Kingdom Haemophilia Centre Doctors Research Articles

Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology.

Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology.

The natural history of bleeding disorder of unknown cause

In the early 2000s, Professor Ingrid Pabinger, working at the Medical University of Vienna and the Vienna General Hospital, noticed that many patients in the hematology clinic referred with an apparent bleeding tendency had no demonstrable laboratory defect on conventional laboratory tests. Subsequently, this was called unclassified bleeding disorder or bleeding of unknown cause; however, recently, the term bleeding disorder of unknown cause (BDUC) has been agreed as a preferred term. BDUC has previously been defined as “a clear bleeding tendency with normal laboratory tests of haemostasis where non-haematological causes of bleeding (eg, scurvy or liver disease) have been excluded” [ [1] Thomas W. Downes K. Desborough M.J.R. Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management. Haemophilia. 2020; 26: 946-957 Crossref PubMed Scopus (17) Google Scholar , [2] Obaji S. Alikhan R. Rayment R. Carter P. Macartney N. Collins P. Unclassified bleeding disorders: outcome of haemostatic challenges following tranexamic acid and/or desmopressin. Haemophilia. 2016; 22: 285-291 Crossref PubMed Scopus (23) Google Scholar ]. For many years, it seems hematologists have recognized this condition, and looking back to the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) registration data, 34 patients with unclassified bleeding disorder (now termed BDUC) were registered in United Kingdom hemophilia centers before 1990 (personal communication with the UKHCDO). However, despite this, there was no research, guidelines, or discussion about this patient group. Perhaps this is because the bleeding disorder community was preoccupied with the severe bleeding disorders in times when treatment was more challenging.

Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders.

The rare coagulation disorders may present significant difficulties in diagnosis and management. In addition, considerable inter-individual variation in bleeding phenotype is observed amongst affected individuals, making the bleeding risk difficult to assess in affected individuals. The last international recommendations on rare inherited bleeding disorders (RIBDs) were published by the United Kingdom Haemophilia Centre Doctors' Organisation in 2014. Since then, new drugs have been marketed, news studies on surgery management in patients with RIBD have been published, and new orphan diseases have been described. Therefore, the two main objectives of this review, based on the recent recommendations published by the French Reference Centre on Haemophilia and Rare Bleeding Disorders, are: (i) to briefly describe RIBD (clinical presentation and diagnostic work-up) to help physicians in patient screening for the early detection of such disorders; and (ii) to focus on the current management of acute haemorrhages and long term prophylaxis, surgical interventions, and pregnancy/delivery in patients with RIBD.

Immune tolerance induction with a high-purity von Willebrand factor containing plasma-derived factor VIII concentrate in a child with hemophilia A with inhibitors

Immune tolerance induction (ITI) is the principal method of inhibitor eradication in patients with hemophilia A. The existing guidelines generally recommend to start ITI with recombinant FVIII concentrates, but the presence of VWF in plasma-derived FVIII concentrates used for ITI may further influence the ITI success rate. A five-year-old male patient with hemophilia A withinhibitors started ITI at our Center. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications. The patient had an inhibitor titer of 0.52 BU/mL at the start of the ITI and a historical inhibitor peak titer of 28 BU/mL. The ITI was started 3.5 years after the first inhibitor detection. We chose a plasma-derived VWF/FVIII containing concentrate (Haemate P) and started the ITI at a dose of 100 units FVIII/kg once per day using central venous access, as proposed in the protocol developed by the United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO). The inhibitor titer rose to 5.5 BU/mL on day 10 and became negative on day 25 of the ITI. The FVIII trough level measured 24 h after the last dose was > 1 % on day 25. The patient discontinued prophylaxis with a bypassing agent. However, FVIII pharmacokinetics had not returned to normal yet, and the patient continued the ITI with the VWF/FVIII containing concentrate at the initial dose. We reassessed the parameters of FVIII pharmacokinetics 120, 270 and 300 days after the start of the ITI. The peak FVIII level, its half-life time and the trough level measured 24 h after the last dose gradually increased over time. On day 300, the half-life time was still less than 7 h (6 h), but the trough level at 24 h was as high as 12.6 %. So, the patient started tapering off the medicine (the dose was initially reduced to 75 units/kg once per day). No adverse events were observed during the 1 year of therapy. Starting from day 423, the patient was switched to prophylaxis with the concentrate administered at a dose of 50 IU/kg every other day. Here, we reported our experience with first-line ITI using the FVIII concentrate with a high content of VWF (Haemate P). A rapid decrease in the inhibitor titer and the normalization of the pharmacokinetic parameters of FVIII in the absence of significant bleeding or thrombotic complications were convincingly demonstrated.

