This thesis begins by examining an unexplored contextual background for sixteenth century local maps. It argues that the architectural drawing techniques developed by master masons in the late twelfth century continued to be taught to the King’s masons well into the sixteenth, and that these drawing techniques lie behind the innovations in sixteenth century topographical mapping. Having provided a history of the craft skills that were adapted to make sixteenth century local maps this thesis moves on to consider why masons adapted craft skills traditionally used in full scale drawings on stone and plaster surfaces to make small, paper maps in the sixteenth century. It examines the way in which sixteenth century local maps were used and argues that the changing demands of patrons put pressure on master masons to alter the way in which local maps portrayed their subjects. The surviving archival evidence suggests that Henry VIII was the principle patron of local maps and my research examines the influence of the king over the shifting form of the map. It uses the letters and drawings sent between Henry VIII and his craftsmen to examine the decisive changes that Henry VIII made to the nature of the relationship between patron and builder, and the consequent effects of these changes over the forms of the image used to communicate between them. My argument suggests that Henry employs and promotes the craftsmen whose drawings allow him the greatest level of design control over the works he finances and that through this system maps and plans rapidly advance to include the technical drawing techniques which had, during the Middle Ages, been used exclusively among masons as on-site, working drawings. This thesis focuses attention on the technical aspects of map making, examining the material skills used to construct Henrician local maps and arguing that sixteenth centry local maps need to be related back to the craft skills of an older tradition of masonic drawing. It also suggests that map historians needs to look more closely at the correspondence sent between the king and his craftsmen and it argues this archival evidence provides a new contextual background with which to understand the changing forms of the Henrican local map.

The role of the nonionic surfactant Tween 80 on the behavior of the therapeutic recombinant protein Factor VIII (rFVIII) was investigated at solid/liquid and air/water interfaces. In order to provide a model system to compare results obtained for the complicated rFVIII-Tween system, a well-characterized globular protein lysozyme was used. The experimental scheme involved the introduction of the protein and Tween to the adsorption substrate in different manners, either lysozyme Tween together or in sequence as lysozyme followed by Tween or vice versa. It was observed that the addition of Tween together with lysozyme reduced the amounts adsorbed at hydrophobic surfaces, while no such reduction was observed on hydrophilic surfaces. A high Tween concentration was required to effect the removal of the lysozyme molecules from the hydrophobic surface and Tween was not effective in removing lysozyme from the hydrophilic surface at any concentration. These results suggest that the Tween-surface interaction is important in determining lysozyme adsorption. Similar observations were made for the rFVIII-Tween system at hydrophobic and hydrophilic silica interfaces. In this case, the presence of interfacial and solution Tween together resulted in complete prevention of rFVIII adsorption. Electrostatic forces were observed to be play an important role in rFVIII adsorption. The rFVIII-Tween interactions at solid interfaces were also evaluated using intrinsic fluorescence and biological activity measurements. Results obtained with respect rFVIII adsorbed mass, and structure or biological activity change upon adsorption, were evaluated in parallel. This parallel evaluation suggested that rFVIII adsorption on hydrophilic, negatively charged surfaces is likely to be highly ordered and oriented in a manner that retains the solvent accessibility of the active sites in rFVIII. On the other hand, rFVIII may adsorb to hydrophobic surfaces in different orientations, with a likelihood of surface induced unfolding. rFVIII-Tween interaction at the air/water interface was investigated separately. Surface tension data recorded for rFVIII-Tween mixtures suggested that Tween dominated the air/water interface as the Tween concentration was increased. Reduced interface-induced unfolding was observed at high Tween concentrations. These results were also thought to contribute to the reduction in rFVIII aggregation typically observed as a result of exposure to the air/water interface. / Graduation date: 2006

During atherosclerosis and restenosis, there is an extensive amount of collagen synthesis and degradation. Changes in the types of collagen present can have profound effects on vascular smooth muscle cell (SMC) proliferation and migration. Type VIII collagen, which is normally present at low levels within the mature vascular system, is greatly increased during atherogenesis. The central theme of this thesis is to determine the role of type VIII collagen in the pathogenesis of atherosclerosis and restenosis. In the first study, we demonstrated the importance of type VIII collagen in SMC migration and proliferation. SMCs from type VIII collagen-deficient mice display increased adhesion and decreased spreading, migration, and proliferation compared to SMCs from wild-type mice. Treatment of SMCs from type VIII collagen-deficient mice with exogenous type VIII collagen can rescue the defects. In the second study, we determined that type VIII collagen exerts its effects through regulation of MMP-2 expression. Type VIII collagen-deficient SMCs have decreased levels of MMP-2 and are impaired in chemotaxis toward PDGF-BB and in their ability to contract thick collagen gels. We found that decreasing endogenous MMP-2 levels in normal SMCs or adding exogenous collagen to type VIII collagen-deficient SMCs is sufficient to recapitulate the type VIII collagen-deficient or wild-type SMC phenotype, respectively. In the third study, we investigated the contribution of type VIII collagen to intimal hyperplasia after mechanical injury in the mouse. We found that type VIII collagen-deficient mice display a 35% reduction in intimal hyperplasia and attenuated vessel remodeling after femoral artery wire injury, establishing a role for type VIII collagen in restenosis. The results of the work presented in this thesis demonstrate that production of type VIII collagen confers an SMC phenotype with a greater propencity for proliferation and migration. These effects are in part mediated through regulation of MMP-2 expression and activation. We conclude that the increases in type VIII collagen production that occur during atherosclerosis and restenosis contribute to the capacity of SMCs to alter the existing extracellular matrix in a manner which permits enhanced migration.

