K. J. Pasi

Use of recombinant factor IX in subjects with haemophilia B undergoing surgery.

Recombinant human FIX (rFIX) was evaluated in 28 subjects, including 26 with mild, moderate, or severe haemophilia B and two haemophilia B carriers undergoing 36 surgical procedures. Preoperative rFIX dose was highly correlated with postinfusion FIX activity, r=0.61, P=0.0158. Peri‐ and post‐operative estimated blood loss was similar to that expected in non‐haemophilic individuals, and haemostasis was rated as excellent or good in 34 of 35 (97.1%) of the operative procedures. Transfusions were required in five of 36 (13.9%) procedures, including one liver transplantation, and three knee and one hip arthroplasties. Adverse events occurred in 15 of 28 (53.6%) subjects, but there were no perioperative haemorrhages, thromboembolic events, coagulation activation, viral transmission, or inhibitor formation. A transient low‐responding FIX inhibitor developed in one subject preoperatively, but required no change in treatment and resolved 15 months later. Thus, rFIX was found to be safe and effective in achieving haemostasis in subjects with FIX deficiency undergoing surgery.

Factor VIII inhibitors in haemophiliacs: a single-centre experience over 34 years, 1964-97.

A retrospective study of the natural history of factor VIII inhibitors in haemophilia A patients experienced in a single comprehensive haemophilia centre over three decades is reported. 431 haemophilia A patients of all severities have been followed‐up for a total of 5626 patient‐years. The frequency of inhibitors was 10% in the severe haemophilia A patients and 37% occurred in children <10 years. The majority of the patients received several products before developing the inhibitors. 59% of patients had <50 exposure days and 48% were high responders (>5 BU). An 8‐year (1987–95) inhibitor‐free period was seen during which all previously untreated patients were treated with an intermediate‐purity factor VIII concentrate. A moderate haemophiliac with a misense mutation that has not been described in association with inhibitor is reported. Six HIV‐positive patients preserved their antibody response to factor VIII even at the advanced stage of their disease.

Clinical experience of factor XI deficiency: the role of fresh frozen plasma and factor XI concentrate.

Summary. Factor XI deficiency is a rare autosomally transmitted coagulopathy that is associated with a variable bleeding tendency. Recently there have been reports of thrombotic events following the administration of a virally inactivated factor XI concentrate (BPL) to factor XI deficient patients. We have therefore reviewed a single centres experience of the use of factor XI concentrate over a 6‐year period and compared this to our previous experience of either no treatment or treatment with fresh frozen plasma (FFP) in 103 patients.

The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV disease progression in individuals with haemophilia.

The chemokine receptor CCR5 is an important co‐receptor for cell fusion. A 32‐bp deletion of the CCR5 gene, leading to complete absence of functional CCR5 expression, has been associated with resistance to human immunodeficiency virus (HIV) infection in homozygotes and slower HIV disease progression in heterozygotes. The objectives of this study were to assess the effects of this 32‐bp deletion on transmission of HIV infection and on HIV disease progression in haemophilic individuals. Six HIV‐negative patients from our centre, known to have been exposed to infectious factor VIII concentrates, have been analysed. Three of these patients possess the CCR5 32‐bp deletion, two patients being homozygous. The presence of the CCR5 32‐bp gene deletion has also been analysed in 71 HIV‐positive patients. In this group of patients, there was a lower than expected incidence of the 32‐bp deletion. Those who possess the 32‐bp deletion progress to AIDS more slowly than those who do not (P = 0·05, log‐rank test). Rates of CD4 loss were slower in those heterozygous for the gene deletion. We confirm that heterozygosity for the 32‐bp gene deletion in CCR5 is partially protective against initial infection with HIV. In those heterozygous patients who became infected with HIV, disease progression was slower.

