Dissertations / Theses: 'Sickle cell disease treatment'

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Al, Balushi Halima. "Novel approach towards pathogenesis and treatment of sickle cell disease." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288739.

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Sickle cell disease (SCD) is one of the most common genetic diseases worldwide. HbS polymerisation causes altered red blood cell (RBC) rheology and fragility, increase in blood viscosity with blockage of small blood vessels, and RBC membrane permeability changes. Excessive levels of cell-free Hb, high autoxidation of Hb, contribute to the production of reactive oxygen species (ROS) in SCD patients. In this work, oxidants showed direct and indirect effects on the main cation permeability pathways involved in dehydration of HbS/S RBCs - Psickle, the Gardos channel and the KCl cotransporter (KCC) - and thus on RBC volume causing polymersation. Psickle and Gardos channel activities showed significant correlation, consistent with the hypothesis that Ca2+ entry via Psickle causes activation of the Ca2+-dependent K+ channel. Treatment of SCD remains inadequate relying on the blood transfusion and supportive therapy depending on the organ affected. In the present study antioxidants and aromatic aldehydes showed some promising results towards future alternative treatments for SCD. Antioxidants showed inhibitory effects on the cation permeability pathways leading to inhibition of polymerisation and haemolysis and thus maintained RBC volume. Aromatic aldehydes interact with HbS and are usually given to increase oxygen affinity, thereby reducing its tendency to polymerise. GBT1118 had a marked inhibitory effect on all three cation permeability pathways. It reduced sickling, Psickle and Gardos activity. It inhibited KCC by affecting the regulatory protein phosphorylation cascade. It maintained RBC hydration, and stabilised RBCs. Historically Oman was the principal trading port of the Persian Gulf region, resulting in the complex mix of social and ethnic backgrounds. In 1989 a second mutation in the β chain of Hb, at position β121 was found in an Omani patient in addition to the usual HbS mutation at the β6 position, and termed HbS-Oman. At low percentage of HbS-Oman patients show severe SCD symptoms. Despite RBCs containing at most 25% HbS-Oman, there was high sickling percentage and K+ permeability showed many features similar to those seen in homozygous HbS/S patients. The presence of α thalassaemia was protective and represents an obvious potential prognostic marker for this rare SCD genotype. Overall, the present work contributes to elucidation of the pathogenesis of SCD, suggests approaches to the development of novel therapies and increases our understanding of a rare SCD genotype, HbS-Oman.

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Battle, Charity Michelle. "Comparing and contrasting different treatment modalities of sickle cell disease." Thesis, Boston University, 2012. https://hdl.handle.net/2144/31506.

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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.
Sickle cell disease (SCD) is an autosomal recessive disorder affecting over 70,000 people in the United States. Following deoxygenation, red blood cells become deformed and appear in the characteristic sickle-shape. This change in protein structure leads to vasa-occlusive episodes, which may result in a variety of clinical manifestation including, but not limited to, painful crisis, stroke, acute chest syndrome, and/or splenic infarct. Due to the diversity of symptoms, management of this disease can be complex.In SCD, some of the treatment modalities involve controlling infections, pain management, fetal hemoglobin stimulation, blood transfusion, hematopoietic stem cell transplant and potentially gene therapy. This paper discusses the risk and benefits of these different treatment modalities.
2031-01-01

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Gilmore, Annette. "Feasibility and utility of a sickle cell disease registry for research and patient management." Thesis, Brunel University, 2009. http://bura.brunel.ac.uk/handle/2438/4445.

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This thesis aimed to evaluate the feasibility and utility of a sickle cell disease registry for clinical patient management and research. Five hospitals out of nine in the North West London health region participated in the registry, with 78 percent coverage of the sickle cell disease population. There was 80% case ascertainment in participating hospitals. Aggregated anonymised demographic and diagnostic data was collected for all haemoglobinopathy patients. This provided the core dataset for quantifying prevalence of sickle cell and thalassaemia and mapping local hospital workloads and service requirements. Thirteen percent of HbSS adult patients were taking hydroxycarbamide. The cohort of patients treated with hydroxycarbamide was evaluated. Sixty two of the 80 patients started on treatment were included. Follow-up was censored after 9 years, totalling 249 person-years of data with a median follow-up of three years (IQR, 1-6). Results showed that haematological benefits were maintained in the long-term with treatment, but evidence of long-term clinical effectiveness was less strong. This appeared to be due to the patterns of clinical management in everyday practice. Patients tend to be treated with modest doses of hydroxycarbamide due to intolerance or inability to attain or maintain maximum tolerated dose. For example maximum tolerated dose was the aim of treatment for 91% of patients but it was achieved for 65% of participants. Non- compliance with treatment and monitoring schedule was the main reason for non- attainment. Results suggest that it is sensible to strive for maximum tolerated dose to ensure therapy remains effective, but with more realistic expectations of the dose patients can attain and maintain. Doses in adult patients average 20mg/kg/day and 25mg/kg/day in children. Adult patients may be able to achieve a higher dose, if there was more stringent monitoring and improved management of non-compliance. The North West London HU Sub-Registry proved useful for measuring long-term effectiveness and tolerability of hydroxycarbamide. Routinely collected data was utilized for both clinical management and research purposes. The novelty lay in examination of the nuances of routine clinical practice. An electronic patient record was developed as a clinical management tool. It is the first study reporting long-term outcomes for UK sickle cell disease patients on hydroxycarbamide. Findings should help clinicians devise effective treatment protocols and strategies for managing patients commenced on this therapy. Interventions need to be targeted at increasing utilisation, patient adherence and persistence with treatment. The electronic patient record could be used to maximise treatment benefit and improve adherence. More effective involvement of the multidisciplinary team and primary care colleagues in patient education and management should improve usage. Patients and carers need up to date and easy to assimilate information to make informed decisions about treatment options. Maintaining a SCD registry is challenging. Models which operate as clinical information systems provide an incentive for participation. These enable active involvement of local care providers in registry management and the ability to keep and utilize their own data. Clinicians require accurate and current data for patient management and to enable them to benchmark their local outcomes against national outcomes and care standards.

