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| Author(s): |
Andrey dos Santos
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2010-02-24 |
| Examining board members: |
Margareth Castro Ozelo;
Suely Meireles Rezende;
Giselle Zenker Justo;
Sara Teresinha Olalla Saad;
Fabíola Traina
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| Advisor: | Margareth Castro Ozelo |
| Abstract | |
The most serious complication of the treatment of hemophilia is the development of neutralizing antibodies to coagulation activity of factor VIII or IX (inhibitors). Several risk factors are related to the development of these inhibitors in patients with hemophilia, including genetic and environmental factors. Among genetic factors, the mutation associated with the diagnosis of hemophilia is a risk factor well documented. Recently, it was observed a higher incidence of inhibitors in African ancestry patients. The aim of this study was to analyze the genetic and non-genetic factors involved in the development of inhibitors. The study included 411 hemophilia patients, of which 321 with hemophilia A (HA) and 99 with hemophilia B (HB), belonging to a total of 238 and 59 families, respectively. The inhibitors were observed only in severe HA patients. From the 220 severe HA, 46 (20.9%) had inhibitor. The high risk mutation for the development of inhibitors were identified in 125 / 220 (58.8 %) severe HA patients, and 33 (26.4 %) of them developed inhibitors. Considering the ethnic group according to physical traits and ancestry, 38 % of severe HA patients were classified as black. The incidence of inhibitors is higher in this group of patients (31%) when compared to Caucasian patients (20%). The higher risk of inhibitor among African-Brazilians, could not be explained by the presence of the distinct factor VIII haplotypes, such as H3 and H4, as suggested in previous study. In fact, the prevalence rates of these haplotypes were distinct between Brazilians and North Americans, probably due to the fact that migrations of blacks to Brazil and to North America were originated from different geographic areas of Africa. In another phase of this study, we performed a comparative analysis of gene expression in samples of messenger RNA (mRNA) extracted from leukocytes of inhibitor and non-inhibitor patients with severe HA was performed. The evaluation consisted of an initial analysis of severe HA patients siblings, or from the same family, discordant for inhibitor development and in a second phase a group of unrelated individuals. Using the bioarrays technology 50 genes were upregulated and 16 were downregulated in inhibitor patients compared with non-inhibitor patients. Ten genes were selected among them, which are involved in immune response and were related to inhibitors development in other studies. It was observed by real time PCR that the genes for interleukin 8 (IL-8) and cystatin F (CST7) were upregulated and for interleukin 10 (IL-10) was downregulated in inhibitor patients. In conclusion, our results strengthen the idea that the mechanism of inhibitor development in hemophilia is complex, not clear and there is a large involvement of several genes related to the immune system in the development of these inhibitors. The study in different populations is important to understand the risk factors for the development of inhibitors. This is the first work in Brazil, to study patients from various regions and to performe analysis of different factors and their involvement in the development of inhibitors. The determination of these risk factors will help in the future to determine differential treatment for the control and in particular, for preventing the development of inhibitors (AU) | |