Laboratory coagulation tests and recombinant porcine factor VIII: A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by development of auto-antibodies to endogenous coagulation factor VIII (FVIII). Recombinant porcine factor VIII (rpFVIII) is currently licensed only for the management of bleeding in patients with AHA. Regular monitoring of rpFVIII is recommended to assess treatment effectiveness. This guideline from the United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) examines the current publications in the area and aims to offer advice for the laboratory monitoring of rpFVIII in patients with AHA. A review of the current literature was undertaken followed by critical review by the authors. A validated one-stage clotting FVIII assay is recommended for the measurement and regular monitoring of rpFVIII. Assessment of cross-reacting rpFVIII inhibitors by one-stage porcine Bethesda assay should be performed as part of the initial diagnosis of AHA or prior to treatment with rpFVIII. Available data show that chromogenic FVIII assays underestimate rpFVIII and this should be considered if measurement of rpFVIII is required in patients receiving Emicizumab.

Current practice and registration patterns among United Kingdom Haemophilia Centre Doctors’ Organisation centers for patients with unclassified bleeding disorders

BackgroundBleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management. ObjectivesTo examine UK haemophilia centre registration patterns and current practice for UBD patients. MethodsIn a two‐step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD. Results/discussionOverall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients. ConclusionThis study provides a snapshot of current practice and real‐world data in this area. Future studies need to address the gaps in evidence.

Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update.

In good risk patients (historic inhibitor peak<200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm. United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi-phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline. This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children. This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies.

Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

Correcting dominant‐negative von Willebrand disease

Correcting dominant‐negative von Willebrand disease

Клинические примеры применения фактора VIII свертывания крови с фактором Виллебранда у рожениц с III типом болезни Виллебранда

Болезнь Виллебранда (БВ) может представлять определенные трудности у рожениц с данной патологией. Приведены 2 клинических примера использования у женщин с БВ фактора VIII свертывания крови с фактором Виллебранда, показана эффективность и безопасность их применения. У одной пациентки было также показано использование фактора свертывания крови VIII с фактором Виллебранда во время экстракорпорального оплодотворения. Von Willebrand disease presents a certain hemostatic problem among parturients. This article shows the effectiveness and safety of using coagulation factor VIII with von Willebrand factor for the prevention of bleeding in childbirth in 2 patients with type 3 von Willebrand disease. In one patient, the use of coagulation factor VIII with von Willebrand factor during in vitro fertilization was also shown.

Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

The factor VIII mimetic emicizumab (Hemlibra, Hoffman-la Roche, Basel, Switzerland) has a novel mode of action that affects the laboratory monitoring of patients receiving this treatment. This guideline from the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) aims to provide advice for clinical and laboratory staff on appropriate use of laboratory assays in patients with Haemophilia A treated with emicizumab. The guideline was prepared by a review of the available literature and discussion and revision by the authors. The guideline describes the effect of emicizumab on commonly used coagulations tests and provides recommendations on the use of assays for measurement of factor VIII and factor VIII inhibitor in the presence of emicizumab. The guideline also provides recommendations on measurement of emicizumab. Knowledge of the effect of emicizumab on coagulation tests and factor assays is required to ensure appropriate testing and monitoring of therapy in patients receiving this drug.

Laboratory measurement of factor replacement therapies in the treatment of congenital haemophilia: A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

Assay discrepancies can occur with laboratory monitoring of FVIII and FIX replacement therapy, particularly for the extended half-life products. This guideline collates current published data and provides advice on appropriate choice of assays for laboratory measurement of replacement therapy for patients with Haemophilia A and B without inhibitors. It is recommended that each haemophilia centre should ensure that appropriate laboratory assays are available for FVIII and FIX products in local clinical use. Patient samples should be assayed against calibrators traceable to WHO Plasma International Standards. Assay discrepancies are common especially for the extended half-life FVIII and FIX products, and assays of these products may need to be verified with the specific CFC being used.

The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom.

Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure. To investigate the immunogenicity of ReFacto AF post licensure in a real-world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs). The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors. One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t≤50)=0.33, [95% CI: 0.25-0.43]), of which 15 (P(t≤50)=0.16, [95% CI: 0.10-0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7-16) EDs. Inhibitors were significantly associated with high-risk mutations and non-significantly associated with non-white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High-titre inhibitors were significantly associated with a family history of inhibitors. Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low- and high-titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom.

Diagnosis and management of von Willebrand disease in the United Kingdom

Treatment of von Willebrand disease (VWD) in the United Kingdom (UK) is based on consensus guidelines, subject to regular review, relating to the diagnosis and management of the condition. Those diagnosed with VWD are registered on a national inherited bleeding disorder database administered by the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) which also records treatment history and aids service planning and commissioning. Selection of therapeutic products suitable for treatment of VWD is based on the observed clinical response. For those individuals where it is not contra-indicated or inappropriate, desmopressin (DDAVP) remains the recommended treatment. In patients where DDAVP treatment is unsuitable, replacement factor concentrate containing von Willebrand factor (VWF) is the recommended alternative. Relevant concentrates are available for all patients in the UK and treatment is administered by a network of 59 haemophilia treatment centres that also provide specialist care for individuals diagnosed with VWD. The treatment guidelines and specialist care network exist to develop comprehensive management plans specific to each patient. Genetic testing is employed in the UK in certain situations, particularly for type 2 VWD and this is also performed in accordance with current guidelines.