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Busbee, Paula. "Geographical Effects on Adult Sickle Cell Disease Treatments, Morbidity, and Mortality." ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2641.

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A small percentage of patients with sickle cell disease (SCD) have experienced an increase in life span by 10 years, while others with the same disease continue to die prematurely. The purpose of the study was to evaluate whether or not regional location was a barrier to care for adults with SCD in relation to emergency department visits and health outcomes at 16 and 21 years after the approval of hydroxyurea therapy as treatment. Secondary data were sourced and a retrospective quantitative correlational design was used to examine the effect of hydroxyurea treatment approval on emergency department visits and mortality (dependent variables) with changes in the regions for Northeast, Midwest, South, and West (independent variables). Insurance status, age, gender, and income level (covariables) were employed to describe the population. Chi-Square analysis was used to examine the association of the variables and sample sizes provided by the HCUP datatsets; Nationwide Inpatient Sample (NIS) 2006 (n=67,214), NIS 2011 (n=80,040), Nationwide Emergency Department Sample (NEDS) 2006 (n=164,698), and NEDS 2011 (n=215,296). The results of the analysis revealed a significant association between regional location, emergency department visits, and deaths among SCD patients. The implications for social change include improvements in health and health outcomes regionally, with adult SCD education for health care providers and patients on SCD treatment protocols. Adults with SCD might possibly benefit from this study with improvements in health and health outcomes for all regions once the barrier to care and specific areas are identified.

