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- Astermark, Jan
(författare)
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Basic aspects of inhibitors to factors VIII and IX and the influence of non-genetic risk factors.
- 2006
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Ingår i: Haemophilia. - 1351-8216. ; 12 Suppl 6, s. 41499-41499
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Tidskriftsartikel (refereegranskat)abstract
- The appearance of polyclonal antibodies inhibiting the function of exogenous factors VIII (FVIII) and IX (FIX) continues to be a major challenge in the treatment of patients with congenital haemophilia. Why these inhibitors develop in 10-20% of patients with haemophilia A, and in 1-5% of patients with haemophilia B, remains largely unexplained. The antibodies, however, are characterized by several features that may have implications for the immune process by which they occur. The FVIII antibodies are mainly directed towards the A2, A3 and C2 domains, thereby interfering with the function of the factor Xase complex, the binding of FVIII to von Willebrand factor, and the binding of FVIII to phospholipid membranes. The FIX epitopes are localized to the NH2-terminal gamma-carboxyglutamic acid region and the serine protease domain. Genetic risk factors are known to be of importance in the development of inhibitors, whereas the impact of non-genetic factors is less clear. However, based on studies of related subjects, it is obvious that non-genetic factors are of importance as well. Putative factors currently debated include age at the start of treatment, treatment in association with immune challenges, the type of product, and the mode of administration. Most of the findings reported to date, however, derive from small cohorts that have not been sufficiently well characterized with respect to genetic risk profile. Therefore, additional studies are required to quantify the impact of non-genetic factors on the pathophysiologic process of inhibitor development.
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- Astermark, Jan, et al.
(författare)
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Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors.
- 2006
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 12:4, s. 363-371
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Tidskriftsartikel (refereegranskat)abstract
- The management of patients with inhibitors is an important challenge in haemophilia care. The lack of randomized controlled trials means that clinical decisions are generally based on subjective opinions, and purchasers' attention is likely to focus on the costs of treatment. In order to assess the current management of inhibitor patients and use of immune tolerance induction therapy (ITI) in Europe, we performed a survey within a European network of 21 comprehensive care centres from 14 countries (the European Haemophilia Therapy Standardisation Board). The survey identified a total of 381 patients with inhibitors attending the centres, 211 (55.4%) of whom had never been exposed to ITI. Between 1998 and 2003, the centres performed 233 procedures and 114 (48.9%) were successful. The survey demonstrated that dosing, which is the time to start and stop the ITI, the type of concentrate to use and the definition of success varied among the centres. Well-designed trials are warranted to guide decision-making, but in the absence of these studies we have developed consensus guidance for the management of inhibitor patients based on current clinical practice, as identified by the survey, and review of the literature.
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- Astermark, Jan, et al.
(författare)
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Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors.
- 2007
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 13:1, s. 38-45
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Tidskriftsartikel (refereegranskat)abstract
- The ultimate goal of treatment for patients with inhibitory antibodies should be to permanently eradicate the inhibitor by immune tolerance induction therapy (ITI). However, ITI procedures fail in a substantial number of patients and in many countries ITI is not even offered owing to its high cost. How patients with inhibitors are managed in different European countries is evaluated with a special focus on the use of by-passing agents, i.e. recombinant FVIIa (rFVIIa) and activated prothrombin complex concentrates (aPCC), as well as the type of monitoring performed. Investigators from 22 large haemophilia centres participating within the network of the European Haemophilia Therapy Standardisation Board (EHTSB) were asked to complete a questionnaire. rFVIIa was routinely used in all centres for both children and adults at dosages ranging from 90 to 250 mu g kg(-1) at an interval of 2-4 h. aPCC was used in 85% of the centres in adults and in 25% of the centres in children with haemophilia A at dosages of 50-100 IU kg(-1) every 6-12 h. The corresponding figures for children and adults with haemophilia B were 40% and 15% of the centres, respectively. Higher dosages of both agents were considered in the case of life-threatening bleeds. General recommendations were developed, based on the information provided by the survey. The results clearly indicate the need for well-designed comparative studies to optimize the use of by-passing agents.
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- Astermark, Jan, et al.
(författare)
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Inhibitor development.
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14 Suppl 3, s. 36-42
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Tidskriftsartikel (refereegranskat)abstract
- The immune response to factor VIII and the development of inhibitory antibodies is a complex multi-factorial process involving a variety of immune regulatory genes and cells, several of which have the potential to determine risk. A better understanding of the mechanisms involved will increase the likelihood of development of new therapeutic options for patients with hemophilia. This review summarizes genetic and non-genetic risk factors currently under evaluation, and the potential modulative effect of the von Willebrand factor on factor VIII immuno- and antigenicity. In addition, the role of T-regulatory cells in the pathogenicity of inhibitors will be discussed.
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- Astermark, Jan
(författare)
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Why do inhibitors develop? Principles of and factors influencing the risk for inhibitor development in haemophilia.
- 2006
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Ingår i: Haemophilia. - 1351-8216. ; 12 Suppl 3, s. 52-60
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Tidskriftsartikel (refereegranskat)abstract
- The formation of inhibitory alloantibodies is, in the postinfectious era, the most severe and costly complication of replacement therapy in patients with haemophilia. The complexity of the immune response to the infused factor becomes more and more obvious as knowledge in the area increases. Antibodies develop as a result of a complex multi-factorial interaction between antigen-presenting cells, T- and B-lymphocytes. Genetic susceptibility of cell surface molecules, such as the major histocompatibility complex, the T-cell receptor and cytokine receptors, as well as various immunomodulatory molecules have a major impact on the outcome. In addition, environmental factors probably influence the risk of inhibitor development. The current concept of inhibitor development is reviewed. A better understanding of the pathophysiological mechanisms involved will facilitate improvement of therapy in the future, and hopefully provide an opportunity to prevent this complication of treatment.
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