Kreuth IV: European consensus proposals for treatment of haemophilia with coagulation factor concentrates.

INTRODUCTION: This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the 'Kreuth IV' meeting in May 2016. AIM: The objective of the meeting was for experts in the field of haemophilia from across Europe to draft resolutions regarding current issues relating to the treatment of haemophilia. RESULTS: Hospitals providing clinical care for people with haemophilia and related disorders are strongly recommended to seek formal designation as either European Haemophilia Treatment Centres (EHTC) or European Haemophilia Comprehensive Care Centres (EHCCC). There should be agreed national protocols or guidelines on management of the ageing patient with haemophilia. The minimum consumption of factor VIII and IX concentrate in any country should be 4 IU and 0.5 IU per capita of general population respectively. Treatment for hepatitis C with direct-acting antiviral agents should be provided to all people with haemophilia on a priority basis. Genotype analysis should be offered to all patients with severe haemophilia. Genetic counselling, when given, should encompass the recommendation that genetic relatives of the affected person be advised to seek genetic counselling. People with inhibitors should have access to bypassing agents, immune tolerance and elective surgery. National or regional tenders for factor concentrates are encouraged. Outcome data including health related quality of life should be collected. Treatment with extended half-life factors should be individualized and protection against bleeding should be improved by increasing trough levels. Steps should be taken to understand and minimize the risk of inhibitor development. CONCLUSION: It is hoped that these recommendations will help to foster equity of haemophilia care throughout Europe.

Haemophilia care in Europe - a survey of 35 countries.

A questionnaire was circulated in 2012 to national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The 35 responses received highlighted major differences in the availability of treatment and care. There was a wide range in factor VIII consumption with usage ranging from 0.20 IU per capita in Armenia to 8.56 IU per capita in Sweden (median: IU per capita). The decrease in health budgets in many countries was not matched by decreases in use of FVIII per capita. In the 19 countries that responded to the previous survey, there was a significant improvement in access to prophylaxis and home treatment.

Haemophilia care in Europe: the ESCHQoL study.

The aim of this study was to determine the clinical conditions of patients with haemophilia within Europe as recommended by the European Commission. In this multicentre, cross-sectional, ambispective study, conducted within 21 European countries patients' clinical data were collected, amongst others haemophilia type, severity, treatment pattern, use of factor products, bleeding, orthopaedic joint scores and infections. A total of 1400 patients, 84.3% with haemophilia A and 15.7% with haemophilia B were enrolled by 42 centres between 2004 and 2006. Thereof, 417 were children (30.0%) and 983 were adults (70.0%). About 70% of patients had severe factor deficiency (<1%). More than half of the adults were carriers of chronic infections (12.6% HIV, 55.8% HCV), compared to only 3.8% children (no HIV, 2.9% HCV). Patients were grouped according to per capita amount of clotting factor used in patients' region of residence in 2005: region 1: >5 IU; region 2: 2-5 IU; region 3: <2 IU. Paediatric and adult patients in region 3 had median numbers of three and eight joint bleeds, respectively, with worse joint scores compared to region 1 with zero and one bleed. Prophylactic therapy was used in only 31.3% children and 8.9% adults with severe haemophilia in region 3 compared to 93.7% and 54.1%, respectively, in region 1. Statistical analysis revealed that residence in areas with low factor consumption/availability is the most prominent risk factor for joint disease. Access of European patients with haemophilia to optimal care with safe factor VIII concentrates is limited and depends on the region of residence.

Haemophilia care in Europe: a survey of 19 countries.

In 2009, a questionnaire was circulated to 19 national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The responses received highlighted differences in the level of care despite the recent promulgation of consensus guidelines designed to standardize the care of haemophilia throughout the continent of Europe. There was a wide range in factor VIII consumption with usage ranging from 0.38 IU per capita in Romania to 8.7 IU per capita in Sweden (median: 3.6 IU per capita). Despite the specific inclusion of coagulation factor concentrate in the WHO list of essential medications, cryoprecipitate is still used in some eastern European countries.

