Prophylaxis in adult patients with severe haemophilia A.

Primary prophylaxis is the standard of care for children and adolescents with severe haemophilia; however, its role in adults is less well defined. To establish to which extent prophylaxis is currently being used in adults with severe haemophilia A, we conducted a systematic review of the literature by searching MEDLINE using the terms "prophylaxis", "adult", "severe" and "haemophilia A". Evidence-based guidelines and national studies relating to the use of prophylaxis in adults with severe haemophilia A were identified and reviewed. One published evidence-based guideline and three published studies fulfilled our inclusion criteria. A combined analysis of published data suggests that almost 45% of adult patients with severe haemophilia A are being treated with prophylaxis. Withdrawal of prophylaxis is attempted relatively infrequently; however, when attempted, around 27% of adolescents and adults with severe haemophilia do not experience an increase in bleeding tendency over a specific treatment period. Prophylaxis (primary and secondary) is an important part of haemophilia treatment that should be granted to all patients depending on their clinical presentation. Further studies are needed to better define this treatment strategy in adults.

Legal requirements for optimal haemophilia treatment in Germany.

The clinical benefits of early prophylaxis in the treatment of haemophilia have been unquestioned since publication of the results of the first randomized study. The question of whether or not prophylaxis is cost-effective remains to be proven. For European physicians treating haemophilia patients, and for German clinicians in particular, the law largely supports the use of prophylaxis in haemophilia, but many doctors are unaware of this. The aim of this review was therefore to describe the German legal framework and outline how it can be used to support appropriate clinical decision-making in the treatment of haemophilia and justify the use of prophylaxis to health insurers and third-party payers. The German Disability Equalisation Law and German Social Law Books V and IX outline legal requirements to prevent or ameliorate disability, and support the argument that all haemophilia patients, including adults, have the right to receive appropriate, adequate, and cost-effective treatment. "Appropriate" treatment means that it must be in accordance with state-of-the-art medical knowledge taking into account medical progress. "Adequate" treatment must be conducive to the goals of haemophilia management, which are to prevent bleeds, treat bleeding episodes, maintain and/or restore joint function, and integrate patients into a normal social life. This can only be achieved when long-term treatment is adequately dosed and regularly administered for as long as it is required. Thankfully, with the availability of virus-safe factor concentrates, the introduction of home treatment programmes, and the law on our side, we are in a very strong position to achieve these goals.

Extracorporeal Treatment for the Acute und Long-Term Outcome of Patients with Life-Threatening Acquired Hemophilia.

OBJECTIVES: In acquired hemophilia (AH), autoantibodies (inhibitors) impede blood coagulation factors leading to severe bleedings. Cornerstones of a successful treatment are the control of bleeding and an eradication of autoantibodies. The present study is an update of our previous documentation of the treatment of high-titer AH patients with severe life-threatening bleeding undergoing the modified Bonn-Malmö-Protocol (MBMP). METHODS: 64 AH patients were treated by a standard combination protocol (MBMP) consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin, immunosuppression, and high-dose FVIII substitution. They underwent a long-term follow-up. RESULTS: Primary study endpoints loss of detection of the activity of the inhibitor and FVIII recovery ? 5% were reached in a median time of 3 days (95% CI: 2.6-3.4 days), the median time of FVIII substitution was 13 days (95% CI 10.6-15.3 days), and the median time of immunoadsorption was 16 days (95% CI 13-18.9 days). In 5 patients the AH occurred as paraneoplastic syndrome, and partial remission was achieved. Relapses without bleeding event occurred only in second-line MBMP. Those responded excellently to short time treatment. Overall patients remained in remission over a median follow-up time of 8 years. Conclusion: Except for paraneoplastic AH, MBMP-treated patients have a remarkable prognosis which is confirmed by long-term follow-up with a complete response rate of 93% (53/57) in the first year post MBMP and 100% during long-term follow-up. These outcome in life-threatening AH is unique and until now not achievable via other treatment schedules. In life-threatening bleedings physicians should take into account MBMP as a first line treatment.

The case for wider use of recombinant factor VIII concentrates.

The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.

Immunoadsorption in the treatment of acquired haemophilia.

