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INTRODUCTION: As people with haemophilia (PWH) receive better treatment and live longer they are more likely to encounter cardiovascular disease (CVD) and other comorbidities. ESC guidelines for the acute management of patients presenting with acute coronary syndrome (ACS) are based on the non-haemophilia population. AIM: To review the guidelines and propose relevant adaptations for PWHA without inhibitors who are treated with prophylaxis and present with ACS. METHODS: As part of the ADVANCE Group, 20 European haemophilia experts used a modified Delphi approach to develop and gain consensus on proposed adaptations of the ESC guidelines for PWHA without inhibitors. RESULTS: Of the 32 Class I recommendations across both guidelines, adaptions were considered necessary and proposed for 15. The adaptions highlight the need to provide sufficient FVIII trough levels at the time of antithrombotic treatment in people with haemophilia A (HA) without inhibitors. Patients receiving emicizumab prophylaxis and requiring oral anticoagulation therapy or combined single antiplatelet plus oral anticoagulation therapy will require additional FVIII replacement therapy. CONCLUSION: In the absence of high-quality clinical evidence, the combined expert opinion used to develop these adaptions to the current ESC guidelines may help to guide clinicians in their treatment decisions when a PWHA presents with ACS. Free to read [see URL]

Introduction A second peak of inhibitors has been reported in patients with severe hemophilia A (HA) aged >50 years in the United Kingdom. The reason for this suggested breakdown of tolerance in the aging population is unclear, as is the potential impact of regular exposure to the deficient factor by prophylaxis at higher age. No data on hemophilia B (HB) have ever been reported. Aim The ADVANCE Working Group investigated the incidence of late-onset inhibitors and the use of prophylaxis in patients with HA and HB aged ≥40 years. Methods A retrospective, observational, cohort, survey-based study of all patients aged ≥40 years with HA or HB treated at an ADVANCE hemophilia treatment center. Results Information on 3,095 people aged ≥40 years with HA or HB was collected. Of the 2,562 patients with severe HA, the majority (73% across all age groups) received prophylaxis. In patients with severe HA, the inhibitor incidence per 1,000 treatment years was 2.37 (age 40–49), 1.25 (age 50–59), and 1.45 (age 60 + ). Overall, the inhibitor incidence was greatest in those with moderate HA (5.77 [age 40–49], 6.59 [age 50–59], and 4.69 [age 60 + ]) and the majority of inhibitor cases were preceded by a potential immune system challenge. No inhibitors in patients with HB were reported. Conclusion Our data do not identify a second peak of inhibitor development in older patients with hemophilia. Prophylaxis may be beneficial in older patients with severe, and possibly moderate HA, to retain a tolerant state at a higher age.

Background: Patient-relevant health outcomes for persons with hemophilia should be identified and prioritized to optimize and individualize care for persons with hemophilia. Therefore, an international group of persons with hemophilia and multidisciplinary health care providers set out to identify a globally applicable standard set of health outcomes relevant to all individuals with hemophilia. Methods: A systematic literature search was performed to identify possible health outcomes and risk adjustment variables. Persons with hemophilia and multidisciplinary health care providers were involved in an iterative nominal consensus process to select the most important health outcomes and risk adjustment variables for persons with hemophilia. Recommendations were made for outcome measurement instruments. Results: Persons with hemophilia were defined as all men and women with an X-linked inherited bleeding disorder caused by a deficiency of coagulation factor VIII or IX with plasma activity levels

Aim: To assess available evidence on the use of rFVIIa in non-orthopaedic surgery including dental surgery in adult patients with congenital haemophilia with inhibitors (PWHI). Methods: A systematic literature search was performed according to a prespecified search string; prespecified criteria were used to select applicable studies including PWHI ≥18 years of age who underwent any non-orthopaedic surgery using rFVIIa. Results: Thirty-three publications met the eligibility criteria, of which 26 publications – including 46 procedures in 44 patients – were selected for the qualitative analysis. Most publications were case reports or case series (21/26). Primary authors assessed rFVIIa as effective in maintaining haemostasis during and after most major surgeries (22/32). rFVIIa dose was mainly on label, with higher doses used in 4 cases, and a lower dose in 1 case. Duration of treatment was mostly 5–10 days (range: 3 days to 1 month post-operatively). Adverse events related to rFVIIa were rare. Conclusions: Assessing non-orthopaedic surgery in this patient population is hampered by a paucity of published data; nevertheless, the current evidence indicates that rFVIIa is effective in achieving haemostasis in haemophilia patients with inhibitors undergoing elective non-orthopaedic or dental surgery. rFVIIa was generally well tolerated in these patients, with thrombotic events occurring rarely. These data, generated to help clinicians manage congenital haemophilia with inhibitors, highlight the need for more systematic reporting of rFVIIa and all other therapeutic agents in non-orthopaedic surgery and dental surgery in patients with congenital haemophilia and inhibitors. (Less)

