Quality management and quality assurance in haemophilia care: a model at the Bonn haemophilia centre.

The severe clotting defects associated with the diagnosis of severe haemophilia A and B require a quality management and quality assurance system designed to avoid both bleeding sequelae (such as damaged joints) through early on-demand or prophylactic treatment in a home-care setting, and side-effects such as infectious diseases (hepatitis A-G and human immunodeficiency virus), allergic reactions, haemolysis and if possible inhibitor formation, by using highly purified, virus-inactivated or recombinant products in which the factor VIII and IX proteins are as natural as possible. As the intravenous injection of the required clotting factor is entrusted to the patients in home treatment, the haemophilia centre has to check treatment protocols and, when necessary, joint and muscle status. In addition, it is imperative to ensure the safety of the product, and checks must be carried out to make sure that batch numbers are recalled as soon as possible if side-effects are observed. These are the reasons for several Acts of Parliament in Germany requiring special treatments and regular checks (the Disabled Act, recommendations by the German Medical Council, the Transfusion Act). Thus, at the haemophilia centre in Bonn we have established a special quality management and quality assurance system taking into account the great number of patients (> 800), the often considerable distance between the centre and the patient, and the aforementioned regulations and laws. Quality management involves dealing with daily practicalities such as 24-h availability of a physician, medical technologist and nurse, careful instruction of patient and family in home care, genetic counselling, regular laboratory tests (especially recovery time, half-life, inhibitors and gene defects, clinical chemistry and serology) and clinical investigations (especially joint and muscle status). It also includes co-operation with family doctors and different departments at our university hospital (e.g. orthopaedic, microbiology), daily conferences with staff, information for nursery schools, schools, training institutions and/or the workplace in case of emergency, and cooperation with German haemophilia foundations. For quality assurance, several self-controlling systems are in place, such as distribution of concentrate, laboratory data, treatment protocols, joint and muscle status and bleeding tendencies. All these and more are double-checked and interactive, controlling data and activities with the help of EDP. Exceptional staff motivation and patient compliance are important for this quality system.

European data of a clinical trial with a sucrose formulated recombinant factor VIII in previously treated haemophilia A patients.

To increase the safety of antihaemophilic treatment, the production process of full-length recombinant factor VIII (FVIII) KOGENATE Bayer (Kogenate FS) has been modified. Human albumin is no longer added as stabilizer during purification and in final formulation. Instead, the new KOGENATE Bayer production process uses sucrose as a stabilizer in the formulation and adds solvent/detergent virus inactivation step. An European clinical trial was carried out in Germany and France in previously treated patients with severe haemophilia A who had more than 100 exposure days to exogenous FVIII. Pharmacokinetic data was analysed according to one-stage and chromogenic assays. Efficacy and safety during home therapy and in surgical procedures were evaluated; inhibitor formation was carefully monitored. Safety and efficacy were evaluated in 33 European patients for 24 months. Patients received more than 13 million IU KOGENATE Bayer. Over 75% of patients accrued more than 100 exposure days with the new product. Of 875 bleeding episodes, 90.7% were treated with 1 or 2 infusions and 75.8% of responses to treatment were rated as 'excellent' or 'good'. Prophylactic treatment was the most common mode of therapy (60.7% of infusions). The product was well-tolerated and FVIII recovery studies were consistent throughout the study period. Only 0.26% of adverse events were reported to be drug related. No evidence of de novo inhibitor formation was observed. Overall, KOGENATE Bayer was efficacious, safe and well-tolerated for the treatment of haemophilia A in multitransfused patients.

Intra-articular hyaluronic acid in the treatment of haemophilic arthropathy of the knee. Clinical, radiological and sonographical assessment.