Acquired Factor VIII Inhibitor and Cardiopulmonary Bypass

ACQUIRED HEMOPHILIA A (AHA) may cause massive bleeding during surgical procedures due to the formation of specific autoantibodies most frequently against coagulation factor VIII (FVIII), which decrease its activity and plasma half-life. Whereas up to 30% of chronically substituted patients with inherited hemophilia A develop inhibitor activity during their treatment, the incidence of AHA is extremely low at 1.5 cases per million. 1 Rodriguez-Merchan E.C. Rocino A. Literature review of surgery management in inhibitor patients. Haemophilia. 2004; 10: 22-29 Crossref PubMed Scopus (35) Google Scholar , 2 Collins P.W. Hirsch S. Baglin T.P. et al. Acquired hemophilia A in the United Kingdom: A 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood. 2007; 109: 1870-1877 Crossref PubMed Scopus (526) Google Scholar Elderly people (aged 60-80 years) are affected especially, although there is another peak at a younger age (20-30 years). 3 Green D. Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost. 1981; 45: 200-203 Crossref PubMed Scopus (681) Google Scholar AHA is associated with malignancy (11.8%), autoimmune diseases (13.4%), pregnancy (8.4%), drugs (3.4%), and dermatologic diseases (1.4%). In the majority of patients, the cause remains unknown. 4 Knoebl P. Marco P. Baudo F. et al. Demographic and clinical data in acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012; 10: 622-631 Crossref PubMed Scopus (316) Google Scholar

The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology.

The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMBASE were searched systematically for publications in English from 2002 using the key word Willebrand. The writing group produced the draft guideline, which was subsequently reviewed by the A United Kingdom Haemophilia Centre Doctors Organization (UKHCDO) advisory committee, a British Committee for Standards in Haematology (BCSH) sounding board of approximately 50 UK haematologists, and the BCSH executive; comments were incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_ GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with von Willebrand disease.

Guidance on the dental management of patients with haemophilia and congenital bleeding disorders

Recommendations for dental preventive strategies and treatment planning were originally developed through consensus meetings by the Scottish Oral Health Group for Medically Compromised Patients and published in 2003 as a Guideline. The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) Dental Working Party has updated these recommendations following the AGREE II approach (www.agreetrust.org), involving a literature search, a review of national and international guidelines and after seeking the opinions of haemophilia treaters in the United Kingdom by an online survey. Where possible, evidence from the literature is graded according to the 'GRADE' system (www.bcshguidelines.com/bsch_process/evidence_levels_and_grades_of_recommendations/43_grade.html); however, overall there is a lack of robust data and most studies have methodological limitations. The objective of this guidance, which is largely consensus-based, is to assist dental practitioners in primary and secondary care to provide routine dental care for patients of all ages with congenital bleeding diatheses in order to improve overall access to dental care. The guidance may not be appropriate in all cases and individual patient circumstances may dictate an alternative approach. Date for guideline review: May 2016.

Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK

Emergency and out of hours care of patients with inherited bleeding disorders

Recently, the United Kingdom Haemophilia Centre Doctors Organisation published recommendations for the standard of care for assessment and treatment of patients with bleeding disorders in the emergency department (A&E). An audit was undertaken to compare the level of care to the acceptable standards in a tertiary hospital A&E, attached to a haemophilia comprehensive care centre. A&E attendances were found by cross referencing all patients with known bleeding disorders against the EDMS attendance system. Visits from the past 3 years were identified to produce sufficient data and electronic notes from these visits were then accessed, and marked against the proforma. Data were available from 45 of a total of 54 patients, who had a total of 75 emergency visits documented. In all aspects of care, the standards were not adequately met including the average length of time between booking and clinical assessment, early initiation of specific haemostatic treatment, seeking haematology advice and arrangement of follow-up. Also no specialist clotting investigations were done with only 9/11 patients admitted having their haematological diagnosis recorded. In addition, only very few patients had the severity of bleeding disorder noted and less than half their first line treatment documented. There were significant differences in the standard of care for haemophilia patients provided by the A&E department when compared with acceptable standards. Measures have been put in place and policies have been drafted to improve this situation and provide the best possible care to persons with haemophilia.

Diagnosis and Management of von Willebrand Disease in the United Kingdom

The UK treatment strategy for von Willebrand disease (VWD) is based on consensus guidelines produced by the United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) relating to the diagnosis and management of VWD. Selection of therapeutic products suitable for treatment of this complex inherited bleeding disorder is based on the observed response. Desmopressin (DDAVP), an analog of vasopressin, is the recommended treatment in individuals who respond to this drug on trial infusion. DDAVP clearly has no effect in type 3 VWD but may have variable clinical effect in individuals with other subtypes or may be contraindicated in some cases. In patients where DDAVP treatment is unsuitable, replacement factor concentrate containing von Willebrand factor (VWF) is the recommended alternative. Relevant concentrates are available for all patients in the United Kingdom, and treatment is administered by a network of 67 hemophilia treatment centers that also provide specialist care for individuals diagnosed with VWD. Patients diagnosed with the condition are registered on a national inherited bleeding disorder database administered by the UKHCDO on behalf of the Department of Health to aid in service planning and commissioning. Genetic testing is employed in the United Kingdom in certain situations, which is also performed in accordance with current UKHCDO guidelines.