Introduction Emicizumab (a bispecific antibody mimicking Factor VIIIa) has been authorised for use in the United Kingdom National Health Service (NHS) in severe hemophilia A patients with and without inhibitors since August 2019. The Summary of Product Characteristics estimates a steady state of emicizumab achieved after four loading doses for patients >12 years of age at between 50-60ug/mL. Real world data outwith trial conditions are lacking to evaluate clinical efficacy, and which assays may be appropriate to determine emicizumab levels in vivo. Methods A prospective analysis of patients switching from FVIII concentrate to emicizumab was conducted at Guy's and St Thomas' Hospital Haemophilia Centre between September 2019 and July 2020 inclusive. Patients' age and weight were recorded and doses of emicizumab prescribed according to United Kingdom Haemophilia Centres' Doctors Organisation guidelines. Post emicizumab initiation, samples for coagulation testing were taken one week, four weeks and eight weeks after commencing emicizumab, with some pre-emicizumab initiation samples obtained. Three assays were used (human chromogenic FVIII assay (CSA) (Hyphen Biomed); bovine chromogenic FVIII assay (BCA) (Siemens); and a modified one-stage emicizumab assay (OSEA) with emicizumab calibrators to derive drug levels). Where possible with sufficient sample volume all three assays were run simultaneously. Results Within the cohort of all severe hemophilia A patients (n=118), 9 patients with inhibitors had already been previously switched from FVIII concentrate. 21 patients switched to emicizumab between September 2019 and July 2020, of which 2 patients had active FVIII inhibitors, with emicizumab prophylaxis patients comprising 25.4% (30/118) of the hospital cohort. Mean age of switchers was 39.3 years (standard deviation ± 13.9), with a mean dose of 116 ± 20.7mg on a weekly basis. 13/21 were on 1.5mg/kg weekly dosing and the remainder on fortnightly dosing at 3mg/kg. OSEA levels at 1 week (n=15), 4 weeks (n=15) and 8 weeks (n=7) were 19.7 ± 14.8ug/mL, 54.8 ± 11.7ug/mL and 61.3 ± 12.2ug/mL respectively. CSA results were 17 ± 9.0 IU/dL (n=9), 27.7 ± 6.7 IU/dL (n=10), and 26.7 ± 9.6 IU/dL (n=5) respectively. Simultaneous 1-stage based OSEA and CSA assays were performed on 20 samples, with high correlation between the two types of assay (Pearson correlation coefficient = 0.909 (CI 0.780-0.964, p BCA in 3 patients at 1 week showed a low level of residual FVIII (all No patients developed anti-emicizumab antibodies as determined by clinical efficacy or by APTT measurement. No patients required any surgical or interventional procedures during this period. One spontaneous bleed and one traumatic bleed were recorded in two separate patients. Conclusion Emicizumab in a real-world setting is confirmed in our experience to have excellent clinical efficacy with infrequent episodes of spontaneous bleeding. 18% of patients switched to emicizumab within a year of its availability on the NHS. It has been well-tolerated with no clinical or laboratory evidence of anti-drug antibodies as measured by APTT. The OSEA correlated well with levels predicted by the emicizumab SPC at each time point. At all concentrations an OSEA and CSA are highly correlated, which may suggest that only one of the two assays is routinely required in laboratory use to assay emicizumab. Caution is however advised in assessing OSEA on its own when FVIII concentrate has recently been administered as this may result in some low level, false positive results. Figure Disclosures Austin: Chugai: Honoraria. Dolan:Pfizer: Consultancy; Roche: Honoraria.