During atherosclerosis and restenosis, there is an extensive amount of collagen synthesis and degradation. Changes in the types of collagen present can have profound effects on vascular smooth muscle cell (SMC) proliferation and migration. Type VIII collagen, which is normally present at low levels within the mature vascular system, is greatly increased during atherogenesis. The central theme of this thesis is to determine the role of type VIII collagen in the pathogenesis of atherosclerosis and restenosis. In the first study, we demonstrated the importance of type VIII collagen in SMC migration and proliferation. SMCs from type VIII collagen-deficient mice display increased adhesion and decreased spreading, migration, and proliferation compared to SMCs from wild-type mice. Treatment of SMCs from type VIII collagen-deficient mice with exogenous type VIII collagen can rescue the defects. In the second study, we determined that type VIII collagen exerts its effects through regulation of MMP-2 expression. Type VIII collagen-deficient SMCs have decreased levels of MMP-2 and are impaired in chemotaxis toward PDGF-BB and in their ability to contract thick collagen gels. We found that decreasing endogenous MMP-2 levels in normal SMCs or adding exogenous collagen to type VIII collagen-deficient SMCs is sufficient to recapitulate the type VIII collagen-deficient or wild-type SMC phenotype, respectively. In the third study, we investigated the contribution of type VIII collagen to intimal hyperplasia after mechanical injury in the mouse. We found that type VIII collagen-deficient mice display a 35% reduction in intimal hyperplasia and attenuated vessel remodeling after femoral artery wire injury, establishing a role for type VIII collagen in restenosis. The results of the work presented in this thesis demonstrate that production of type VIII collagen confers an SMC phenotype with a greater propencity for proliferation and migration. These effects are in part mediated through regulation of MMP-2 expression and activation. We conclude that the increases in type VIII collagen production that occur during atherosclerosis and restenosis contribute to the capacity of SMCs to alter the existing extracellular matrix in a manner which permits enhanced migration.

Reproduction de : Thèse de doctorat : Philosophie : Paris 8 : 2007. / Titre provenant de l'écran-titre. Bibliogr. f. 201-211. Index.

Thesis (M.S.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 42-44). Also available on the World Wide Web.