Management of difficult-to-treat inhibitor patients.

The workshop looked at seven scenarios based on fictional and real-life cases of difficult-to-treat patients with haemophilia A or haemophilia B and inhibitors with the aim of sharing clinical opinion and experience from around the world. Delegate opinions on the best treatment option for each scenario are described together with actual treatment given in real-life cases and its outcome.

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

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 microg 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.

European principles of inhibitor management in patients with haemophilia.

BACKGROUND: In spite of recent major advances in the understanding and treatment of inhibitor development in patients with haemophilia, multidisciplinary management of many of these patients remains suboptimal and highly heterogenous across Europe. METHODS: Following a series of multidisciplinary meetings and a review of the literature, the European haemophilia community of health professionals and patients jointly defined practical optimum standards for ensuring and harmonizing treatment and care for patients with an inhibitor. RESULTS: Ten complementary principles for the management of inhibitors in haemophilia have been developed, emphasizing the importance and benefits of a centralized, multidisciplinary, expert and holistic approach. CONCLUSIONS: This document will serve as a benchmark to improve the multidisciplinary and practical management of patients with inhibitor. Implementation and adherence to each of these principles should have a major positive impact on the management and outcomes of patients developing an inhibitor.

The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99.

BACKGROUND: Previous studies of the development of inhibitors and their impact on mortality have been small. OBJECTIVES: To examine the development of inhibitors in people with hemophilia in the UK and their effect on subsequent mortality. PATIENTS: 6078 males with hemophilia A and 1172 males with hemophilia B registered in the UK Haemophilia Centre Doctors' Organisation database, 1977-98. RESULTS: In severe hemophilia A inhibitors developed at rates of 34.4, 5.2 and 3.8 per 1000 years at ages <5, 5-14 and 15+years; cumulative risks at ages 5 and 75 were 16% and 36%. In hemophilia A the rate of inhibitor development decreased during 1977-90, but increased during the 1990s. In severe hemophilia B inhibitors developed at rates of 13.3 and 0.2 per 1000 years at ages <5 and 5+ and cumulative risks at ages 5 and 75 were 6% and 8%. With HIV, inhibitor development did not increase mortality. In severe hemophilia without HIV, inhibitor development doubled mortality during 1977-92, but during 1993-99 mortality was identical with and without inhibitors. In severe hemophilia without HIV but with inhibitors, mortality from causes involving bleeding decreased during 1977-99 (P = 0.001) as did mortality involving intracranial hemorrhage (P = 0.007). CONCLUSIONS: These data provide estimates of the rate of inhibitor development in hemophilia A and hemophilia B, and they show that the rate of inhibitor development has varied over time, although the reasons for this remain unclear. They also show that in severe hemophilia the substantial increase in mortality previously associated with inhibitors is no longer present.

Complications in HIV-infected and non-HIV-infected haemophiliacs and other patients after oral surgery.

Dental extractions and other oral surgical procedures, including local analgesic injections, potentially can cause problems in haemophiliac and HIV infected persons. There are few data on treatment results in HIV-infected haemophiliacs compared with non-HIV-infected haemophiliacs. The oral surgery treatment results in 48 patients with special needs, including HIV-infected haemophiliacs, non-HIV-infected haemophiliacs, HIV-infected non-haemophiliacs, and a group with other medical problems were therefore studied. Around 20% of the haemophiliacs developed post-oral surgical complications, which was not significantly different whether or not they were HIV-infected. However, complications were less frequent (8%) in HIV-infected non-haemophiliacs or other patients with special needs. Although the patient groups are not large, it would appear that haemophiliacs had more postoperative complications but that the presence of HIV infection had no notable influence on treatment outcome.

Treatment of patients with haemophilia and inhibitory antibodies.