INTRODUCTION:Hemophilia is a rare, inherited bleeding disorder affecting an estimated 400,000 people worldwide (1). Characterized by spontaneous bleeding and long-term, irreversible joint damage, persons with hemophilia are often limited in normal day-to-day activities, including work/school, and require comprehensive care at specialized treatment centers. With replacement therapies extending survival by decades and vastly improving quality of life (QoL), routine prophylaxis is considered the standard-of-care in developed countries. However, due to the cost of replacement factor, access to treatment remains a challenge, and increased scrutiny over funding has been augmented by growing demands on healthcare budgets (2). Thus, the hemophilia community shares a unified goal of objectively defining patient-centered value in hemophilia care.METHODS:Using a three-tiered outcomes hierarchy model initially described by Porter (3), an international, multidisciplinary panel of health economics outcomes researchers and hemophilia experts developed a value framework for decision makers to assess value of various healthcare interventions in hemophilia.RESULTS:The three tiers for assessing value are: (i) Health status achieved/retained; (ii) Process of recovery; and (iii) Sustainability of health. Tier one measures survival, quality of life (QoL), and hemophilia-specific outcomes of bleeding frequency, musculoskeletal complications, and severe bleeds, as well as function/activity (that is, lifestyle impairment). Tier two measures time to initial treatment or recovery and time missed at education/work, as well as disutility of care (that is, inhibitor development, pathogen transmission/infections, orthopedic intervention, and venous access). Tier three measures avoidance of bleeds, maintenance of productive lives, and long-term health, while capturing long-term consequences of insufficient therapy or age-related complications. Applicability of the framework can be demonstrated in areas of healthcare delivery, treatment regimen, and innovation for new therapies.CONCLUSIONS:This value framework represents an initial collaboration with stakeholders to define and organize an array of patient-centric outcomes of importance in hemophilia into a practical tool that can influence treatment and funding decisions in hemophilia care.

Acquired hemophilia A is a severe bleeding disorder caused by an autoantibody to factor VIII. Previous reports have focused on referral center patients and it is unclear whether these findings are generally applicable. To improve understanding of the disease, a 2-year observational study was established to identify and characterize the presenting features and outcome of all patients with acquired hemophilia A in the United Kingdom. This allowed a consecutive cohort of patients, unbiased by referral or reporting practice, to be studied. A total of 172 patients with a median age of 78 years were identified, an incidence of 1.48/million/y. The cohort was significantly older than previously reported series, but bleeding manifestations and underlying diseases were similar. Bleeding was the cause of death in 9% of the cohort and remained a risk until the inhibitor had been eradicated. There was no difference in inhibitor eradication or mortality between patients treated with steroids alone and a combination of steroids and cytotoxic agents. Relapse of the inhibitor was observed in 20% of the patients who had attained first complete remission. The data provide the most complete description of acquired hemophilia A available and are applicable to patients presenting to all centers.

BACKGROUND: Laboratory studies suggest that the clotting cascade is activated in fibrotic lungs. Since humans vary in their tendency to clot due to a variety of inherited or acquired defects, we investigated whether a prothrombotic state increases the chance of developing idiopathic pulmonary fibrosis (IPF) and/or worsens the prognosis of IPF. \ud \ud METHODS: We recruited 211 incident cases of IPF and 256 age-and sex-matched general population controls and collected data on medical history, medication, smoking habit, blood samples as well as lung function and high-resolution CT scans done as part of routine clinical care. A prothrombotic state was defined as the presence of at least one inherited or acquired clotting defect or marker of fibrinolytic dysfunction. We used logistic regression to quantify the association between a prothrombotic state and IPF adjusted for age, sex, smoking habit and highly sensitive C reactive protein. Cox regression was used to determine the influence of a prothrombotic state on survival. \ud \ud RESULTS: Cases were more than four times more likely than controls to have a prothrombotic state (OR 4.78, 95% CI 2.93 to 7.80; p

Two new factor X mutations (Pro382Leu and Phe356Cys) associated with low activity and low antigen levels

For a brief period, modern medical science was considered to have relegated infectious disease to that of a minor clinical challenge. However, several infectious diseases have emerged or re-emerged in recent years, raising epidemiological concerns, as well as issues over the availability of effective measures of control and treatment. Invariably, these infectious agents have been studied carefully in relation to the safety of blood products, often resulting in concern and action. Emerging diseases arise from many sources. Some are the result of viruses crossing the species barrier from animals to humans. In addition, combinations of these newly identified viruses may make each more difficult to treat, as in the case of human immunodeficiency virus and hepatitis C virus coinfection. Still others can arise from completely new biological mechanisms, such as the prion disease variant Creutzfeldt-Jacob disease, which has spread from infected cattle to humans, particularly in the United Kingdom. The emergence of new viruses and new disease sources has had a significant impact on coagulation factor therapies and blood donation policies. We must deal with these multiple threats and their potential to compromise the safety of our blood supply.