A hemofilia A (HA) é uma doença hemorrágica hereditária ligada ao cromossomo X, causada pela atividade reduzida ou ausente do fator VIII da coagulação (FVIII). Essa doença é o resultado de mutações heterogêneas no gene do FVIII. A identificação das mutações patogênicas é importante para o aconselhamento genético e para a avaliação das manifestações clínicas. Embora mais de 700 mutações no gene já tenham sido descritas como responsáveis pela HA grave (nível de FVIII <1%), não existem dados a respeito na população do Rio Grande do Sul. O objetivo desse trabalho é a identificação das alterações genéticas em 48 pacientes hemofílicos graves, de diferentes famílias, com resultado negativo para a presença das inversões nos íntrons 22 e 1. Tais inversões são as mutações mais comumente encontradas (40-50% e 5%, respectivamente) em hemofílicos A graves. Todos os pacientes foram analisados para a presença de grandes deleções por PCR multiplex, utilizando-se 35 pares de primers que abrangem os 26 éxons e as regiões 5’ e 3’UTR do gene. Os pacientes que não apresentaram grandes deleções foram analisados por sequenciamento direto dos exons. As variações nas sequências foram verificadas com os softwares Codon Code Aligner e MEGA5.04, para realizar alinhamentos múltiplos e para analisar a tradução da proteína mutada. O software PolyPhen-2 foi utilizado para verificar se as mutações alterariam a estrutura e a função da proteína; o software SDM foi utilizado para verificar se as mutações alterariam a estabilidade da proteína. Uma figura com a localização das mutações no gene do FVIII foi desenhada com o programa Pymol. Foram encontradas em 70% dos pacientes: uma grande deleção (incluindo os éxons 4, 5 e 6), nove pequenas deleções, cinco pequenas inserções, oito mutações de sentido trocado e seis mutações sem sentido, das quais treze são recorrentes e dezesseis são novas mutações, não descritas no banco de dados online HAMSTeRS. Quarenta e quatro por cento dos indivíduos com mutação encontrada desenvolveram inibidores, sugerindo um maior risco de desenvolvimento de inibidores em pacientes com grandes deleções, mutações sem sentido e pequenas deleções/inserções, quando comparado com pacientes com mutações de troca de sentido. Entre outras mutações de efeito evidente, foram encontradas duas mutações (D542G e S109P) que podem interferir em sítios de ligação ao cálcio, uma mutação (P2205R) que pode ser prejudicial à interação entre o FVIII e o fator de von Willebrand (FvW) e uma mutação (L2297R), que altera a superfície eletrostática da proteína. Esses dados contribuem para o melhor entendimento da funcionalidade e da estrutura do FVIII. / Hemophilia A (HA) is an X-linked inherited bleeding disorder caused by reduced or absent clotting factor VIII (FVIII) activity, determined by heterogeneous mutations in the FVIII gene. Identification of these pathogenic mutations is important for genetic counseling and the assessment of clinical manifestations. Although more than 700 mutations of the FVIII gene have been reported as responsible for severe hemophilia (FVIII: C<1%), the corresponding data is currently insufficient for Southern Brazilian populations. The aim of this study was to identify genetic changes in 48 unrelated severe HA patients, who showed negative results for inversions in introns 22 and 1. These inversions are the most common mutations (40-50% and 5%, respectively) in severe HA patients. All patients were screened for gross deletions by multiplex PCR, with 35 pairs of primers for the 26 exons and 5’- and 3’- UTR of the gene. Those without any gross deletion were then analyzed by direct sequencing for all exons. Sequence variation was analyzed with the Codon Code Aligner and the Mega0.4 softwares for multiple alignments and protein translation. PolyPhen-2 was used to predict if the mutations would alter protein’s structure and function; SDM was used to verify if the mutations would alter the protein stability. One image with the location of FVIII mutations was drawn with the Pymol software. In 70% of the patients one gross deletion (including exons 4, 5 and 6), nine small deletions, five small insertions, eight missense and six nonsense mutations were found, of which thirteen were recurrent and sixteen were novel, never reported in the HAMSTeRS database. Forty-four per cent of these mutation carriers developed FVIII inhibitors, suggesting a higher risk of inhibitors development in patients with large deletions, small deletions/insertions, and nonsense mutations than in patients with missense mutations. Among mutations of clear effect, two mutations (D542G and S109P) that may interfere with calcium binding, a mutation that may affect FVIII and von Willebrand factor (FvW) interaction (P2205R), and L2297R, that clearly affects the molecule’s electrostatic surface were found. The results enable us to better understand structural and functional aspects of this protein.

