Registries and databases-A European perspective.

Registries will enable cohort studies to be performed, which are usually considered to be the best quality of observational studies. The quality of data of registries can be increased if is it possible to merge results ('crosstalk') between registries. A prerequisite for that is an agreed uniform core set of data to be collected and uniform definitions on the items to be collected. This paper discusses problems and barriers with existing registries and provides recommendations from an EMA workshop (European Medicines Agency), for core common data sets and how to secure the quality of data collected. The PedNet registry including >2200 children with haemophilia is presented as an example of a registry/cohort study.

Prevention and Management of Bleeding Episodes in Children with Hemophilia.

Regular prophylactic treatment with factor VIII (FVIII) and factor IX (FIX) concentrates in hemophilia A and B, respectively, is introduced in early infancy and has resulted in dramatic improvement of the conditions. Recombinant FVIII and FIX concentrates have been available for > 25 years and have been modified and refined through the years; however, unfortunately frequent intravenous administrations are still necessary. The half-lives of these products have now been extended (EHL) by fusion with albumin, the Fc-portion of IgG, or by being PEGylated. This has been very successful for EHL-FIX, with 3-5 times longer half-life, and to a lesser degree for EHL-FVIII with a half-life extension of only 1.5 times the conventional products. New treatment principles using FVIII mimetics or monoclonal antibodies that rebalance the pro- and anti-coagulation system by interfering with production of anti-thrombin or tissue factor pathway inhibitor have the benefits of long-lasting activity, subcutaneous administration, and being useful in patients both with and without neutralizing antibodies. As the ultimate treatment, recent progress has also been made with gene therapy of both hemophilia A and B.

How I manage patients with inherited haemophilia A and B and factor inhibitors.

Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. 'Bypassing agents' may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at 'good' or 'bad risk' for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities.

How to manage invasive procedures in children with haemophilia.

Invasive procedures can be performed safely in children with haemophilia due to the availability of factor VIII/IX for patients without inhibitors. Most guidelines are based on the experiences in adults, but still there is no established consensus on the optimal factor levels or duration of replacement therapy for adults undergoing surgery. Few publications have focused on surgery in children with haemophilia. Children who have developed inhibitors to factor VIII/IX have to be treated with bypassing agents and constitute a group at higher risk for bleeding complications during surgery. The aim of this review is to summarize the experiences and opinions in the literature on replacement treatment of children with haemophilia, with and without inhibitors, during and after surgery, with a focus on the most prevalent clinical situations.

Intracranial haemorrhage in haemophilia A and B.

In countries with a good standard of health care, intracranial haemorrhage (ICH) during the neonatal period affects 3.5-4.0% of all haemophilia boys, which is considerably (40-80 times) higher than expected in the normal population. ICHs are also frequent after the neonatal period, affecting 3-10% of the haemophilia population who are mainly treated on demand. The risk is higher in inhibitor patients. Spontaneous haemorrhage is reported more frequently than trauma-induced haemorrhage in most studies. The prevalence of ICH in patients treated with a prophylactic regimen is not known. Although more frequent in younger patients, a substantial proportion of ICH occur in adults, suggesting that general risk factors because of age, such as hypertension, are increasingly important as the haemophiliac gets older. Some studies have reported a substantial proportion of ICH affecting patients with milder forms of haemophilia. The risk of ICH has to be considered when discussing treatment strategies for haemophilia patients.

Functional analysis of the factor IX epidermal growth factor-like domain mutation Ile66Thr associated with mild hemophilia B.

The present study focused on the functional role of the mutation Ile66Thr located in the N-terminal epidermal growth factor-like domain of coagulation factor IX (FIX). This mutation causes mild hemophilia B with approximately 25% FIX coagulant activity and FIX antigen levels of around 90% of normal. In the 3-dimensional structure of porcine FIXa and in the subsequent 3-dimensional model of human FIXa that we have previously developed, residue 66 is exposed to the solvent and can be replaced by many amino acids, including Thr, without affecting the major folding/stability of the molecule. This is consistent with the basically normal antigen levels observed. We found that the FIX Ile66Thr mutant was activated to a normal extent by FVIIa/TF and FXIa. However, the ability of FIX Ile66Thr to activate FX was impaired in both the presence and absence of FVIIIa, indicating that Ile66 is not directly involved in the binding of FIX to FVIIIa.