G. Dolan

The rare coagulation disorders – review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation

Summary.  The rare coagulation disorders are heritable abnormalities of haemostasis that may present significant difficulties in diagnosis and management. This review summarizes the current literature for disorders of fibrinogen, and deficiencies of prothrombin, factor V, FV + VIII, FVII, FX, the combined vitamin K‐dependent factors, FXI and FXIII. Based on both collective clinical experience and the literature, guidelines for management of bleeding complications are suggested with specific advice for surgery, spontaneous bleeding, management of pregnancy and the neonate. We have chosen to include a section on Ehlers‐Danlos Syndrome because haematologists may be consulted about bleeding manifestations in such patients.

European Study on Orthopaedic Status of haemophilia patients with inhibitors

Summary.   Development of inhibitors against factor VIII (FVIII) or factor IX (FIX) in haemophilia patients is one of the most serious complications of repeated exposure to replacement therapy and has major clinical and economic consequences. To evaluate the relationship between inhibitor status of haemophilia patients and their quality of life (QoL) and degree of arthropathy and to compare the orthopaedic status of patients with/without inhibitors. An observational, cross‐sectional, case control study enrolling: group A (n = 38), males aged 14–35 years, with severe congenital haemophilia A or B who had inhibitors against FVIII/FIX >5 years; group B (n = 41), as group A, but aged 36–65 years and group C (n = 49), as group A, but without inhibitors. Socio‐demographics: medical history, clinical characteristics and QoL were assessed. In groups A and B, 16% and 27% were hospitalized for orthopaedic procedures vs. 4% in group C. Patient mobility was also severely reduced in groups A and B, with 24% and 22% using wheelchairs vs. 4% in group C, and 50% and 51% needing a walking aid vs. 29% in group C. Significantly more joint pain was reported by patients in group A vs. those in group C; clinical/radiological orthopaedic scores were also worse in group A vs. group C. Significantly more joint abnormality was reported by patients in group A vs. group C. The burden of orthopaedic complications and the impact on QoL are more severe in haemophilia patients who have developed inhibitors than in those without inhibitors.

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations.

Summary.  Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14 days; for liver biopsy, 70–100%, 1–7 days; tonsillectomy: 90–100%, 5–11 days; indwelling venous access device insertion: 100%, 3–10 days; circumcision: 50–60%, 2–4 days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better‐designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.

Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data

Summary.  A survey of 21 haemophilia doctors, throughout Europe, who care for a total of approximately 5000 patients with bleeding disorders addressing practice and opinions regarding prophylaxis in patients aged 16–24 years and adults aged over 50 years, is presented. The outcome of adolescent patients who reduced or stopped prophylaxis was recorded. Eighteen of 19 respondents would consider modification of established prophylaxis in the adolescent age group, principal considerations being avoidance of risks of further concentrate exposure, predicted poor compliance and treatment costs. The preferred age for modification was 16–20 years, but there was very little consensus on the particular prophylactic regime recommended. Approximately, half of a cohort of 218 patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached adolescence. Only 26 of 92 (28%) of the patient cohort who stopped prophylaxis, required reintroduction of a prophylactic regime and 12 of 59 (20%) of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. A majority of respondents would consider starting prophylaxis in those over 50 years. There was no consensus as to indications for this practice or the nature of the prophylaxis protocol. We conclude that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, and reach the age of 50. Aggregate outcome data suggest a significant proportion of patients in the 18–22 years age range may be able to reduce or stop prophylaxis. A substantial number of older patients are on prophylaxis.

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven®] in elective orthopaedic surgery in haemophilic patients with inhibitors

Summary.  Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120–180 μg kg−1 to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as ‘excellent’ or ‘extremely satisfactory’ by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

Changing patterns of bleeding in patients with severe haemophilia A

Summary.  Previous studies on the pattern of joint bleeding in patients with haemophilia have reported that the knee joint is most frequently affected. Home treatment data reporting bleeding frequency and location collected from 100 patients registered at six haemophilia centres in the UK have been analysed to determine current patterns of bleeding. Bleeding frequency has markedly decreased although bleeding into joints remains the main characteristic of haemophilia. However, the ankle joint has replaced the knee joint as the most common joint affected. Furthermore, it seems that the frequency of knee joint bleeding is also less than the elbow joint suggesting that the traditional pattern of joint bleeding in haemophilia has now changed significantly.