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Pedrosa, Alano Martins. "Study cytotoxicity, inflammation and oxidative stress in neutrophils of patients with sickle cell disease: the influence treatment with hydroxyurea." Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=9331.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Falciform Anemia (FA) is a hereditary hemoglobinopathy resulting from a β-globin gene mutation (α2β26 GLU→ VAL) that originates a hemoglobin variant called S (HbS). Its polymerization promotes hemolytic and vaso-occlusive crises (VOC). Nowadays it is known that these reactions are initial FA events that unleash a chain reaction that ends with the generation of oxygen reactive types (ORT) nitric oxide (NO) bioavailability reduction, endothelial lesion, susceptibility to infections and a chronic inflammatory process with direct involvement of neutrophils in the development of such mechanisms. Neutrophils of FA patients, besides developing more rigid, non-deformable structures, also show alterations in the expression of adhesion molecules and the production of cytokines and other mediators that may induce or aggravate clinical events observed in the disease. Hydroxyurea (HU) is the most important improvement in FA treatment and the only medicine with a strong impact on the patientsâ quality of life, reducing the number of VOC, hospitalizations and deaths resulting from this condition. However, not much is known about the effects of this medicine on neutrophils and on the functionality of these cells. The present study aimed at investigating cytotoxicity, inflammation and oxidative stress markers in neutrophils of FA patients, as well as the effect of HU treatment over these parameters in hematology ambulatory patients from a university hospital and a blood center, both reference centers in Fortaleza â CearÃ. The sample included 101 adult patients of both sexes diagnosed with FA through molecular study and it was divided into two groups: the SS Group â composed of 47 FA patients and the SSHU Group â composed of 54 FA patients under HU treatment. A control Group AA was composed of 50 healthy individuals, voluntary blood donors matched by age and sex. Neutrophils were isolated from whole blood by differential gradient and used to measure test. In toxicity tests carried out, it was observed that HU did not have any cytotoxic effect on patientsâ neutrophils, however, was shown a cytoprotective action when compared to group AA and SS patients, with a significant reduction (p<0,001) in lactate dehydrogenase (LDH) levels and an increase in the percentage of viable cells through the metil tiazol tetrazolium (MTT) (p<0,001) and the Trypan Blue exclusion tests. Analyzing neutrophil involvement in inflammatory and oxidative stress processes and in FA, there was a significant elevation in the levels of cytokines and pro-inflammatory markers (TNF-α, MPO) and reduced antiinflammatory interleukin IL-10 group SS, as well as a significant decrease in the activity of antioxidant enzymes (SOD and GSH-Px). Patients under medical treatment with the tested medicine showed similar levels to those found in group AA. Oxidative damage were analyzed through malonaldehyde measurement (MDA), which was evidenced statistical differences between all studied groups (p<0,001), however with a higher average value in the non-treated group of patients. The present study ratified the important role of neutrophils in the inflammatory response promoted by the AF, and shown in an unprecedented way, with the Northeast-BR patients, treatment with HU did not reduce the viability of neutrophils, and modulates its mechanisms pro-inflammatory and pro -oxidants at levels comparable to those of healthy individuals.
Anemia Falciforme (AF) Ã uma hemoglobinopatia hereditÃria resultante de uma mutaÃÃo pontual do gene da β-globina (α2β26 GLU→ VAL), originando a hemoglobina S (HbS), cuja polimerizaÃÃo promove crises hemolÃticas e vaso-oclusivas (CVO). Atualmente, sabe-se que as mesmas sÃo eventos iniciais na AF desencadeando uma cascata de reaÃÃes que culmina com geraÃÃo de espÃcies reativas de oxigÃnio, reduÃÃo da biodisponibilidade do Ãxido nÃtrico, lesÃo endotelial, susceptibilidade Ãs infecÃÃes e processo inflamatÃrio crÃnico, com envolvimento direto dos neutrÃfilos nesses mecanismos. Os neutrÃfilos de pacientes com AF exibem estruturas mais rÃgidas e indeformÃveis e alteraÃÃes na expressÃo de molÃculas de adesÃo e produÃÃo de citocinas e outros mediadores que podem induzir ou agravar as manifestaÃÃes clÃnicas da doenÃa. A hidroxiurÃia (HU) constitui o avanÃo mais importante no tratamento da AF, sendo o Ãnico medicamento que, efetivamente, tem forte impacto na melhora da qualidade de vida dos pacientes, reduzindo o nÃmero de CVO, hospitalizaÃÃes e Ãbitos. No entanto, pouco se sabe sobre os efeitos deste medicamento sobre os neutrÃfilos e na funcionalidade dessas cÃlulas. O estudo teve como objetivo principal investigar a citotoxicidade, inflamaÃÃo e estresse oxidativo em neutrÃfilos de pacientes com AF, bem como o efeito do tratamento com HU sobre esses parÃmetros em pacientes atendidos pelos serviÃos ambulatoriais de hematologia de um hospital universitÃrio e de um hemocentro, ambos de referÃncia em Fortaleza-CearÃ. A amostra foi constituÃda por 101 pacientes adultos, de ambos os sexos, diagnosticados por estudo molecular, sendo divididos em dois grupos: Grupo SSâ formado por 47 pacientes com AF, e, Grupo SSHUâ formado por 54 pacientes em tratamento com HU. Um grupo controle, Grupo AA, foi formado por 50 indivÃduos saudÃveis, doadores voluntÃrios de sangue, com idade e sexo pareados. Os neutrÃfilos foram isolados do sangue total por diferenÃa de gradiente e utilizados para mensuraÃÃo dos testes. Nos ensaios de toxicidade, observou-se que a HU nÃo exerceu efeito citotÃxico nos neutrÃfilos dos pacientes, entretanto, foi evidenciado uma aÃÃo citoprotetora sobre os mesmos quando comparados aos pacientes SS e grupo AA, com uma reduÃÃo significativa (p<0,001) na atividade de lactato desidrogenase (LDH) e aumento no percentual de cÃlulas viÃveis pelo teste de exclusÃo por Azul de Tripan e ensaio do metil tiazol tetrazÃlio (MTT) (p<0,001). Analisando o envolvimento dos neutrÃfilos nos processos de inflamaÃÃo e estresse oxidativo na AF, constatou-se uma significativa elevaÃÃo nos nÃveis de citocinas e marcadores prÃ-inflamatÃrios (TNF-α, MPO) e uma reduÃÃo da interleucina anti-inflamatÃria IL-10 no grupo SS, bem como uma diminuiÃÃo significante da atividade das enzimas antioxidantes (SOD e GSH-Px). Os pacientes em terapia com HU apresentaram nÃveis semelhantes aos encontrados no grupo AA. Danos oxidativos foram analisados pela mensuraÃÃo do malonaldeÃdo (MDA), evidenciando diferenÃa estatÃstica entre todos os grupos do estudo (p<0,001), porÃm, com valor de mÃdia superior no grupo SS. O presente estudo ratificou o papel preponderante dos neutrÃfilos na resposta inflamatÃria promovida pela AF, e mostrou de maneira inÃdita, com pacientes do Nordeste-BR, que o tratamento com HU nÃo reduziu a viabilidade de neutrÃfilos, e modulou seus mecanismos prÃ-inflamatÃrios e prÃ-oxidantes a nÃveis comparÃveis aos de indivÃduos sadios.