The development of inhibitory antibodies is a complication which arise in approximately 10% of patients with haemophilia A. The underlying genetic mutation is the single most important predisposing cause, although other risk factors have been identified. Periodic screening for inhibitors is a vital aspect of haemophilia care. The consequences of inhibitor development are very significant in terms of morbidity and cost. Several agents are now available for control of bleeding, but these are often very expensive. The most useful agents include recombinant activated factor VII, prothrombin complex concentrates and porcine factor VIII. It is possible to suppress antibody production with immune tolerance, which is successful in approximately 85% of cases and relapse is rare.

Achievement of immune tolerance in a patient with haemophilia B and inhibitory antibodies, complicated by an anaphylactoid reaction.

We describe a young boy with severe haemophilia B who developed inhibitory antibodies and an anaphylactoid reaction to factor IX. Immune tolerance was achieved by desensitisation with escalating doses of factor IX followed by the Malmö regimen.

Safety and efficacy of KOGENATE Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs).

Safety and efficacy of KOGENATE Bayer (Kogenate FS), a second-generation full-length recombinant factor VIII formulated with sucrose as stabilizer and produced without the addition of human albumin during purification and the final formulation, was assessed in a prospective, international clinical trial including 31 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe haemophilia A in home therapy and surgery. Factor VIII inhibitor development was monitored and mutation type profiles were analysed. As of 30 June 2000, the patients received a total of 2.729 infusions (mean 88; range 6-274) for bleeding episodes, surgery or prophylactic treatment. No unexpected drug-related adverse events were observed. Four patients developed an inhibitor after 3-12 exposure days (EDs). One patient successfully underwent immune tolerance treatment; inhibitors in two patients disappeared spontaneously with on-demand treatment, while the inhibitor titre remains low in one patient. Twenty-nine patients (93%) with more than 20 EDs can be regarded as at low risk for inhibitor development. In conclusion, KOGENATE Bayer is efficacious and well-tolerated for treatment of children with severe haemophilia A. The incidence of inhibitor formation is not different to that observed with other recombinant or plasma-derived products.

Adverse events in the prophylaxis of haemophilia.

Whilst prophylaxis undoubtedly offers many advantages, the potential for adverse effects must also be borne in mind. Modern plasma-derived products have an extremely good safety record with regard to transmission of pathogens, although continuous vigilance is required as new pathogens continue to emerge, eg new variant Creutzfeldt-Jakob disease. There is no evidence that prophylactic treatment is associated with an increased incidence of inhibitors, and it is now recognized that genetic factors are the most significant in conferring susceptibility. Although subtle immunological abnormalities have also been observed in patients with haemophilia, there is no evidence that these are of any clinical significance. There has been a growing trend to use indwelling venous catheters for prophylaxis. The risk of infection has been appreciated for some time, although it has only recently been possible to quantify this with more precision. The risk of catheter-associated thrombosis is now recognized to be higher than hitherto appreciated. Whilst sporting activities are to be encouraged, there is a potential for significant trauma in children with prophylaxis, as plasma coagulation factor levels remain far below normal with the usual regimens.

Fondaparinux (Arixtra): a new anticoagulant.

Fondaparinux is a promising new antithrombotic agent. This pentasaccharide selectively and specifically inhibits coagulation factor Xa, and requires antithrombin as co-factor It is entirely synthetic, in contrast to conventional heparin and low molecular heparins which are derived from animal tissues. Fondaparinux exhibits a high bioavailability and is convenient to use as it only needs to be given once daily by subcutaneous injection. Peak plasma levels are achieved within two hours of dosing and the plasma half-life of fondaparinux is approximately 17 hours. There is no specific antidote for fondaparinux: it is not neutralised by protamine sulphate. Fondaparinux shows no cross-reactivity with antibodies associated with heparin-induced thrombocytopenia. Several randomised, double-blind studies have demonstrated superiority with respect to a low molecular weight heparin (enoxaparin) in preventing venous thromboembolism in the setting of orthopaedic surgery. The results of clinical trials of fondaparinux in the treatment of deep vein thrombosis and acute coronary syndrome are also presented.