Congenital Bleeding Disorders

Abstract

Both clinical and basic problems related to the congenital bleeding disorders continue to confront hematologists. On the forefront are efforts to bring genetic correction of the more common bleeding disorders such as hemophilia A to the clinic in a safe and accessible manner. A second issue, particularly for patients with hemophilia, is the development of inhibitors-questions of how they arise and how to prevent and treat these problems that confound otherwise very successful replacement therapy and allow patients to maintain normal lifestyles. A third issue is the continuing question of diagnosis and management of von Willebrand disease, the most common congenital bleeding disorder, especially in individuals who have borderline laboratory values, but have a history of clinical bleeding.In Section I, Dr. Christopher Walsh discusses general principles of effective gene transfer for the hemophilias, specific information about viral vectors and non-viral gene transfer, and alternative target tissues for factor VIII and factor IX production. He highlights information about the immune response to gene transfer and reviews data from the hemophilia gene transfer trials to date. The future prospects for newer methods of therapy such as RNA repair and the use of genemodified circulating endothelial progenitors are presented as possible alternatives to the more traditional gene therapy approaches.In Section II, Dr. Nigel Key focuses on inhibitor development in patients with hemophilia A. He reviews the progress in our understanding of the risk factors and presents newer information about the immunobiology of inhibitor development. He discusses the natural history of these inhibitors and the screening, laboratory diagnosis, and treatment, including the use of different modalities for the treatment of acute bleeding episodes. Dr. Key also presents information about the eradication of inhibitors by immune tolerance induction and reviews recent information from the international registries regarding the status and success of immune tolerance induction.In Section III, Dr. Margaret Rick discusses the diagnosis, classification, and management of von Willebrand disease. Attention is given to the difficulty of diagnosis in patients with mild bleeding histories and borderline laboratory test results for von Willebrand factor. She presents the value of different laboratory assays for both diagnosis and classification, and she relates the classification of von Willebrand disease to the choice of treatment and to the known genetic mutations. Practical issues of diagnosis and treatment, including clinical cases, will be presented.

Pharmacology and clinical use of recombinant activated factor seven in neurosciences

“…Clinically relevant inherited abnormalities of plasmatic components have a prevalence of 0.01-1% in the general population, with deficiency or dysfunction of factor VIII (hemophilia A), factor IX (hemophilia B), and von Willebrand factor (von Willebrand disease) being the most common [33,34]. Hemophilias predispose to bleeding by impairing amplifier loops of plasmatic coagulation.…”

Desenvolvimento de inibidores do fator VIII na hemofilia A

“…Citocinas secretadas pelo clone de célula T expandido induzem a síntese de anticorpos inibidores do FVIII pelas células B. 8 Esta resposta imune ao FVIII é considerada policlonal e também heterogênea na sua especificidade. 9 Os inibidores do FVIII são imunoglobulinas policlonais principalmente da subclasse IgG4, cuja síntese é direcionada por células T CD4+ específicas para o FVIII.…”

Biosynthesis of FVIII in megakaryocytic cells: improved production and biochemical characterization

“…Two strategies were pursued using either a retroviral vector or a 'gutless' adenovirus (Powell et al, 2003;Rick et al, 2003). These human trials demonstrated the proof of principle of the gene therapy of haemophilia A but they were moderately encouraging because only low FVIII levels were obtained (no more than 6%) and that in vivo FVIII expression was not maintained for extended periods of time.…”

“…These human trials demonstrated the proof of principle of the gene therapy of haemophilia A but they were moderately encouraging because only low FVIII levels were obtained (no more than 6%) and that in vivo FVIII expression was not maintained for extended periods of time. In addition, the finding that some viral particles could induce a hepatitis or could be detected in body fluids, especially in semen (Powell et al, 2003;Rick et al, 2003;High, 2004) suggested a preference for the ex vivo approach of haemophilia gene therapy based on safety (Roth et al, 2001). Among the various cells that could be considered as putative targets for ex vivo gene therapy, haematopoietic cells were demonstrated to be potential candidates for many diseases, with severe combined immunodeficiencies being a notable example (Cavazzana-Calvo et al, 2000;Aiuti et al, 2002).…”