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Ehrich, Angela. "Effects of Stress on Adherence and Responsibility to Routine Daily Activities and Treatment in Adolescents with Sickle Cell Disease." Kent State University Honors College / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors148129940559327.

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Kitowski, Katherine Anne. "A LENTIVIRAL VECTOR CONFERRING COREGULATED, ERYTHROID-SPECIFIC EXPRESSION OF γ-GLOBIN AND shRNA SEQUENCES TO BCL11A FOR THE TREATMENT OF SICKLE CELL DISEASE." OpenSIUC, 2016. https://opensiuc.lib.siu.edu/theses/1995.

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Sickle cell disease (SCD) is a severe hemoglobin disorder caused by co-inheritance of a single mutation in the β-globin gene of adult hemoglobin (HbA; α2β2). This alteration leads to the formation of sickle hemoglobin (HbS; α2βS2) and deformed, sickle-shaped red blood cells (RBCs). Sickle RBCs obstruct small blood vessels resulting in anemia, excruciating pain crises, organ damage, and stroke. For the millions of people affected by this disease, life expectancy is only 40-60 years of age. The only cure for SCD is hematopoietic stem cell (HSC, CD34+) transplantation, which requires a human leukocyte antigen (HLA)-matched donor. However, this option runs the risk of complications associated with graft versus host disease and infection. Before birth, individuals with SCD do well because their RBCs are filled with γ-globin containing fetal hemoglobin (HbF; α2γ2), which inhibits the formation of HbS. In fact, some SCD patients who co-inherit mutations that allow for high-level expression of HbF into adulthood are asymptomatic. This suggests that genetic modification of the patient’s own HSCs to permit HbF production would be a viable therapeutic alternative to HSC transplantation. Our work has focused on the use of lentiviral vectors to introduce an exogenous γ-globin gene or shRNA sequences designed to knockdown repressors of γ-globin, such as the zinc-finger transcription factor, BCL11A, to prevent silencing of the endogenous γ-globin genes allowing for persistent expression of HbF. Despite significant progress using both approaches, we have been unable to increase the level of HbF > 30%; a curative threshold for SCD patients who continue to produce HbF into adulthood. The goal of my project was to combine these approaches into a single lentiviral vector to achieve co-regulated, erythroid-specific expression and augmented levels of HbF. I successfully modified the insulated, erythroid-specific γ-globin vector (termed V5m3-400) to include microRNA (miR)-adapted shRNAs (or shmiRs) targeting BCL11A (based on miR-30 and miR-E architectures) in the first and second noncoding introns of the γ-globin genomic sequences. Inclusion of shmiRs had no appreciable effect on integrity of the integrated provirus or vector titer. Vector performance was initially tested using human K562 erythroleukemia cells expressing a flag-tagged version of BCL11A. In this cell line, BCL11A knockdown was significantly improved using miR-E-shRNAs due to a dramatic increase (up to 350-fold) in processing of mature shRNA sequences. The miR-E vectors also provided high-level expression of γ-globin. Erythroid-specific expression of the γ-globin transgene and BCL11A knockdown was confirmed in maturing erythroid cells derived from transduced CD34+ cells of a healthy donor resulting in a 50% increase in HbF levels compared with cells transduced with V5m3-400 as a control. While encouraging, I was unable to discriminate HbF derived from the vector-encoded versus endogenous γ-globin genes. To address this, I introduced a single base change in exon 2 of the γ-globin gene encoded by V5m3-400 such that threonine replaces isoleucine at amino acid 75 (I75T). This variant was successfully distinguished from endogenous γ-globin gene products by reverse phase high performance liquid chromatography (HPLC) in culture-differentiated erythroid cells. Based on these findings, I created compound γ-globin/shmiR-E vectors that include the I75T substitution (I75Tγ-globin/shmiR-E). Future studies will focus on testing this novel vector design in erythroid cells derived from transduced CD34+ cells of healthy donors and patients with SCD. I anticipate that this compound vector has the potential to maximize γ-globin expression and promote levels of HbF that are unlikely to be safely and effectively achieved by conventional globin gene addition or shRNA knockdown approaches alone.

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Barroso, Nathalia Vasconcelos. "Comparação do tratamento com bota de unna e o curativo convencional em pacientes com anemia falciforme e úlceras em membros inferiores ensaio clínico controlado randomizado." Universidade Federal de Sergipe, 2015. https://ri.ufs.br/handle/riufs/3874.