Hyaluronic acid has been used successfully in the treatment of osteoarthritis since 1989. There is no experience in haemophiliacs in larger study groups. In a prospective study, 20 patients (21 knees) with haemophilic arthropathy of the knee received 20 mg hyaluronic acid by intra-articular injection for 5 consecutive weeks. Assessment included clinical scores, X-ray, magnetic resonance imaging (MRI) and biomechanical motion analysis before and 3 months after the first injection. The score of the WFH advisory committee and the Aichroth score for special evaluation of the knee were used. After an average period of 26 months, the World Federation of Hemophilia (WFH) score, the Aichroth score and the visual analogue scale were evaluated again. All patients had pain caused by their arthropathy, nine of them had positive antibodies to human immunodeficiency virus, and 15 had chronic hepatitis C. The mean WFH score was 8.1 points, the Petterson score was 7.3 points and the Aichroth score was 38 points (maximum 55 points). The WFH score decreased to 7.3 points, the Aichroth score improved to 40 points and the subjective assessment measured with a visual analogue scale improved from 5.3 to 3.7 points. No differences from MRI controls were detected. After 3 months, 14 of 20 patients improved subjectively, particularly in longer walking distance, stair-climbing or initial pain. These positive aspects were limited by arthropathy in adjacent joints. After 26 months 10 patients still are benefiting for up to 31 months follow-up. The average WFH score was 7.3 points, the Aichroth score 39 points, the visual analogue scale 4.0 points. We recommend hyaluronic acid for haemophilic arthropathy of the knee when regular conservative therapy has failed and operative treatment is not feasible.

Antibodies to factor VIII in hemophilia A patients.

Inhibitor development represents the main complication in the treatment of haemophilia A. The risk of inhibitor formation is in part genetically determined by the type of the underlying factor VIII gene lesion but environmental factors may also play an important role. Due to the lack of efficiency of factor VIII in these patients other therapeutic agents must be used for the treatment of bleedings, however, none is as effective as factor VIII in a non-inhibitor patient. Therefore, the eridication of the inhibitor through immune tolerance therapy is the treatment of choice. Centralized national and international immune tolerance registries have collected the results and show cost effectiveness of this treatment.

Congenital deficiency of vitamin K dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex.

Hereditary combined deficiency of the vitamin K dependent coagulation factors is a rare bleeding disorder. To date, only eleven families have been reported in the literature. The phenotype varies considerably with respect to bleeding tendency, response to vitamin K substitution and the presence of skeletal abnormalities, suggesting genetic heterogeneity. In only two of the reported families the cause of the disease has been elucidated as either a defect in the gamma-carboxylase enzyme (1) or in a protein of the vitamin K 2,3-epoxide reductase (VKOR) complex (2). Here we present a detailed phenotypic description of two new families with an autosomal recessive deficiency of all vitamin K dependent coagulation factors. In both families offspring had experienced severe or even fatal perinatal intracerebral haemorrhage. The affected children exhibit a mild deficiency of the vitamin K dependent coagulation factors that could be completely corrected by oral substitution of vitamin K. Sequencing and haplotype analysis excluded a defect within the gamma-carboxylase gene. The finding of highly increased amounts of vitamin K epoxide in all affected members of both families indicated a defect in a protein of the VKOR-multienzyme-complex. Further genetic analysis of such families will provide the basis for a more detailed understanding of the structure-function relation of the enzymes involved in vitamin K metabolism.

Protection against parenteral HIV-1 infection by homozygous deletion in the C-C chemokine receptor 5 gene.

OBJECTIVES: To investigate the role of the CC chemokine receptor 5 (CCR5) for parenteral transmission of HIV-1. DESIGN: The prevalence of the delta32 deletion within the CCR5 gene was determined in a cohort of 207 patients, who had received documented amounts of non-antibody-tested and non-inactivated clotting factor concentrate. METHODS: Chromosomal DNA of haemophiliacs was isolated from whole blood. A portion of the CCR5 gene spanning the delta32 deletion was amplified by PCR. The resulting DNA fragments were analysed by agarose gel electrophoresis. RESULTS: The rate of HIV-1 infection was correlated strongly with increasing amounts of inoculated clotting factor concentrate. None of the HIV-positive patients (n = 129) had the delta32/delta32 genotype, whereas 12 out of 78 HIV-negative haemophiliacs had the homozygous delta32 deletion. CONCLUSIONS: The delta32/delta32 genotype was highly protective against HIV-1 infection, even in patients who had received millions of non-inactivated clotting factor units. As it is likely that in the early 1980s plasma pools were contaminated not only with monocyte-tropic HIV-1 strains, CCR5 appears to be the major mediator of HIV-1 infection. Furthermore, we conclude that there must be other protective mechanisms in multiply exposed non-infected haemophiliacs who have wild-type CCR5.

GB virus C/hepatitis G virus infection in HIV infected patients with haemophilia despite treatment with virus inactivated clotting factor concentrates.

