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Le premier objectif de cette thèse était de déterminer les effets isolés et combinés de l'alpha thalassémie, des polymorphismes inducteurs (QTLs) de l'HbF et du génotype G6PD dans un contexte d'évolution naturelle de la drépanocytose (Etudes 1 et 2). L'étude 1 a permis d'évaluer pour la première fois les fréquences alléliques de ces gènes modificateurs chez 301 enfants sénégalais SS. Contrairement aux autres populations africaines, le Variant Betica de la G6PD était majoritaire par rapport au variant A(-). De plus, 12% de notre cohorte avait un déficit en G6PD combiné à une absence d'alpha-thalassémie. Ces patients-là seront à privilégier pour la réalisation d'un Doppler transcrânien. Les résultats obtenus dans l'étude 2 nous ont permis de conclure que l'alpha-thalassémie et les QTLs de l'HbF sont interdépendants et ne doivent pas être étudiés séparément pour une prédiction clinique précise. En effet, une combinaison d'alpha-thalassémie avec au moins 2 QTLs de l'HbF est nécessaire pour retarder de manière significative la première complication de la maladie. Cependant, une alpha-thalassémie homozygote, même associée à 3 à 6 QTLs de l'HbF, augmente la fréquence des CVO pendant l'enfance. Par conséquent, une alpha-thalassémie hétérozygote avec au moins deux QTL HbF constituerait le génotype le plus favorable relativement à la survenue des CVO. Le deuxième objectif de cette thèse était d'étudier les interrelations entre le stress oxydant (phénotype et génotype) et la sévérité clinique de la maladie (Etudes 3 à 4). La drépanocytose est caractérisée par un stress oxydatif élevé pouvant expliquer une partie des manifestations cliniques. Nos résultats ont montré que l'alpha-thalassémie homozygote semble diminuer le stress oxydatif, ce qui contribuerait à son effet protecteur sur certaines complications du sous-phénotype hémolytique. En outre, les patients qui ont le moins d'hospitalisations et de CVO semblent présenter une meilleure défense antioxydante (activités catalase et GPx augmentées). Dans l'étude 4 nous avons étudié 4 SNPs de gènes du stress oxydant (rs4880 du gène SOD2, rs207454 du gène XO, rs233322 du gène MPO et rs35652124 du gène NFE2L2). Le SNP rs4880 aurait un effet favorable au niveau biologique (réticulocytose moindre, activité GPx augmentée) mais sans traduction clinique associée. Il en est de même pour rs233322 qui serait associé à une hémolyse et à un stress oxydatif (AOPP) plus importants. En revanche, une tendance à un effet protecteur de rs207454 vis-à-vis de certaines complications (hospitalisations, ostéonécrose, sepsis, STA) a été observée. Notre travail contribue à la compréhension de l'impact des gènes modificateurs dans la drépanocytose. Il pourrait donc permettre, via une sélection positive des patients à risque, d'améliorer la prise en charge de la maladie dans les pays où les traitements de fond (hydroxyurée, doppler transcrânien, échanges transfusionnels) ne peuvent être proposés à tous / The primary objective of this thesis was to determine the isolated and combined effects of alpha-thalassemia, inductors polymorphisms (QTLs) of HbF and genotype G6PD in a context of natural progression of sickle cell disease (Studies 1 and 2). Study 1 was undertaken to evaluate for the first time the allelic frequencies of these modifiers genes in 301 Senegalese SS children. Unlike other African populations, the G6PD Betica Variant was predominant over the A (-) variant. In addition, 12% of our cohort had G6PD deficiency combined with no alpha-thalassemia. These patients will be favoured for the realization of a transcranial doppler. The results obtained in Study 2 allowed us to conclude that alpha thalassemia and QTLs of HbF are interdependent and should not be studied separately for accurate clinical prediction. Indeed, a combination of alpha thalassemia with at least 2 QTLs of HbF is required to significantly delay the first complication of the disease. However, a homozygous alpha thalassemia, even associated with 3 to 6 QTLs of HbF, increases the frequency of CVOs during