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The ulcers of the lower limbs are cited as the main cutaneous manifestation of sickle cell anemia, presenting a chronic course, with pain and many complications. Treatment of sickle ulcers is complex, involving care wound bed, management of anemia, pain management and treatment of opportunistic infections, among the various proposed treatments highlight the use of covers with inelastic bandage impregnated with zinc, the boot Unna. However there are still no controlled trials to prove the efficacy of treatment. Objective: Compare treatment with conventional dressing to the use of Unna boot in patients with sickle cell anemia and ulcers in the limbs. Methodology: This is a randomized clinical trial, which analyzed patients with sickle cell ulcers that took the Unna boot , comparing them with patients with sickle cell ulcers who used the conventional dressing . Treatments were performed in a period of six weeks. Statistically analyzed the areas of lesions in three periods: at baseline (D0) in the third week (D3) and the sixth week (D6). Results: Participated in this study 19 patients with a mean age of 35.9 years (95% CI 29.1 to 42.8), 53% (10/19) were male. In these individuals was analyzed the healing of ulcers in 40 lower limbs of people with sickle cell anemia 57% (23/40) in the experimental group and 43% (17/40) in the control group. There was a mean variation in lesion area when used Unna boot of 20.2 cm2 at T0 time, 17.9 cm2 in time T3 and 6.2 cm2 in time T6 (P < 0.001), mean percentage of total reduction of 77 1%, obtained by Tarajad index, when used as a simple dressing ranged from 31.3 cm2 35.8 cm2 33.9 cm2 at times T0, T3 and T6, respectively (P <0.001) and an average percentage of 22.8 %. Conclusion: The results suggest that the use compression therapy with Unna boot is an effective treatment of lower limb ulcers in patients with sickle cell anemia, aimed at reducing ulcer area, improvement of the injury aspect and pain alleviation.
As úlceras em membros inferiores são citadas como a principal manifestação cutânea da anemia falciforme, apresentando um curso crônico, com dor e muitas complicações. O tratamento das úlceras falcêmicas é complexo, envolvendo cuidados com o leito da lesão, manejo da anemia, controle da dor e tratamento de infecções oportunistas, dentre os diversos tratamentos propostos destaca-se o uso de coberturas com bandagem inelástica impregnada com zinco, a bota de Unna. No entanto ainda não existem ensaios clínicos que comprovem a eficácia do tratamento. Objetivo: Comparar o tratamento com curativo convencional à utilização de bota de Unna em pacientes com anemia falciforme e úlceras em membros inferiores. Método: Trata-se de um ensaio clínico randomizado, onde foram analisados pacientes com úlcera falcêmica que fizeram uso da bota de Unna, comparando-os com pacientes com úlceras falcêmicas que fizeram uso do curativo convencional. Os tratamentos foram realizados em um período de seis semanas. Foram analisadas estatisticamente as áreas das lesões em três períodos: no momento inicial (D0), na terceira semana (D3) e na sexta semana (D6). Resultados: Participaram dessa pesquisa 19 pacientes com idade média de 35,9 anos (IC95% = 29,1 a 42,8), sendo 53% (10/19) do sexo masculino. Nesses indivíduos foi analisada a cicatrização de 40 úlceras em membros inferiores de pessoas com diagnóstico de anemia falciforme sendo 57% (23/40) no grupo experimental e 43% (17/40) no grupo controle. Houve uma variação média da área lesional quando utilizado bota de Unna de 20,2 cm2 no tempo T0, 17,9 cm2 no tempo T3 e 6,2 cm2 no tempo T6 (P<0,001), com média percentual de redução total de 77,1%, obtido através do índice de Tarajad, enquanto quando se usou o curativo simples teve uma variação de 31,3 cm2, 35,8 cm2, 33,9 cm2, nos tempos T0, T3 e T6 respectivamente (P<0,001), e um percentual médio de 22,8%. Conclusão Os resultados sugerem que a utilização da terapia compressiva com bota de Unna constitui um tratamento efetivo das úlceras de membros inferiores em pacientes portadores de anemia falciforme, atuando na redução da área da úlcera e na melhora do aspecto lesional.

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Weber, Leslie. "New therapeutic strategies for the treatment of β-hemoglobinopathies." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC272.