Efficacy of recombinant interferon‐alpha (rIFN‐α) in polycythaemia vera: a study of 17 patients and an analysis of published data

The efficacy and tolerability of rIFN‐α has been evaluated in 17 selected patients with symptomatic polycythaemia vera, diagnosed according to the PRV Study Group criteria. Complete disease control (CR) was achieved, after 1–12 months, in nine patients, with partial control in a further five cases. Three patients failed to respond. Pruritus significantly improved in 83% (10/12) of cases, following 1–28 weeks of treatment. Six patients (35%), however, were unable to tolerate rIFN‐α, on account of weight loss, myalgia and mental changes. Overall, α‐interferon therapy significantly improved venesection requirements, MCV and PCV values, platelet counts, pruritus scores and the degree of splenomegaly. Analysis of pooled published data (100 evaluable patients, including the present study) revealed an overall CR of 60%, a PR of 27%, and a failure rate of 13%. Significant pruritus control (>50% improvement) occurred in 77% of cases. rIFN‐α appears to be an effective therapy for PV‐associated myeloproliferation and/or pruritus, although side‐effects remain a concern. Long‐term studies are now indicated to determine if the natural history of the disease is altered, in particular whether the incidence of myelofibrosis and/or leukaemic transformation is reduced.

Haemophilia care then, now and in the future.

Summary.  Epidemiological data show the benefits of dramatically improved haemophilia care in all life‐stages. There are improved administration techniques and dosing regimens, a shift from on‐demand treatment to prophylaxis, successful treatment protocols for immune tolerance induction in patients with inhibitors and enhanced approaches to overall patient management. Improvements also include the introduction of virus inactivation methods for plasma derived clotting factor concentrates and the development of recombinant factor VIII therapy, which practically eliminated the risk of infectious disease transmission. Recombinant factor concentrates are recommended as treatment of choice by several guidelines today. All these developments have resulted in increased health‐related quality of life and life expectancy in haemophilia patients, who are transitioning from childhood to adulthood with healthy joints and an overall healthy status today. Because of increased life expectancy, these patients are expected to experience age‐related clinical problems that were not previously observed in this population. With respect to this, the spectrum of haemophilia care will be extended to diseases of older ages with the need of including further disciplines in comprehensive haemophilia care programmes. Despite these advances, the short half‐life of factor VIII, requiring re‐administration every 2 or 3 days and the development of inhibitors remains a challenge. Bayer’s research and development currently focuses on the optimization of recombinant coagulation factors to address these challenges. Haemophilia care has experienced significant improvements within the past decades. Novel technologies and continued clinical research have facilitated the development of treatment regimen that resulted in dramatic increases in the life expectancy and quality of life of haemophilia patients. To set the scene for the following papers dealing with haemophilia care from paediatrics to geriatrics, developments behind these improvements and some aspects of future research will be presented in this paper.

The challenge of an ageing haemophilic population

Summary.  Life expectancy for haemophilia has increased significantly in many countries. This represents a major success of the improved safety of therapeutic materials to treat haemophilia and of improved quality of care. This improved longevity will generate a population of older individuals with haemophilia with complex medical problems associated with age and managing such clinical issues is likely to be challenging.

Management of acute haemarthrosis in haemophilia A without inhibitors: literature review, European survey and recommendations

Summary.  Acute haemarthrosis is a frequent type of bleeding in individuals with haemophilia. Delayed and/or inadequate treatment can trigger a series of pathological changes within the joint, leading to a painful and disabling arthropathy. The early management of intra‐articular bleeding has the potential to prevent chronic joint disease and may include a combination of factor replacement, rest, ice, rehabilitation and, in certain cases, joint aspiration. Little data are, however, available regarding the optimal management of acute haemarthrosis, especially with respect to replacement therapy and the use of adjunctive therapies (aspiration, avoidance of weight bearing and immobilization, as well as the use of anti‐inflammatory medication and embolization). To provide more insight into the management of acute haemarthrosis in patients with haemophilia, a literature review was conducted. Concomitantly, current management was surveyed in 26 European haemophilia comprehensive care centres representing 15 different countries. The review highlights the need for future robust studies to better define the appropriate replacement therapy and the role of adjunctive therapies such as aspiration. The survey reveals much heterogeneity in the management of acute haemarthrosis across the EU. Within the constraints discussed, treatment recommendations are presented that reflect the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board (EHTSB).