childhood. Therefore, a heterozygous alpha-thalassemia with at least two QTL HbFs would be the most favourable genotype for the occurrence of CVOs. The second objective of this thesis was to study the interrelationships between oxidative stress and the clinical severity of the disease (Studies 3 to 4). Sickle cell disease is characterized by high oxidative stress that may explain some of the clinical manifestations. Our results showed that homozygous alpha-thalassemia appears to reduce oxidative stress, which would contribute to its protective effect on certain complications of the hemolytic sub-phenotype. In addition, patients with the least hospitalization and CVO appear to have better antioxidant defense (catalase and GPx activities increased). In Study 4 we studied 4 SNPs of oxidative stress genes (rs4880 of the SOD2 gene, rs207454 of the XO gene, rs233322 of the MPO gene and rs35652124 of the NFE2L2 gene). The rs4880 SNP would have a favourable effect on the biological level (less reticulocytosis, increased GPx activity) but without associated clinical translation. The same is true for rs233322, which is associated with greater haemolysis and oxidative stress (AOPP). On the other hand, a tendency to a protective effect of rs207454 for some complications (hospitalizations, osteonecrosis, sepsis, STA) was observed. Our work contributes to the understanding of the impact of modifiers genes in sickle cell disease. It could therefore, through a positive selection of at-risk patients, improve the management of the disease in countries where the basic treatments (hydroxyurea, transcranial doppler, blood transfusion) cannot be offered to all

Objetivo: Comparar o tratamento cirúrgico convencional das varizes de membros inferiores com a escleroterapia com espuma ecoguiada nos pacientes com úlcera venosa. Como objetivo secundário, foi comparada a incidência de complicações com os métodos empregados e a melhora na qualidade de vida após a realização dos procedimentos. Casuística e Métodos: Foi realizado um estudo randomizado e prospectivo de 49 pacientes com úlceras ativas (C6), que foram submetidos ao tratamento cirúrgico (28 membros) ou escleroterapia espuma (23 membros), tendo como desfechos a cicatrização de úlceras de origem venosa, complicações do tratamento e qualidade de vida,. Os pacientes completaram o Questionário Aberdeen Veias Varicosas (QAVV), o escore de severidade clínica venoso (ESCV) e o Escore de Incapacidade Venosa (EIV). Resultados: A média e desvio padrão de acompanhamento foi de 502 ± 220 dias. A úlcera cicatrizou em 100% e 91,3% dos doentes tratados com cirurgia ou escleroterapia espuma, respectivamente (P > 0,05). QAVV, ESCV e EIV melhoraram em ambos os grupos após o tratamento. Não houve diferenças significativas no resultado final do QAVV, ESCV e EIV entre os dois grupos, vários meses após os procedimentos (p = 0,45, 0,58 e 0,66, respectivamente; Mann- Whitney U). As complicações ocorreram em 14,2% e 13,0% nos grupos cirúrgico e escleroterapia com espuma, respectivamente. Conclusão: A escleroterapia com espuma não foi inferior ao tratamento cirúrgico de úlceras venosas. Portanto a escleroterapia é uma alternativa ao tratamento cirúrgico, particularmente adequada para pacientes de alto risco cirúrgico que apresentam insuficiência venosa avançada e úlcera ativa / Objective: To compare the results of varicose vein treatment using ultrasoundguided foam sclerotherapy versus conventional surgery in patients with venous ulcers. As a secondary outcome, we compared the incidence of complications related to the employed technique and improvements in quality of life after the procedures. Methods: A randomized and prospective study was conducted in 49 patients with active venous ulcers (C6), submitted to surgical treatment (28 limbs) or foam sclerotherapy (23 limbs). The primary outcomes analysed included healing of venous ulcer, treatment complications and improvements in quality of life. All patients completed the Aberdeen Varicose Veins Questionnaire (AVVQ), the Venous Clinical Severity score (VCSS) and Venous Disability Score (VDS). Results: The mean and standard deviation follow-up was 502 ± 220 days. Ulceration healing was observed in 100% and 91.3% of patients treated with surgery or foam sclerotherapy, respectively (P > 0.05). AVVQ, VCSS and VDS improved in both groups following treatment. There were no significant differences in AVVQ, VCSS and VDS between the two groups several months after the procedures (p = 0,45, 0.58 and 0.66, respectively; Mann-Whitney U test). Complications occurred in 14.2% and 13.0% in the surgical and foam sclerotherapy groups, respectively. Conclusion: Sclerotherapy was non-inferior to surgical treatment in the management of venous ulcers. Therefore sclerotherapy can be considered an alternative to surgical treatment, especially in high surgical risk patients presenting with advanced venous insufficiency and an active ulcer

Objetivo: Comparar o tratamento cirúrgico convencional das varizes de membros inferiores com a escleroterapia com espuma ecoguiada nos pacientes com úlcera venosa. Como objetivo secundário, foi comparada a incidência de complicações com os métodos empregados e a melhora na qualidade de vida após a realização dos procedimentos. Casuística e Métodos: Foi realizado um estudo randomizado e prospectivo de 49 pacientes com úlceras ativas (C6), que foram submetidos ao tratamento cirúrgico (28 membros) ou escleroterapia espuma (23 membros), tendo como desfechos a cicatrização de úlceras de origem venosa, complicações do tratamento e qualidade de vida,. Os pacientes completaram o Questionário Aberdeen Veias Varicosas (QAVV), o escore de severidade clínica venoso (ESCV) e o Escore de Incapacidade Venosa (EIV). Resultados: A média e desvio padrão de acompanhamento foi de 502 ± 220 dias. A úlcera cicatrizou em 100% e 91,3% dos doentes tratados com cirurgia ou escleroterapia espuma, respectivamente (P > 0,05). QAVV, ESCV e EIV melhoraram em ambos os grupos após o tratamento. Não houve diferenças significativas no resultado final do QAVV, ESCV e EIV entre os dois grupos, vários meses após os procedimentos (p = 0,45, 0,58 e 0,66, respectivamente; Mann- Whitney U). As complicações ocorreram em 14,2% e 13,0% nos grupos cirúrgico e escleroterapia com espuma, respectivamente. Conclusão: A escleroterapia com espuma não foi inferior ao tratamento cirúrgico de úlceras venosas. Portanto a escleroterapia é uma alternativa ao tratamento cirúrgico, particularmente adequada para pacientes de alto risco cirúrgico que apresentam insuficiência venosa avançada e úlcera ativa / Objective: To compare the results of varicose vein treatment using ultrasoundguided foam sclerotherapy versus conventional surgery in patients with venous ulcers. As a secondary outcome, we compared the incidence of complications related to the employed technique and improvements in quality of life after the procedures. Methods: A randomized and prospective study was conducted in 49 patients with active venous ulcers (C6), submitted to surgical treatment (28 limbs) or foam sclerotherapy (23 limbs). The primary outcomes analysed included healing of venous ulcer, treatment complications and improvements in quality of life. All patients completed the Aberdeen Varicose Veins Questionnaire (AVVQ), the Venous Clinical Severity score (VCSS) and Venous Disability Score (VDS). Results: The mean and standard deviation follow-up was 502 ± 220 days. Ulceration healing was observed in 100% and 91.3% of patients treated with surgery or foam sclerotherapy, respectively (P > 0.05). AVVQ, VCSS and VDS improved in both groups following treatment. There were no significant differences in AVVQ, VCSS and VDS between the two groups several months after the procedures (p = 0,45, 0.58 and 0.66, respectively; Mann-Whitney U test). Complications occurred in 14.2% and 13.0% in the surgical and foam sclerotherapy groups, respectively. Conclusion: Sclerotherapy was non-inferior to surgical treatment in the management of venous ulcers. Therefore sclerotherapy can be considered an alternative to surgical treatment, especially in high surgical risk patients presenting with advanced venous insufficiency and an active ulcer