AIM: To determine the frequency of GB virus C (GBV-C)/hepatitis G virus (HGV) infection before and after switch to the use of virus inactivated concentrates in haemophiliac patients infected with human immunodeficiency virus (HIV). PATIENTS AND METHODS: Initial and follow up sera from 49 children with haemophilia were analysed for the presence of GBV-C/HGV RNA and antibodies to HGV (anti-HGV). All patients had been infected with HIV while receiving concentrates without virus inactivation before 1984 and were subsequently treated with virus inactivated concentrates. RESULTS: In the first available serum sample (1987 or later), two of 49 patients were GBV-C/HGV RNA positive and two further patients were anti-HGV positive. During follow up (mean, 6 years), 14 patients developed markers of GBV-C/HGV infection. Eleven of these had received no blood products except clotting factor concentrates that had been prepared with virus inactivation. CONCLUSIONS: Despite being treated with virus inactivated clotting factor concentrates, HIV positive patients with haemophilia are at an increased risk of manifesting GBV-C/HGV infection. We hypothesise that GBV-C/HGV is transmitted by these clotting factor concentrates. However, we cannot rule out the emergence of markers of GBV-C/HGV infection as a result of the progression of immune impairment in the course of HIV infection.

Port-A-Cath usage in children with haemophilia: experience of 53 cases.

Experience of the Port-A-Cath implantable venous access system in 53 children with severe or moderate haemophilia A or B from seven centres in five countries is reviewed. The cumulative duration of follow-up was 1578 months (median 30 months, range 1-114). Of the devices implanted, 70% (37/53) were used without complications (median follow-up 32 months; range 1-114) and the remaining 30% (16/53) were associated with various types of complication: infection, bacteraemia or septicaemia in 56% (9/16) of cases, i.e. a rate of 0.07 per follow-up year or 0.19 per 1000 patient days, or various technical complications occurring after a median of 32 months (range 4-75) of uncomplicated use in the remaining 44% (7/16). Of the patients with inhibitors, 64% (7/11) manifested complications. Both doctors and parents considered that the Port-A-Cath device can be used with an acceptable frequency and severity of complications, and that it enables regular prophylactic or on-demand home treatment of children with haemophilia to be begun at an early age.

Spinal epidural haematoma in haemophilia A.

We report on a 27-year-old male Caucasian with severe haemophilia A who presented with acute onset of neck pain with cervical nerve root irritation, due to a spinal epidural haematoma. His past medical history revealed carrying of a moderate weight as a possible traumatic mechanism. Under immediate factor VIII replacement therapy complete remission of the symptoms was achieved within several days. The diagnosis of spinal epidural haematoma and complete resorption was revealed by initial and follow-up magnetic resonance imaging studies of the cervical spine. Having reviewed the literature on spinal epidural haematoma, we present an overview of the treatment and outcome as regards haemophilia.

Immune tolerance induction: a role for recombinant activated factor VII (rFVIIa)?

The development of factor VIII (FVIII) and FIX inhibitors is one of the most serious complications of repeated transfusions in patients with haemophilia. Management of patients with haemophilia with inhibitors must be separated into 2 concepts: the control of acute bleeding episodes and, in the long term, the treatment of the inhibitor itself. This paper will discuss both aspects of the management of these patients, focusing in particular on the therapeutic options available for the treatment of bleeding episodes during immune tolerance induction (ITI) therapy. The second part of the paper will review the management and outcomes of 10 patients with severe haemophilia in whom recombinant activated FVII (rFVIIa: NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used to treat bleeding episodes in the Haemophilia Centre at Bonn University; 6 patients were treated with rFVIIa for bleeding episodes while undergoing ITI. The results obtained demonstrate that rFVIIa is a safe and effective treatment for bleeding episodes and haemostatic cover for surgical procedures in patients with inhibitors. Inhibitor titres were not boosted in patients with haemophilia and inhibitors on treatment with rFVIIa. Therefore, rFVIIa is also a suitable treatment for bleeding episodes or control of haemostasis during surgery in patients prior to initiation of ITI therapy.

Uncoupling of respiration in turimycin fermentations.

Results furnish evidence for a partial uncoupling of respiration at conditions of phosphate limitation in turimycin fermentations. The uncoupling was primarily caused by the high intracellular ATP hydrolase activity and probably also by the CN-resistant respiration. The results support the idea that high dephoshorylating enzyme activities may have a regulatory effect on the secondary product biosynthesis.