIII (FVIII) antibody formation is the greatest clinical and laboratory challenge within the haemophilia centre. The Nijmegen-Bethesda assay (NBA) is the gold standard for inhibitor quantification, but affected by pre-analytical variables including a patient's FVIII activity (FVIII:C). Pre-analytical heat treatment (PHT) provides a methodology for inhibitor testing when measurable FVIII:C is present. METHODS We evaluated the effect of different PHT conditions (time/temperature) on FVIII:C as well as on potency of inhibitory activity in samples containing FVIII:C (endogenous pooled plasma and exogenous recombinant FVIII (rFL-FVIII) concentrate) or FVIII inhibitor. RESULTS PHT of endogenous FVIII at 37°C, 47°C and 52°C resulted in declining measurable FVIII:C at 120 minutes (69%, 57% and 13% of the original FVIII:C, respectively). Incubation at 56°C resulted in FVIII:C ≤ 1IU/dL after 60 minutes for endogenous FVIII and 120 minutes for rFL-FVIII. Incubation at 58°C resulted in FVIII:C

There is an associated link between clinical research engagement and improved patient outcomes.[1][1] Not only does this apply to the subjects of research but also to those patients who are not active participants but are treated at sites where research is conducted.[2][2] Unfortunately, clinical

Introduction Factor XI (FXI) deficiency is the commonest of the rare bleeding disorders, affecting 2079 individuals in the United Kingdom. Treatment options for bleeding or surgery include antifibrinolytics, fresh frozen plasma or plasma-derived (pd) FXI concentrates. There were a number of reports of thrombosis following treatment with FXI concentrates prior to changes in their manufacturing processes made in the mid-1990's. Aims: The aim of the study was to determine the occurrence of adverse events (haemorrhagic and thrombotic) following usage of pd-FXI concentrates at two large UK haemophilia centres. Retrospective chart review of all consecutively treated patients with BPL Factor XI® or Hemoleven® over a 5-year period (11/06–11/11) was performed. Results Twenty-nine patients (median age = 57.1 years) received treatment over 64 treatment episodes (surgery = 56, bleeding = 5, other = 3), using 126 000 U of concentrate. Median baseline FXI:C was 9 U dL−1 (range =

SummaryAntibody formation to factor VIII (FVIII) remains the greatest clinical and diagnostic challenge to the haemophilia-treating physician. Current guidance for testing for inhibitory FVIII antibodies (inhibitors) recommends the functional Nijmegen-Bethesda assay (NBA). A FVIII ELISA offers a complementary, immunological approach for FVIII antibody testing. It was the aim of this study to retrospectively evaluate the performance of a FVIII ELISA (index) for detection of FVIII antibodies, compared with the NBA (reference). All samples sent for routine FVIII antibody testing at two haemophilia Comprehensive Care Centres, were tested in parallel using the NBA and a solid-phase, indirect FVIII ELISA kit (Immucor). A total of 497 samples from 239 patients (severe haemophilia A=140, non-severe haemophilia A=85, acquired haemophilia A=14) were available for analysis. Sixty-THree samples tested positive by the NBA (prevalence 12.7 %, 95 % confidence interval [CI], 9.9–15.9 %), with a median inhibitor titre of 1.2 BU/ml (range 0.7–978.0). The FVIII ELISA demonstrated a specificity of 94.0 % (95 %CI, 91.3–96.0), sensitivity of 77.8 % (95 %CI, 65.5–87.3), negative predictive value of 96.7 % (95 %CI, 94.5–98.2), positive predictive value 65.3 % (95 %CI, 53.5–76.0), negative likelihood ratio 0.2 (95 %CI, 0.1–0.4), positive likelihood ratio 13.0 (95 %CI, 8.7–19.3) and a diagnostic odds ratio of 54.9 (95 %CI, 27.0–112.0). Strong positive correlation (r=0.77, p< 0.001) was seen between the results of the NBA (log adjusted) and FVIII ELISA optical density. In conclusion, FVIII ELISA offers a simple, specific, surveillance method enabling batch testing of non-urgent samples for the presence of FVIII antibodies.