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Le développement de stratégies thérapeutiques curatives pour les patients affectés de β-hémoglobinopathies, c’est à dire drépanocytose et β-thalassémies, fait face à une grande demande. En effet, un accès restreint à des donneurs compatibles limite l’unique thérapie définitive autorisée, la transplantation allogénique de cellules souches hématopoïétiques (CSH). Au cours de la première partie de cette thèse,nous avons optimisé une alternative thérapeutique,la transplantation autoloque de CSH corrigées par le biais de lentivirus (LV). Le développement de lentivirus exprimant la β-globine et l’amélioration des conditions de transduction des CSH a débouché sur de probants bénéfices cliniques pour les patients drépanocytaires et thalassémiques traités par cette approche dans le cadre d’essais cliniques récents. Malgré ces progrès majeurs,cette thérapie pourrait bénéficier d’améliorations. En effet,la correction de thalassémies majeures, dépendantes de transfusion, ainsi que de la drépanocytose requiert de forts niveaux d’expression du transgène. Le but de ce projet est de choisir un LV à titre élevé, capable de transduire une large portion de CSH et d’entraîner une forte expression du transgène dans des globules rouges (GR) dérivés de CSH. A cet effet, nous avons comparé différentes combinaisons d’éléments régulateurs afin de définir la cassette régulatrice minimale nécessaire pour l’obtention de forts niveaux d’expression de la β-globine. Nous avons construit 2 mini-LCRs contenant soit HS2 et HS3 (taille totale 2.6 kb) ou HS2, HS3 et HS4 (taille totale 3.7 kb) provenant du Locus Control Region (LCR). Ces cassettes ont été insérées dans les LV β-AS3 et β-AS3 HS4, respectivement, qui contrôlent l’expression d’une globine anti-falciformante, βAS3-globine.Premièrement, nous avons comparativement évalué l’efficacité de transduction des vecteurs β-AS3 et β-AS3 HS4 dans des cellules souches progéniteurs hématopoïétiques (CSPH) drépanocytaires et dans des CSH drépanocytaires. Le deuxième volet de cette étude a permis de déterminer l’expression de la βAS3-globine issue de ces deux constructions dans des GR dérivés de CSPH drépanocytaires, et d’évaluer l’efficacité du LV le plus efficace pour secourir le phénotype drépanocytaire.La seconde partie de cette thèse vise à développer une nouvelle stratégie thérapeutique par édition du génome pour réactiver l’hémoglobine fœtale (HbF). Cette approche s’appuie sur l’observation d’une meilleure évolution clinique des β-thalassémies et de la drépanocytose en présence de niveaux élevés d’HbF.Par l’utilisation de la technologie CRISPR/Cas9, nous avons invalidé les sites de liaisons de répresseurs transcriptionnels au niveau des promoteurs de la γ-globine pour réactiver l’expression de l’HbF dans des GR dérivés de CSPH drépanocytaires. La réactivation des gènes de γ-globine fœtale dans leur locus génomique endogène permet de s’affranchir des difficultés liées à l’expression relativement faible de transgène par copie de LV, principalement lié à la faible capacité des LV qui ne permet d’insérer que de courts fragments d’ADN du LCR, arrangés de manière non-physiologique. De plus,cette stratégie offre une approche potentiellement plus sûre comparée à une stratégie addition de gène basée sur l’usage de LV. Dans la drépanocytose, cette approche thérapeutique favorise l’expression de la γ-globine anti-falciformante aux dépens de la globine βS-globine mutée. Dans le cadre d’une approche comparative,nous avons évalué des cibles thérapeutiques connues et nouvelles au niveau des promoteurs de la γ-globine. A cet effet, plusieurs ARN guides (ARNg) ont été designés pour cibler 3 régions des promoteurs de la γ-globine, où des variants associés à des niveaux élevés d’HbF et/ou à des sites de liaison de répresseurs de l’HbF ont été décrits
Highly efficient curative therapeutic strategies are in great demand for patients affected by β-hemoglobinopathies, namely sickle cell disease (SCD) and β-thalassemia. Indeed, the poor access to compatible donors restrains the application of the only approved definitive therapy, the allogeneic hematopoietic stem cell (HSC) transplantation. In the first part of this thesis, we aimed at optimizing an established therapeutic alternative consisting in the autologous transplantation of lentivirus (LV)-corrected hematopoietic HSCs. The development of β-globin expressing LVs and the improvement of HSC transduction conditions have led to a clear clinical benefit for SCD and β-thalassemia patients treated with this approach in the frame of recent clinical trials. Despite these significant progresses, there is room for further improvement. Indeed, the correction of severe transfusion-dependent B-thalassemia and SCD patients requires high levels of transgene expression. The goal of this project was to select a high-titer LV able to transduce efficiently HSCs and to drive high levels of transgene expression in HSC-derived RBCs. To this purpose, we compared different combinations of regulatory elements, in order to define the minimal regulatory cassette needed for achieving high levels of globin expression in the frame of LVs. We constructed 2 mini-LCRs containing either HS2 and HS3 (total size 2.6 kb) or HS2, HS3 and HS4 (total size 3.7 kb) derived from the 16-kb Locus Control Region. These cassettes were inserted in the β-AS3 and β-AS3 HS4 LVs, respectively, driving the expression of an anti-sickling βAS3-globin transgene. First, we aimed at comparatively evaluate the transduction efficiency of β-AS3 and β-AS3 HS4 in SCD hematopoietic stem progenitor cells (HSPCs) and long term-repopulating HSCs. The second aim of the study was to assess β-AS3 and β-AS3 HS4 derived transgene expression in RBCs produced from SCD HSPCs, and to evaluate the efficacy of the best-performing LV in rescuing the SCD phenotype. The second part of this thesis aimed to develop a novel genome editing-based strategy to restore fetal γ-globin genes expression. This therapeutic approach stems from the observation that the clinical course of β-thalassemia and SCD is improved in the presence of elevated HbF levels. By using the innovative CRISPR/Cas9 technology, we aimed at disrupting repressors binding sites in the γ-globin promoters to reactivate HbF expression in SCD HSPCs-derived RBCs. Reactivating fetal γ-globin genes at their endogenous genomic locus can circumvent the difficulties associated with the relatively low LV-derived transgene expression per vector copy, likely because the low LV vector capacity allows the usage only of short DNA stretches from the LCR, arranged in a non-physiological manner. In addition, this strategy offers a potentially safer targeted approach compared to the LV-based gene addition. In SCD, this therapeutic approach can favor the anti-sickling γ-globin expression, at the expense of the mutated βS-globin, given the competition between the fetal and the adult genes for the interaction with the LCR. In a comparative approach, we intended to evaluate novel and known therapeutic targets in the γ-globin promoters. To this purpose, several gRNAs have been designed to target 3 regions of the γ-globin promoters, where variants associated with elevated HbF levels and/or binding sites for HbF repressors have been described. We aimed to screen these gRNAs in an adult erythroid cell line (HUDEP-2) and SCD HSPCs-derived RBCs in terms of HbF reactivation and correction of the patient phenotype, to select the best therapeutic target for an efficient and safe therapeutic approach for β-hemoglobinopathies