Introdução: A Hemofilia A (HA) é a doença hemorrágica ligada ao X mais freqüente na população mundial, causada por alterações no fator VIII (FVIII), afetando 1:5000 nascimentos masculinos. A forma grave dessa doença é encontrada em 50% dos pacientes e é caracterizada por intensos episódios hemorrágicos. O principal problema no tratamento desses pacientes é o desenvolvimento de anticorpos que neutralizam o FVIII infundido, chamados de inibidores contra o FVIII. Alterações estruturais no gene do fator VIII são possíveis fatores de risco ao desenvolvimento de inibidores. Duas inversões (Inv1 e Inv22) são as mais freqüentes e ocorrem exclusivamente em famílias de pacientes com HA grave, afetando cerca de 50% das famílias. Outros fatores genéticos e ambientais estão descritos na literatura como candidatos a fatores de risco ou associados com a produção de anticorpos contra o FVIII. Objetivos: Estabelecer as freqüências dessas inversões em hemofílicos graves do Rio Grande do Sul e verificar a associação entre o desenvolvimento dos inibidores e a presença das inversões nos pacientes, bem como estudar outros fatores relacionados ao surgimento dos inibidores. Metodologia: Foram entrevistadas e estudadas 158 famílias não aparentadas, representadas por 229 pacientes com hemofilia A graves (<1% FVIII) provenientes dos centros de hemoterapia do Rio Grande do Sul (Hemocentro-RS) que aceitaram livremente participar desse estudo. A partir disso, os pacientes foram genotipados para as duas inversões. Desses, foram dosados inibidores de 136 famílias (168 pacientes). Resultados: As freqüências das inversões do intron 1 e 22 nas famílias foram de aproximadamente 4% e 45%, respectivamente, estando essas de acordo com as freqüências de outras populações mundiais. Não foi encontrada uma associação estatisticamente significativa entre o surgimento de inibidores e a presença das inversões nos pacientes. Outros possíveis fatores de risco como tipo de tratamento, a etnia e a idade dos pacientes, a dose administrada de FVIII, a duração do tratamento e a presença de infecções virais crônicas foram também estudados. Quando analisados em separado, o tempo de uso de FVIII, a utilização de crioprecipitado, a dose do fator e a idade dos pacientes estão associados com desenvolvimento de inibidores, porém quando analisados em conjunto em um modelo preditor da formação de inibidores esse modelo fornece resultados não significativos. Conclusões: Esse estudo constitui-se em uma primeira aproximação ao problema, que é complexo; a continuação das pesquisas, agora envolvendo também fatores específicos do sistema imune dos pacientes, poderá fornecer dados mais conclusivos. / Introduction: Hemophilia A (HA) is the most common sex-linked bleeding disorder caused by genetic changes in factor VIII, affecting 1:5000 male births. Severe HA is the most frequent form and occur in 50% of the patients and is characterized by intense hemorragic episodes. The main problem in the treatment of these patients is the development of FVIII antibodies that neutralize the infused FVIII, called FVIII inhibitors. Structural alterations in the factor VIII gene are possible risk factors for the development of inhibitors. Two inversions (Inv1 and Inv22) are the most frequent and they occur exclusively in patients of families with severe HA, affecting about 50% of the families. Other genetic and environmental factors are described in the literature as candidates to risk factors or as being associated with the production of FVIII antibodies. Objectives: To establish the frequencies of these inversions in Rio Grande do Sul and to verify the association between the development of the inhibitors and the presence of the inversions in the patients, as well as to study other factors related to the appearance of the inhibitors. Patients and Methods: The study was carried out on 158 unrelated families, represented by 229 patients with severe HA (<1% FVIII) ascertained from Rio Grande do Sul’s centers of hemotherapy (Hemocentro-RS) that freely accepted to participate in the investigation. The patients were genotyped for the two inversions, and their inhibitor levels tested in 136 families (168 patients). Results: Intronn 1 and 22 inversion frequencies were approximately 4% and 45%, in agreement with those reported for other world populations. No statistically significant association between the occurrence of inhibitors and the presence of these inversions in the patients was found. Other possible risk factors as the type of treatment, ethnic group, patients' age, administered FVIII dose, duration of treatment and the presence of chronic viral infections were also studied. When separately analyzed, duration of FVIII, treatment, cryoprecipitate use, the factor dose and the patients' age are associated with inhibitor development, but when analyzed together in a model of inhibitors formation prediction the model yields non-significant results. Conclusions: This study is a first approximation to this complex problem; the continuation of the research, now involving also specific factors of the patient’s immune system, could furnish more conclusive data.