In acquired haemophilia (AH) healthy humans can suddenly develop severe bleeding due to autoantibodies (inhibitors) against clotting factors, especially factor VIII. The mortality rate of 21 % is considerable, and standardized treatment protocols have not been developed due to the low disease frequency (1-4 per million). Major goals of treatment are the control of bleeding events and rapid inhibitor elimination. Conventional treatment regimens induce immune tolerance via long-term immunosuppression with success rates between 52% and 82%. However, treatment related mortality can rise to 39%. Lack of complete remission, advanced age, underlying malignancies and infections related to immunosuppressive therapy are regarded as principal risk factors for death. The modified Bonn-Malmö Protocol (MBMP), an immune tolerance protocol consisting of antibody depletion through immunoadsorption, i.v. immunoglobulin treatment, immunosuppression and high dose FVIII supplementation, achieves rapid and safe control of acute bleeding. In the largest published single centre study of high risk patients with AH, we previously demonstrated that complete remission (CR) can be achieved in 88.5% of all patients (54/61) within a median time of 3.9 wks (range: 3.2-4.5 wks) and in 97% (54/56) of AH patients without cancer as an underlying condition. Those 5 patients, who suffered also from cancer, achieved partial remission (PR). Mortality or severe treatment-related side effects were not observed. This study confirmed that MBMP is a safe and effective treatment with a high curative potential for severe AH. However, the severity of bleeding, and therefore the cost-effectiveness of the approach, needs to be considered when initiating this treatment protocol.

Rhenium-186 hydroxyethylidenediphosphonate (186Re HEDP) for the treatment of hemophilic arthropathy: first results.

OBJECTIVES: The aim of this study was to evaluate the efficacy of a systemic application of rhenium-186 hydroxyethylidenediphosphonate (Re HEDP) for pain treatment in patients with hemophilic arthropathies. METHODS: Twelve patients with hemophilic arthropathy with at least 3 involved joints with persistent pain were included in this prospective study. A single dose of 15 mCi (555 MBq) Re HEDP was administered intravenously. Before and 12 weeks after treatment, pain assessment was performed using the visual analog scale (VAS). The pain status assessment included the general status, pain of all joints affected, and pain of the 3 mostly involved joints. Furthermore, quality of life was assessed. RESULTS: With regard to the 3 most involved joints, an improvement of the pain symptoms in 25 of 36 (69.4%) joints was observed. With regard to all involved joints a median of 3 joints per patient improved after Re HEDP therapy. General pain status after treatment was 2.0 VAS points lower as compared with pretreatment. The total number of involved joints remained unchanged in 7 patients, increased in 1 patient, and decreased in the remaining 4 patients. CONCLUSIONS: The results of this study show an improvement of the pain symptoms of the involved joints 12 weeks after therapy with Re HEDP in patients with hemophilic arthropathy. The only moderate success regarding a reduction of the total number of involved joints is by the fact that despite this improvement most affected joints remained still painful on a lower level after the therapy or due to newly affected joints not painful before initiation of the radionuclide therapy.

Haemophilia A: from mutation analysis to new therapies.

Haemophilia is caused by hundreds of different mutations and manifests itself in clinical conditions of varying severity. Despite being inherited in monogenic form, the clinical features of haemophilia can be influenced by other genetic factors, thereby confounding the boundary between monogenic and multifactorial disease. Unlike sufferers of other genetic diseases, haemophiliacs can be treated successfully by intravenous substitution of coagulation factors. Haemophilia is also the most attractive model for developing gene-therapy protocols, as the normal life expectancy of haemophiliacs allows the side effects of gene therapy, as well as its efficiency, to be monitored over long periods.

Clinical outcomes of HIV-HCV co-infection in a large cohort of hemophiliac patients.

OBJECTIVE: To determine the disease progression of HIV-HCV co-infected hemophiliacs in a large cohort of patients (n = 288) cared for at a single medical institution. PATIENTS AND METHODS: Annual mortality rates for AIDS- and liver-related death were calculated and Kaplan-Meier survival plots were drawn to determine the progression to AIDS and death. RESULTS: Between January 1985 and December 2002, 179 (62.2%) and 195 (67.7%) of these patients had developed AIDS or died, respectively. Overall, AIDS accounted for 128 deaths, which almost entirely (93.7%) occurred prior to the introduction of highly active antiretroviral therapy (HAART) at the end of 1995. A total of 29 patients died of liver failure, most of them (69%) during the years 1991-1996. Since 1997, only five cases of fatal liver failure were reported. Non-HIV-HCV related reasons were responsible for 38 deaths and occurred predominantly (47%) in the years 1997-2002. Starting November 1995, 72 patients were treated with HAART. However, by December 2002, only 52.5% and 83% of all HAART-treated patients had a stable viremia (<400 copies/ml) and a sufficient CD4(+) T-cell count (>200/microl), respectively. CONCLUSION: These data indicate that liver-related mortality peaked in the years 1991-1996, but subsequently tended to decline. Moreover, despite widespread treatment of patients with HAART, a significant proportion of individuals had an unsatisfactory immunological and virological status at the end of 2002.

Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept.

Acquired hemophilia (AH) is an extremely rare condition in which autoantibodies (inhibitors) against clotting factor VIII induce acute and life-threatening hemorrhagic diathesis because of abnormal blood clotting. The mortality rate of AH is as high as 16%, and current treatment options are associated with adverse side effects. We investigated a therapeutic approach for AH called the modified Bonn-Malmo Protocol (MBMP). The aims of MBMP include suppression of bleeding, permanent elimination of inhibitors, and development of immune tolerance, thereby avoiding long-term reliance on coagulation products. The protocol included immunoadsorption for inhibitor elimination, factor VIII substitution, intravenous immunoglobulin, and immunosuppression. Thirty-five high-titer patients with critical bleeding who underwent MBMP were evaluated. Bleeding was rapidly controlled during 1 or 2 apheresis sessions, and no subsequent bleeding episodes occurred. Inhibitor levels decreased to undetectable levels within a median of 3 days (95% confidence interval [95% CI], 2-4 days), factor substitution was stopped within a median of 12 days (95% CI, 11-17 days), and treatment was completed within a median of 14 days (95% CI, 12-17 days). Long-term follow-up (7 months-7 years) showed an overall response rate of 88% for complete remission (CR). When cancer patients were excluded, the CR rate was 97%.

Contamination of coagulation factor concentrates with human parvovirus B19 genotype 1 and 2.

Human parvovirus B19 (B19) DNA has frequently been detected in plasma-derived coagulation factor concentrates. Furthermore, transmission of B19 infection was observed, indicating presence of the infectious virus despite routine viral inactivation/removal procedures during the manufacturing process. Recently, human parvovirus DNA isolates, variant from B19, have been identified resulting in classification of B19 virus into three distinct genotypes, with all viruses previously classified as B19 belonging to genotype 1. So far, there is no information available on contamination of clotting factor concentrates with genotype 2. Therefore, we analysed 202 different factor concentrate lots for genotype 1 and 2 DNA by PCR. Analysis of one hundred eighty-one lots representing 13 different products, administered over the last three years, was compared to 21 lots (8 products) used until the early 1980s which had not been treated by viral inactivation procedures. Genotype 1 DNA was detected in 77/181 (42.5%) currently administered lots, and 17/21 (81%) previously used lots. The level of genotype 1 DNA contamination was similar in currently and previously administered concentrates. Genotype 2 DNA was found in 5/202 (2.5%) lots, all of which were co-contaminated with genotype 1 DNA. DNA sequence analysis showed that the PCR-double positive concentrates contained typical genotype 1 and genotype 2 DNA. Because genotype 2 appears to cause a similar spectrum of diseases as genotype 1, simultaneous detection of genotype 2 by nucleic acid amplification testing (NAT), now widely applied to plasma pools for genotype 1, would give an added level of safety to blood products.

Environmental and genetic factors influencing inhibitor development.

Inhibitor formation occurs at a frequency of 20% to 30% in severe hemophilia A, and 3% in hemophilia B. Today, it represents the major complication in patient care and renders classical substitution therapy ineffective. Genetic factors, such as factor VIII (FVIII) gene mutations and immune response genes, particularly the major histocompatibility complex, have been shown to constitute decisive risk factors for the development of inhibitors. In severe hemophilia A and B, those mutations that result in the absence or severe truncation of the FVIII/factor IX (FIX) proteins are associated with the highest risk for inhibitor formation, indicating that a major driving force in inhibitor development is the presentation of a novel antigen to the patient's immune system. An alternative pathomechanism may underlie inhibitor development in patients with mild hemophilia A. Missense mutations, especially those in the C1/C2 domains, may alter the immunogenicity of the FVIII protein, eliciting an inhibitor response against the mutated epitope. In some patients with hemophilia B, especially those with large deletions to the FIX gene, a severe allergic reaction occurs simultaneously with inhibitor onset. Despite the obviously strong genetic predisposition, discordant inhibitor status in monozygotic hemophilia A twins demonstrates that environmental factors also play a role in the development of inhibitors.

Regulation of human factor IX expression using doxycycline-inducible gene expression system.