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10

Tozatto, Maio Karina. "Immunogenetics in sickle cell disease." Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC093.

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La drépanocytose est l’hémoglobinopathie héréditaire la plus fréquente, causée par un polymorphisme unique d’un nucléotide (SNP) dans le gène de la beta-globine (HBB). Ce SNP détermine la synthèse de l’hémoglobine S, qui polymérise lorsqu’elle est soumise au stress, et ceci change la forme des hématies drépanocytaires en faucille. Les drépanocytes sont moins déformables, plus adhérents à l’endothélium, et plus susceptibles à l’hémolyse. Les complications cliniques de la drépanocytose peuvent être expliquées par l’interaction entre la vaso-occlusion, l’hémolyse et l’activation inflammatoire résultant de la présence des drépanocytes dans la circulation. Les patients drépanocytaires peuvent présenter de nombreuses complications, qui touchent tous les organes. La présentation clinique de cette maladie est très hétérogène, variant entre des patients qui ont très peu de symptômes à des patients qui décèdent de la maladie. Sachant que l’inflammation joue un rôle majeur dans la physiopathologie de la drépanocytose, des polymorphismes dans les gènes inflammatoires peuvent être évoqués pour expliquer cette hétérogénéité. La greffe de cellules souches hématopoïétiques est la seule thérapie curative disponible actuellement pour la drépanocytose, avec des bons résultats démontrés après la greffe d’un donneur apparenté HLA identique. Néanmoins, la plupart des patients n’a pas de donneur apparenté. Les patients drépanocytaires sont d’origine africaine, le groupe ethnique le moins représenté dans les registres de donneurs non apparentés de cellules souches. A ce jour, peu d’études, utilisant des registres locaux, ont été faites pour estimer la probabilité des patients drépanocytaires de trouver un donneur potentiel non apparenté dans les registres internationaux.Cette étude a eu pour objectif d’évaluer le rôle de quelques gènes inflammatoires liés aux Toll-like récepteurs (TLR) dans la survenue des infections bactériennes chez les patients drépanocytaires, vu que les infections sont une cause majeure de mortalité chez ces patients, et les TLR sont impliqués dans la reconnaissance de plusieurs types de bactéries. Les patients inclus avaient des échantillons d’ADN et des données cliniques disponibles. Les SNPs ont été génotypés par réaction en chaîne par polymérase en temps réel (RT-PCR). Quatre-cents trente patients, la plupart d’origine brésilienne ou africaine subsaharienne, ont été divisés en deux groupes : infectés (n=235, patients qui ont eu au moins un épisode d’infection bactérienne documentée) et non infectés (n=195, patients qui n’ont jamais présentés d’infections sévères). Le génotype T/A du SNP rs4696480 in TLR2 a été plus fréquent chez les patients non infectés (50% versus 67%, OR=0.50, 95% CI 0.34-0.75, p<0.001). En outre, le génotype T/T de ce SNP a été plus fréquent chez les patients infectés (15% versus 5%, OR=0.50, 95% CI 0.34-0.75, p<0.001). Des études précédentes ont démontré que les individus A/A avaient plus de sécrétion de marqueurs inflammatoires, lorsque l’allèle T était associé à moins de fréquence et de sévérité des maladies inflammatoires. Cette étude a également eu pour objectif d’estimer la probabilité de trouver un donneur potentiel non apparenté, antigène leucocytaire humain (HLA) allélique identique pour les loci HLA-A, HLA-B et HLA-DRB1. Dans cette étude, 185 patients ont été inclus, 116 suivis dans un centre brésilien et 69 greffés d’un donneur apparenté ou non apparenté dans des centres de greffe qui reportent leurs données à la Société Européenne de Greffe de Cellules Souches (EBMT). Les patients inclus avaient des données HLA testés en moyenne ou haute résolution. Les haplotypes HLA ont été estimés à travers un logiciel, HaploStats, et classifiés selon l’ethnicité. Ensuite, nous avons recherché des potentiels donneurs HLA alléliques identiques pour les loci HLA-A, HLA-B et HLA-DRB1 (6/6) dans des registres internationaux (WMDA)