Editor—Recently the United Kingdom Haemophilia Centre Directors Organisation issued evidence based guidelines on therapeutic products for treating haemophilia. Before finalisation the draft guidelines were circulated to professional societies, royal colleges, and departments of health and modified accordingly. The final guidelines were unanimously approved at the organisation's annual geneal meeting and published.1 One recommendation was that the treatment of choice for haemophilia A was recombinant factor VIII concentrate (rFVIII). This is because plasma derived factor VIII concentrates (pdFVIII) still transmit viral infections—for example, those caused by non-lipid coated viruses such as hepatitis A and parvovirus—despite the incorporation of viral inactivation steps in the manufacturing process.2 3 At present the licenced rFVIIIs contain human …

Background Our previous case-control study demonstrated that a prothrombotic state was almost five times more common in people with idiopathic pulmonary fibrosis (IPF) than general population controls. We followed up the incident cases of IPF to determine if a prothrombotic state altered prognosis in terms of survival. Methods People with IPF were recruited from five teaching and eight district general hospitals in England and Wales. All participants were asked for details of medical history, medication and smoking habit. Venous blood samples were taken to test for inherited and acquired clotting defects. We also collected high resolution computed tomography (HRCT) scans and pulmonary function tests done as part of routine care. All HRCT scans were reviewed by two thoracic radiologists to confirm the diagnosis of IPF. A prothrombotic state was defined as having at least one of the inherited or acquired clotting defects tested. Cox regression modelling was used to investigate the association between a prothrombotic state and survival amongst people with IPF, adjusting for age, sex, highly sensitive C Reactive Protein (hsCRP), smoking habit and baseline pulmonary function indices. Results There were 211 incident cases of definite or probable IPF with a median follow up of 2 years (IQR: 1.2 to 2.5). During this time, 86 out of the 211 (40.8%) cases died, which equates to an overall mortality rate of 220.5 per 1000 person years (95% CI: 178.2 to 272.7). 78 out of the 86 deaths (90.7%) were in individuals with a prothrombotic state (see Table 1). The proportion of the IPF cohort surviving at 2 years was 84.7% in patients without any clotting defects and 61.1% in patients with a prothrombotic state (p = 0.0035). Conclusions A prothrombotic state is associated with increased mortality amongst people with IPF. Further research into manipulation of the clotting cascade to improve the outlook of people with IPF is warranted.

Background The aetiology of idiopathic pulmonary fibrosis (IPF) remains poorly understood. Recent animal studies and epidemiological data have suggested that activation of the coagulation cascade in the lung may have an important role in the pathogenesis of IPF. Methods We recruited incident cases of physician diagnosed IPF from five teaching hospitals and eight district general hospitals in England and Wales. Age and sex matched general population controls were recruited from the same region. Participants were asked for details of lifetime occupational history, current or previous illnesses, medication and smoking. Each case and control then had a venous blood sample taken for a thrombophilia screen, including inherited and acquired clotting defects. We also collected high resolution computed tomography (HRCT) scans for all cases, which were reviewed by two experienced thoracic radiologists to confirm the diagnosis of IPF. After excluding individuals on warfarin, logistic regression was used to estimate odds ratios for the association between a prothrombotic state and IPF, adjusting for age, sex and highly sensitive C Reactive Protein (hsCRP). Individuals were defined as being prothrombotic if they had at least one clotting defect present. The analysis was then repeated, stratifying cases by radiological diagnosis. Results Our study included 306 incident cases of IPF(mean age at diagnosis 72.6 years, 70.6% male) and 256 controls (see Table 1). We found an increased tendency to clot among our cases (Odds Ratio [OR] 4.67; 95% Confidence Interval [CI] 3.00 to 7.23) compared to controls. After stratifying by radiological diagnosis, this association was stronger in those with definite usual interstitial pneumonia (UIP) (OR 5.86; 95% CI 3.08 to 11.15) compared to probable UIP (OR 3.47; 95% CI: 1.92 to 6.29). There was no effect modification by age, sex or hsCRP. Conclusion An increased tendency to clot appears to be an independent risk factor for developing IPF. A clinical trial using one of the new, safer anticoagulants may be warranted.

An alternating treatment design was used to measure the differing impact of visual screening and an auditory blocking procedure in the suppression of the screaming behaviour of a profoundly retarded girl. The auditory blocking procedure made use of white noise to mask any background or personal sounds. During separate sessions both screening procedures were applied for a duration of 1 minute following an occurrence of the screaming behaviour. Results showed that both techniques were successful in reducing the frequency of the behaviour. The visual screening procedure was the preferred treatment for maintaining and generalizing the suppression, because of ease of use and mobility.