Submitted by Nuzia Santos (nuzia@cpqrr.fiocruz.br) on 2016-06-29T16:33:37Z No. of bitstreams: 1 Tese_BCM_AmandaCassette_CPqRR2016.pdf: 28401284 bytes, checksum: 5f5576e6c7cbda5f18321ed6b3dbad38 (MD5) / Approved for entry into archive by Nuzia Santos (nuzia@cpqrr.fiocruz.br) on 2016-06-29T16:33:51Z (GMT) No. of bitstreams: 1 Tese_BCM_AmandaCassette_CPqRR2016.pdf: 28401284 bytes, checksum: 5f5576e6c7cbda5f18321ed6b3dbad38 (MD5) / Made available in DSpace on 2016-06-29T16:33:51Z (GMT). No. of bitstreams: 1 Tese_BCM_AmandaCassette_CPqRR2016.pdf: 28401284 bytes, checksum: 5f5576e6c7cbda5f18321ed6b3dbad38 (MD5) Previous issue date: 2016 / Made available in DSpace on 2016-07-22T13:27:36Z (GMT). No. of bitstreams: 3 Tese_BCM_AmandaCassette_CPqRR2016.pdf.txt: 2885 bytes, checksum: 53b9b6cc9653fe21e615e546bbbab789 (MD5) Tese_BCM_AmandaCassette_CPqRR2016.pdf: 28401284 bytes, checksum: 5f5576e6c7cbda5f18321ed6b3dbad38 (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2016 / Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil / A hemofilia A (HA) congênita é um distúrbio hemorrágico com transmissão hereditária ligado a deficiência do fator VIII (FVIII). O tratamento da HA é baseado na reposição do FVIII, requerendo infusões intravenosas de concentrados de FVIII exógeno. Durante o tratamento, alguns pacientes desenvolvem uma resposta imune que produz anticorpos anti-FVIII (inibidores). Os inibidores neutralizam a atividade procoagulante do FVIII e diminuem a eficiência do tratamento. Apesar da relevância dos inibidores, os mecanismos imunológicos associados aos inibidores ainda não foram completamente elucidados. Neste trabalho analisou-se o perfil de citocinas intracitoplasmáticas de células do sistema imune inato e adaptativo de pacientes com HA e inibidores [HA-FVIII(+)] e com HA sem inibidores [HA-FVIII(−)]. Os resultados mostraram uma menor frequência de monócitos e neutrófilos TNF-, monócitos IL-5eneutrófilos IL-4e uma maior frequência de neutrófilos linfócitos T CD4+, T CD8+e T CD19+IL-10em pacientes do grupo HAα-FVIII(+). Em pacientes do grupo HAα-FVIII(−) observou-se uma maior frequência de monócitos TNF-elinfócitos B IL-4e uma menor frequência de linfócitos T CD4+e T CD8+IL-10. Observou-se o predomínio de um padrão anti-inflamatório/regulador no grupo HAα-FVIII(+) e um padrão pró-inflamatório no grupo HAα-FVIII(−), sugerindo que o microambiente celular pode ser um elemento importante associado à capacidade de desenvolvimento de inibidores. Analisou-se também a presença de micropartículas plasmáticas (MPs) em pacientes com HA. Os resultados mostraram uma maior frequência de MPs derivadas de células endoteliais, granulócitos e linfócitos T em pacientes do grupo HAα-FVIII(−) e uma maior frequência de MPs derivadas de hemácias em pacientes do grupo HAα-FVIII(+). O predomínio de MPs no grupo HAα-FVIII(−) pode ser relacionado ao aumento da ativação celular e influência do microambiente pró-inflamatório. MPs derivadas de hemácias induziram a investigação da presença de anticorpos em hemácias de pacientes com HA. Os resultados demonstraram que pacientes do grupo HAα-FVIII(+) têm uma maior frequência de anticorpos na superfície de hemácias. Em função deste resultado, investigou-se a presença de anticorpos anti-FVIII em concentrados de hemácias de pacientes do grupo HA-FVIII(+). Foi possível detectar anticorpos anti-FVIII em concentrados de hemácias, sugerindo que essas células podem interagir com anticorpos anti-FVIII. Determinou-se ainda, a avidez de anticorpos anti-FVIII de pacientes do grupo HAα-FVIII(+). Os resultados demonstraram avidez superior de anticorpos IgG total e IgG1 anti-FVIII quando comparados a IgG4. Foi observada também uma correlação negativa entre os índices de avidez de anticorpos IgG4 anti-FVIII de pacientes grave saos títulos de Bethesda, sugerindo que existem variações na avidez dos anticorpos anti-FVIII dependendo do perfil dos pacientes com HA. No contexto da avaliação da resposta imune contra o FVIII, foi possível identificar biomarcadores fenotípicos celulares e humorais característicos de pacientes com e sem inibidores que podem contribuir para o monitoramento do desenvolvimento e manutenção de anticorpos inibidores do FVIII / Congenital hemophilia A (HA) is a bleeding disorder with hereditary transmission associated to deficiency of factor VIII (FVIII). The treatment of HA is based on replacement of FVIII, requiring exogenous FVIII intravenous infusions. During the treatment some patients develop an immune response that produces anti-FVIII antibodies (inhibitors). Inhibitors neutralize the procoagulant activity of FVIII and affect the treatment efficiency. Despite the relevance of