Future perspectives in paediatric haemophilia

Over the next 5 years there are likely to be significant developments in the treatment of haemophilia, particularly with regard to prophylaxis, implantable venous access devices, and a number of potential new products. Beyond that, our future goal in paediatric haemophilia may well be gene therapy. There is considerable experience of prophylaxis in The Netherlands, Germany, and especially Sweden, where it is now a regular treatment option for all children with haemophilia. Evidence from these countries shows that prophylaxis leads to a substantial reduction in joint damage and orthopaedic scores, with fewer days lost from school (and from work, when prophylaxis is continued into adulthood). In many respects this enables patients to lead a more normal life. In addition, it has been shown that morbidity from severe bleeding episodes is reduced. Ideally, prophylaxis should be started at a young age, before the first joint bleed, although it is recognized that predicting the severity of bleeding likely to be encountered is often difficult. There are, however, potential problems with employing prophylactic regimes: cost of increased use, provision of infusions (in hospital or at home), and venous access in small children. Potential side-effects, the risks of treatment and whether or not the duration of therapy should continue beyond the age of 18, are other considerations which need to be addressed. A consensus now exists that prophylaxis is the optimal childhood treatment. A protocol and treatment recommendation for the use of prophylaxis in children has been drawn up by a working party of the UK Haemophilia Centre Directors Organization, and this will incorporate a national audit of prophylaxis experience. There is no doubt that prophylaxis is beneficial to patients, and that the concentrates now available are safe and effective. With gene therapy on the horizon, it should be our aim through prophylaxis to preserve the status of our patients as best we can until such therapies become routinely available. The potential problem of venous access in small children has already been alluded to. One possible solution is the use of venous access devices, either external lines (Hickman, Broviac) or, ideally, one of the implantable subcutaneous systems (Portacath, Cordis). Venous devices have the advantage of ready access, not only for infusion but also for sampling. They can be used by parents, and home therapy can be initiated at a relatively early stage, with the potential to simplify prophylaxis regimes. However, venous access systems have potential disadvantages. Implants have to be inserted surgically, and the potential for sepsis to occur cannot be discounted. Scrupulous aseptic techniques are critical, with antibiotic prophylaxis a n important consideration. The usual problems with venous lines bleeding at insertion site, becoming blocked, dislodged, or failing altogether are magnified in children with haemophilia, and a second surgical procedure will be required when the original line becomes unusable. Finally, children and parents may become so dependent on a venous line that they refuse to accept a standard venepuncture. Practical experience of venous access devices has been reported at the World Federation of Hemophilia in April 1994. One study [l] revealed that the average lifespan of implanted devices was more than twice that of external lines: 3.5 years in each of 58 implants, compared to 1.7 years in each of 10 external lines. The authors concluded that education of children and parents, and care of the line, were of utmost importance. The lifespan of the line was dependent on the number of times it was used. A smaller study presented at the same meeting investigated the use of 16 venous access devices in children, seven of which were inserted for immune tolerance regimes [ 2 ] . Nine of these devices were associated with sepsis, and in four out of nine there were two or more episodes. Complications necessitated the removal of lines in six patients, five of whom had inhibitors, clearly a risk factor for complications of venous access systems. This experience emphasizes some practical advice for those considering the use of venous access devices. Parents need to understand both the advantages and disadvantages involved; they should therefore take part in comprehensive and informed discussions with the specialist when considering a n implant. A wide range of pathogens may be implicated in the incidence of sepsis (clearly a greater problem with external than with implanted lines), and the presence of inhibitors indicates a much higher rate of complications. Defined protocols for insertion and maintenance of these devices will help to minimize any problems.

Identification and eradication of Helicobacter pylori infection in haemophilic patients

The aim of this study was to identify and eradicate H. pylori infection in patients with haemophilia. Patients were screened for IgG antibodies against H. pylori; active infection was determined using a 13C‐urea breath test and infected patients were given combination therapy with antibiotics to eradicate infection. Seventy‐eight of 219 (36%) patients with haemophilia were found to have an elevated serum antibody titre against H. pylori; of 36 antibody‐positive patients with confirmatory testing, 14 were found to have active H. pylori infection. H. pylori infection was successfully eradicated in every infectedpatient using acombination of ranitidine plus two antibiotics (usually amoxycillin and metronidazole). It is concluded that eradication of H. pylori infection is likely to be a cost‐effective screening strategy in patients with haemophilia, to prevent complications of peptic ulcer disease.

Carrier detection and prenatal diagnosis by intron 22 inversion analysis of the factor VIII gene.

Summary In approximately 50% of severe haemophilia A patients the mutation is present in the form of a large chromosomal disruption in the factor VIII gene; this disruption is described as an inversion. It results in the physical breakage and separation of exons 1‐2 and exons 23‐26 of the factor VIII gene.

Announcement: Non-malignant haematology research in the UK: looking forward to new opportunities

Over the last few years there has been rapid and radical change in the way clinical research in the UK is funded and supported within the NHS. This has resulted from restructuring and major new investment in research infrastructure, co‐ordinated through Clinical Local Research Networks (CLRNs) and equivalent organisations in the devolved nations. CLRNs have resources to support local researchers undertake studies that have been adopted on to the national research portfolio. For example, CLRNs can help with gaining local approvals or provide research nurses to recruit patients, undertake study procedures and perform data entry. CLRNs can establish Local Speciality Groups in a number of areas of medicine, including non‐malignant haematology. These new networks offer non‐malignant haematology access to significant new resources and a major opportunity to support clinical research for the benefit of our patients.

Non-malignant haematology research in the UK: looking forward to new opportunities

Over the last few years there has been rapid and radical change in the way clinical research in the UK is funded and supported within the NHS. This has resulted from restructuring and major new investment in research infrastructure, co‐ordinated through Clinical Local Research Networks (CLRNs) and equivalent organisations in the devolved nations. CLRNs have resources to support local researchers undertake studies that have been adopted on to the national research portfolio. For example, CLRNs can help with gaining local approvals or provide research nurses to recruit patients, undertake study procedures and perform data entry. CLRNs can establish Local Speciality Groups in a number of areas of medicine, including non‐malignant haematology. These new networks offer non‐malignant haematology access to significant new resources and a major opportunity to support clinical research for the benefit of our patients.