Following substitution therapy with human factor IX (hFIX) concentrate, therapy of haemophilia B by viral gene transfer has become an attractive alternative therapy in recent years. However, high doses of expressed hFIX, which can already be achieved in animal studies, may cause thrombosis in humans (van Hylckama Vlieg et al., 2000). Thus, it should be possible to maintain transgene expression within the therapeutic range. Therefore, we inserted elements of the tetracycline (Tet)-dependent Tet-On gene regulatory system into replication deficient adenovectors. The new system consists of two adenovectors: a response vector expressing hFIX (Ad5.TRE.hFIX), and a regulator vector expressing a second generation reverse tetracycline transactivator controlled by a CMV- (Ad5.CMV.rtTA) or human alpha1-antitrypsin-promoter (Ad5.hAAT.rtTA). Expression studies in four human cell lines showed high expression of hFIX from Ad5.TRE.hFIX in all cell lines in combination with Ad5.CMV.rtTA regulator vector, but only high specific expression in HepG2-cells in combination with Ad5.hAAT.rtTA regulator vector. Additionally, up- and down-regulation of hFIX expression could be demonstrated in vitro with the Ad5.TRE.hFIX/Ad5.CMV.rtTA combination and modulating doxycycline concentrations. When SCID-mice were infected with the Ad5.TRE.hFIX/Ad5.CMV.rtTA combination, up- and down-regulation of hFIX expression was achieved by oral doses of doxycycline for a period of at least two months. Replacement of the Ad5.CMV.rtTA vector by the Ad5.hAAT.rtTA vector showed minimal expression of hFIX in vivo. Although hFIX expression showed a slow and gradual decrease over time in vivo with the Ad5.CMV.rtTA vector, it remained within the therapeutic range. To date, regulation of hFIX has not been described in this way.

Bleeding complications after percutaneous liver biopsy. An analysis of risk factors.

BACKGROUND AND AIMS: To assess the risk of bleeding after percutaneous liver biopsy, we retrospectively analyzed 629 procedures with particular respect to patients with an increased a priori bleeding risk. METHODS: Factors possibly related to the risk of bleeding were analyzed by univariate analysis. Those variables which were significant in the univariate analysis were then entered into a forward conditional logistic regression model. RESULTS: Biopsy-related bleeding events defined as clinically overt complication (n = 10; 1.6%), an otherwise unexplained drop in serum hemoglobin concentration of greater than 2 g/dl (n = 45; 7.1%) or intra- or extrahepatic hematoma assessed by ultrasound (n = 17; 2.7%) were identified in 72 patients. 58% of the bleeding events occurred in patients with particular risk factors for bleeding. Biopsy-related mortality in the study cohort was 0.48%. Logistic regression analysis indicated mycobacterial infection [odds ratio (OR) 24.0], pre-biopsy prophylactic platelet substitution (OR 9.9), acute liver failure (OR 9.1), heparin administration on the day of biopsy (OR 8.7), advanced liver cirrhosis (OR 5.1), therapy with corticosteroids (OR 3.5) or metamizole (OR 2.8) and leukemia or lymphoma (OR 2.8) as significant (p < or = 0.05) independent risk factors. Delayed bleeding (>24 h after biopsy) was identified in 70% of the bleeding events. CONCLUSIONS: In our study cohort which comprised a high proportion of patients with particular risk factors for bleeding, biopsy-related bleeding occurred more frequently and later than commonly observed and was associated with only a few prognostic factors. Considering these predictors before liver biopsy will aid to reduce the rate of bleeding complications.

The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients.

Besides preventing bleeding episodes, common goals of the treatment of hemophilia include integrating of patients into a normal social life and optimizing their quality of life. Sufficient amounts of factor VIII (FVIII) concentrates, whether recombinant or plasma-derived, are continuously needed. Guidelines for quality assurance of treatment will be a cornerstone to maintain optimal clinical management of patients especially considering financial aspects. Advances in manufacturing technologies have made possible general availability of modern concentrates for the management of hemophilia A patients. Safety, cost and continuous supply of concentrates must be considered when deciding on a product for replacement therapy. As todays' products have reached an excellent margin of safety with regard to virus transmission, the development and treatment of inhibitors is currently the main concern for physicians and patients. The incidence of inhibitors is influenced by various patient-related factors such as mutation type or severity of the disease. Plasma-derived FVIII concentrates containing von Willebrand factor (VWF) may have clinical advantages over pure FVIII concentrates with regard to inhibitor development and inhibitor eradication. Clinical trials comparing FVIII/VWF concentrates with pure FVIII concentrates are lacking, thus a lower inhibitor incidence has not yet been proven. Data from Germany on immune tolerance induction with FVIII/VWF concentrates indicate higher success rates with these than with pure FVIII concentrates. In addition FVIII/VWF concentrates are the therapy of choice when immune tolerance therapy with pure FVIII products is not successful.