inhibitors, the immunological mechanisms associated to inhibitors are still unknown. In this work, the intracytoplasmic cytokine pattern of innate and adaptive cells from patients with HA and inhibitors [HAα-FVIII(+)] and with HA and without inhibitors [HAα-FVIII(−)] was analyzed. Results showed a lower frequency of TNF-α+monocytes and neutrophils, IL-5+ monocytes and IL-4+neutrophils and an increased frequency of IL-10+neutrophils, lymphocytes T CD4+, T CD8+and T CD19+in HAα-FVIII(+) group. In HAα-FVIII(−) group was observed an increased frequency of TNF-α+monocytes and IL-4+lymphocytes B and a lower frequency of IL-10+lymphocytes T CD4+and T CD8+. A predominance of an anti-inflammatory/regulatory pattern in HAα-FVIII(+) patients and a mixed pattern, with a bias toward inflammatory cytokine profile, in HAα-FVIII(−) patients was observed. The occurrence of these profiles seems to be associated to the capacity of inhibitors development. The presence of plasmatic microparticles (MPs) in HA patients was also analyzed. The results showed increased levels of circulating MPs derived from endothelial cells, granulocytes, and T lymphocytes in patients without FVIII inhibitors and MPs from erythrocytes were higher in patients with inhibitors. The predominance of MPs in HAα-FVIII(−) patients probably was provided by the increased of cellular activation due to an inflammatory microenvironment. MPs from erythrocytes induced to the investigation of the presence of antibodies in the surface of erythrocytes of HA patients. The results demonstrated that HAα-FVIII(+) patients have a higher frequency of antibodies in the surface of erythrocytes. Due to this result, the presence of anti-FVIII antibodies in erythrocytes concentrates in HAα-FVIII(+) patients was investigated. It was possible to detect anti-FVIII antibodies in erythrocytes concentrates, suggesting that FVIII can interact with anti-FVIII antibodies. The avidity of anti-FVIII antibodies in HAα-FVIII(+) patients was also determined. Results demonstrated a high avidity of anti-FVIII total IgG and IgG1 antibodies when compared to IgG4. A negative correlation between the avidity of anti-FVIII IgG4 antibodies in severe patients and Bethesda titer was observed, suggesting that there are variations in the avidity of anti-FVIII antibodies depending on the profile of HA patients. In the context of the evaluation of the immune response directed to FVIII, it was possible to identify phenotypic cellular and humoral biomarkers profiles of patients with and without inhibitors, thereby contributing to tracking the development and maintenance of FVIII inhibitors antibodies.

Foi realizada inicialmente uma revisão sobre o processo de hemostasia, as características da hemofilia A, e os fatores que influem na formação de inibidores contra o Fator VIII, um dos principais problemas na terapêutica de reposição do mesmo em hemofílicos A graves. Posteriormente, visando verificar possíveis suscetibilidades genéticas no desenvolvimento de tais anticorpos, foram descritos estudos envolvendo 154 hemofílicos A graves localizados no Rio Grande do Sul, 47 com e 107 sem inibidores. A pesquisa envolveu 10 polimorfismos em cinco sistemas relacionados à resposta imune (IL4, IL4R, IL10, TNFα e TNFR1). Três desses polimorfismos (IL4R 1902A>G, TNFα -863A>C, e TNFR1 303A>G) nunca haviam sido estudados dentro desse contexto. Não foram observadas diferenças estatisticamente significativas nas prevalências desses polimorfismos entre as duas séries, em concordância com algumas, mas não todas as investigações prévias. A questão de por que alguns pacientes desenvolvem tais inibidores, mas outros não, permanece em aberto. / A review was initially made on the hemostatic process, the characteristics of hemophilia A, and the factors that influence the formation of inhibitors against Factor VIII, one of the main problems that exist in the therapeutics of its replacement in severe hemophilia A patients. Afterwords, in an attempt to verify possible genetic susceptibilities in the development of such antibodies, a description was made of studies involving 154 severe hemophilia A subjects living in Rio Grande do Sul, 47 with and 107 without inhibitors. The research included 10 polymorphisms in five systems related to the immune response (IL4, IL4R, IL10, TNFα and TNFR1). Three of them (IL4R 1902A>G, TNFα -863A>C, and TNFR1 303A>G) had never been studied in this context. No statistical significant differences were found between the two series, in agreement with some, but not all previous investigations. The question of why some, but not all severe hemophilia A patients develop anti-Factor VIII antibodies remain open.