Haemophilia treatment centres in Germany

An adequate number of qualified haemophilia centres is an essential requirement for effective and cost-efficient haemophilia care. During a reassessment of the delivery of haemophilia care in Germany a broad range of criteria relating to structure and quality of the centres were defined and a questionnaire was developed. Results: Of 137 doctors who received the questionnaire, 113 (82%) replied. Based on data related to diagnostic and treatment services, together with voluntary information from PEI forms (Paul Ehrlich Institut, Germany), 72 haemophilia centres were established. Three levels of haemophilia care were defined by the Medical Advisory Council of the German Haemophilia Society. This is in accordance with criteria defined by European working parties. 17 haemophilia centres were designated CCC (Comprehensive Care Centre), 24 were designated HTC (Haemophilia Treatment Centre) and 31 smallest centres were allocated the status HTR (Haemophilia Treatment Regional). In comparison to the survey in 2007, there was only slight variance in the CCC centres (+ 2 centres/-1 centre). From the previous HTC centres, 7 have withdrawn from this treatment level: 4 maintain treatment on the lower level HTR, and 3 centres had ceased treatment. On the HTR level of treatment, 6 of 29 (21%) had ceased to offer treatment. 9 had been able to increase the number of patients and were designated HTC. 5404 patients with haemophilia and 3047 with the severe form of haemophilia were reported. 67% were treated in CCC, 25% in haemophilia treatment centres and 8% in the 31 smallest centres. 13 of the adult CCC are situated in the department of internal medicine and 4 in the section of transfusion medicine. Conclusions: The survey and analysis of the haemophilia treatment centres in Germany show that the delivery of haemophilia care through 17 CCC, 24 HCT and 31 HTR appears to be adequately structured. But it is noticeable and alarming, however, that on both HTC and HTR levels of treatment, 32% and 21%, respectively, have left their treatment level. 9 centres (12.5%) have finished working in haemophilia care in the last four years. On the strength of these results, endeavours to maintain haemophilia centres must be intensified. A high level of effective care can be guaranteed only through continued existence of the centres.     

Immune tolerance therapy for inhibitors in haemophilia A

The development of inhibitors at start of therapy with factor VIII concentrates represent the most serious complication of haemophilia treatment. The only way to a long lasting eradication of the inhibitor is the induction of immune tolerance. A successful immune tolerance therapy (ITT) is the precondition for a regular prophylactic treatment regime and subsequently safe life perspective with a good quality of life. All ITT protocols have been developed empirically without knowing the pathophysiological mechanisms. The guidelines of the Federal Chamber of Physicians (1), the German recommendations for ITT (2) and the consensus recommendations of an international working group (3) provide an important lead for the conduction of immune tolerance therapy.     

Haemophilia A: molecular insights.

Haemophilia A is the most common inherited bleeding disorder caused by defects in the F8C gene that encodes coagulation factor VIII. This X-linked recessive disorder occurs in approximately 1:5000 males. Haemophilia A is diagnosed based on normal prothrombin time, altered activated partial thromboplastin time and reduced factor VIII activity in plasma. Carrier females are usually asymptomatic and can be identified only by molecular analysis. The most frequent mutations in F8C are intron 22 and 1 inversions, which occur in approximately 50% and 5% of patients, respectively, with a severe phenotype. Large gene deletions are observed in approximately 5% of alleles from patients with severe haemophilia A. The remaining severe cases and all moderate and mild cases result from numerous point mutations and small insertions/deletions, which are de novo mutations in one-third of cases. Thus, molecular diagnosis of carrier status and prenatal diagnosis in families without intron 22 or 1 inversions is based on scanning techniques or gene sequencing. When the disease-causing mutation cannot be identified, molecular diagnosis is performed by linkage analysis of several DNA polymorphic markers linked to F8C. Given the clinical heterogeneity among haemophilic patients, many groups, including our own, have examined the relationships between prothrombotic gene variants and haemophilic phenotype to investigate whether prothrombotic gene variants modify clinical expression of the disease.     

Haemophilia B: from molecular diagnosis to gene therapy.

Thanks to its typical expression, haemophilia can be identified in writings from the second century AD. Haemophilia B, an X-linked recessive bleeding disorder due to factor IX (FIX) deficiency, has an incidence of about 1:30,000 live male births. The factor 9 (F9) gene was mapped in 1984 on Xq27.1. Haemophilia is diagnosed from prothrombin time, activated partial thromboplastin time, and FIX levels. Carrier females are usually asymptomatic and must be identified only with molecular analysis. Linkage analysis of F9 polymorphisms is rapid and inexpensive but limited by non-informative families, recombinant events, and the high incidence of germline mutations; thus, various procedures have been used for the direct scan of F9 mutations. We set up a novel denaturing high performance liquid chromatographic procedure to scan the F9 gene. This rapid, reproducible procedure detected F9 mutations in 100% of a preliminary cohort of 18 haemophilia B patients. Parallel to the development of more efficient diagnostic tools, the life expectancy and reproductive fitness of haemophilic patients have greatly improved and will continue to improve thanks to the use of less immunogenic recombinant FIX. Hopefully, new approaches based on gene therapy now being evaluated in clinical trials will revolutionise haemophilia B treatment.     

Haemophilia and inhibitors. 1: Diagnosis and treatment

This is a two-part unit on haemophilia and inhibitors. This article, part 1, examines the condition, the problem of inhibitors and treatment options for patients with inhibitors. It also discusses the practical challenges nurses may face in patients' surgical management.     

Lentivirus-mediated platelet-derived factor VIII gene therapy in murine haemophilia A

BACKGROUND: Previous studies from our laboratory have demonstrated that lineage-targeted synthesis of factor VIII (FVIII) under the direction of the platelet-specific integrin alphaIIb gene promoter (2bF8) can correct the murine haemophilia A phenotype even in the presence of high titer inhibitory antibodies in a transgenic mouse model. OBJECTIVE: In this study, we assessed the efficacy of using a genetic therapy approach to correct haemophilia A in FVIII-deficient (FVIII(null)) mice by transplantation of bone marrow (BM) transduced with a lentivirus (LV)-based gene transfer cassette encoding 2bF8. RESULTS: Functional FVIII activity (FVIII:C) was detected in platelet lysates from treated mice and the levels were similar to 2bF8 heterozygous transgenic mice. Mice transplanted with 2bF8 LV-transduced BM survived tail clipping and we did not detected inhibitory or non-inhibitory FVIII antibodies over the period of this study (11 months). Furthermore, BM transferred from the primary transplant recipients into FVIII(null) secondary recipients demonstrated sustained platelet-FVIII expression leading to correction of the haemophilia A phenotype showing that gene transfer occurred within long-term repopulating haematopoietic stem cells. CONCLUSIONS: These results demonstrate that ectopic expression of FVIII in platelets by lentivirus-mediated bone marrow transduction/transplantation may be a promising strategy for gene therapy of haemophilia A in humans.     

A creative art centre for adults with developmental disabilities

An art centre for adults with developmental disabilities is described, and its origins and dissemination are presented. Differences between such art centres and more traditional work-oriented programmes for people with developmental disabilities are indicated. The number of similar art centres for this population has increased substantially during the past 20 years.     

Rituximab in the treatment of acquired haemophilia A in a patient with polymyalgia rheumatica

Acquired hemophilia A is a rare but potentially life-threatening bleeding disorder. It is caused by the development of autoantibodies directed against coagulation factor VIII in adults or elderly patients, who do not have a personal or family history of bleeding. Case: A man (age: 76 years) on prednisone and leflunomide for polymyalgia rheumatica developed spontaneous severe haematomas. The patient was diagnosed with acquired factor VIII deficiency (FVIII activity 1.2%, FVIII inhibitor 31.7 BU). Due to the active bleeding diathesis, treatment was administered with activated prothrombin complex concentrates (FEIBA®, Baxter). Immunosuppressive treatment with a combination of oral prednisone (1 mg/kg daily) and cyclophosphamide (1,5 mg/kg daily) was administered to reduce the FVIII inhibitor. However, after two weeks of treatment, FVIII was only 3% and no clinical improvement was observed. Treatment with the anti CD20 monoclonal antibody rituximab intravenously at 375 mg/m2 once weekly for four consecutive weeks was started. The patient showed rapid clinical improvement following rituximab treatment. He achieved a complete remission defined as return to normal FVIII activity and undetectable FVIII inhibitor titer. After a follow-up of six months no relapse occurred. Conclusion: Rituximab appears an effective and well-tolerated treatment for patients with acquired haemophilia.     

A centre for advice and treatment

The first wave of NHS walk-in centres opened in 2000. Since then, a total of 57 centres have opened in England with 25 more planned in the next few months. These centres do not aim to replace existing primary or secondary care services but to complement them and provide the public with an alternative means of accessing health care for minor illnesses, minor injuries and emergency contraception. Two models of walk-in centre exist: those based in primary care and those based in secondary care.     

Liver abscess in adults: ten years experience in a UK centre

BACKGROUND: The epidemiology and management of liver abscess (LA) have evolved over time. Aim: To examine our experience over 10 years in a UK teaching centre. DESIGN: Retrospective review of patient records. METHODS: We reviewed the records of all patients aged >16 years discharged from Royal Hallamshire Hospital with a diagnosis of LA between April 1988 and December 1999. RESULTS: There were 69 patients with LA (65 pyogenic, 4 amoebic), giving a crude annual incidence rate of 2.3/100,000/year (18.15/100,000 hospital admissions). Median age was 64 years. Single lesions were found in 41 patients, multiple lesions in 28. Pre-admission, patients were symptomatic for a median 14 days, with the most common symptoms and signs being fever and abdominal pain/tenderness. Pathogens were identified in 74% and predisposing aetiology in 92% of those undergoing investigation. Spread of infection to the liver via the portal venous system was the commonest route of infection (46%), most frequently in patients aged >/=60 years (p=0.019). Abdominal ultrasound (US) was diagnostic for LA in >90% of cases. Treatment with anti-microbial therapy plus interventional radiology was optimal. The case fatality rate was 12.3%, mainly from associated underlying pathology. DISCUSSION: LA is commonly associated with underlying gastrointestinal pathology. Seeking out this underlying aetiology is an integral part of management. We recommend US as the first-line diagnostic tool with guided intervention plus antibiotic(s) as first-line treatment. Prognosis depends chiefly on the underlying pathology.     

血友病甲的诊治体会(附一例报告)

1病例资料男,1岁。因碰伤致皮肤淤斑半月余,牙龈反复出血7天入院。患儿于半月前因碰伤后出现皮肤淤斑,未重视,7天前牙龈碰伤后出血不止,经一般压迫止血无效,渗血不止长达60小时,估计总失血量为200ml,面色苍白。在门诊予肾上腺素液纱布压迫止血后出血停止,有针刺后出血不易止住病史。查血红蛋白82g/L,红细胞3.21×1012/L,白细胞6.8×109/L,嗜酸细胞0.36,淋巴细胞0.64,血小板200×109/L;活化部分凝血活酶时间(APTT)68.8秒。予酚磺乙胺、维生素C、氨甲环酸静脉滴注,出血停止。复查红蛋白92g/L,红细胞3.17×1012/L,白细胞7.5×109/L,嗜酸细…     

Moxalactam therapy for a wide spectrum of bacterial infections in adults.

We evaluated the efficacy and toxicity of moxalactam during treatment of 45 documented infections in 36 patients. A majority of patients received 4.5 g of moxalactam per day. There was a good clinical response in 42 of the 45 (94%) infections, including 3 bacteremias, 20 skin and soft tissue infections, 6 gram-negative lower respiratory tract infections, 6 purulent diabetic foot ulcers, 3 wound infections, 3 urinary tract infections, and 4 miscellaneous infections (meningitis, suppurative phlebitis, peritonitis, bursitis). Previously, 11 of these patients had failed to respond to other antibiotics. Our three treatment failures were attributed to abnormal host defense in two patients and to a resistant enterococcal urinary tract infection in another. Moxalactam was tolerated well as produced minimal renal, hepatic, and hematological toxicities. The only serious adverse effect were the development of documented pseudomembranous colitis in one patient and progressive renal dysfunction in another. Acquisition of resistance among noneradicated isolates during therapy was not demonstrated.