Sickle cell disease (SCD) is the most common inherited hemoglobinopathy, caused by a single nucleotide polymorphism (SNP) in the beta-globin (HBB) gene. This SNP determines the synthesis of S haemoglobin (HbS), which polymerizes under stress conditions, sickling the red blood cell (RBC). Sickle RBC are less deformable, more adherent to the endothelium, and more susceptible to haemolysis. SCD complications are explained by the interaction between haemolysis, vaso-occlusion and inflammatory activation, determined by the RBC sickling. Patients with SCD may present several complications, affecting all organs. Clinical presentation is very heterogeneous, ranging from patients who have mild symptoms to patients who die from disease complications. Because inflammation plays a major role in SCD, polymorphisms in inflammatory genes are potential targets to explain this heterogeneity. Haematopoietic stem cell transplantation (HSCT) is the only curative therapy currently available for SCD, with good results shown after human leukocyte antigen (HLA) identical sibling HSCT. However, most patients will not have a matched sibling donor. Patients with SCD are mostly from African origin, the less represented ethnic group in stem cell donor registries. To date, few studies using local registries were performed to find the probability of having a potential unrelated donor in SCD settings. This study aimed to assess the role of inflammatory genes encoding Toll-like receptors (TLR) in the occurrence of bacterial infections in patients with SCD, because infection is a leading cause of mortality in SCD, and TLR recognize a wide range of bacteria. Patients included had DNA samples and clinical data available. SNPs were genotyped by real-time polymerase chain reaction (RT-PCR). Four hundred thirty patients, mostly from Brazilian and Sub-Saharan African origin, were divided in two groups: infected (n=235, patients who presented at least one episode of bacterial infection), and non-infected (n=195, patients who never presented bacterial infections). The T/A genotype of SNP rs4696480 in TLR2 was less frequent in infected patients (50% versus 67%, OR=0.50, 95% CI 0.34-0.75, p<0.001). In addition, the T/T genotype of this SNP was more frequent among infected patients (15% versus 5%, OR=0.50, 95% CI 0.34-0.75, p<0.001). Previous reports in other settings showed that A/A carriers had higher secretion of inflammatory markers, while T allele was associated with less occurrence and severity of inflammatory diseases. Hence, T/A genotype might express the ideal inflammatory response to defeat bacteria, while the weaker inflammatory response determined by the T/T genotype increases susceptibility to bacterial infections in SCD settings
A doença falciforme (DF) é a hemoglobinopatia hereditária mais frequente, causada por um polimorfismo de nucleotídeo único (SNP) no gene da betaglobina (HBB). A ocorrência desse SNP determina a síntese de hemoglobina S, que polimeriza sob condições de stress, alterando a conformação das hemácias, que adquirem forma de drepanócitos. Os drepanócitos são menos deformáveis, mais aderentes ao endotélio e mais suscetíveis à hemolise. As complicações clínicas da DF podem ser explicadas pela interação entre a vasoclusão, hemólise e ativação inflamatória resultantes da presença dos drepanócitos na circulação. Os pacientes com DF podem apresentar numerosas complicações, que afetam todos os órgãos. A apresentação clínica da DF é muito heterogênea, variando de pacientes pouco sintomáticos a pacientes que falecem por complicações da doença. Visto que a inflamação tem um papel importante na fisiopatologia da DF, polimorfismos em genes inflamatórios poderiam explicar essa heterogeneidade.O transplante de células tronco hematopoiéticas (TCPH) é a única terapia curativa disponível atualmente para a DF, com bons resultados demonstrados em TCPH de doador aparentado antígeno leucocitário humano (HLA) idêntico. Não obstante, a maioria dos pacientes não dispõe de doador aparentado HLA idêntico. A DF ocorre em pacientes normalmente de origem africana, o grupo étnico menos representado em registro de doadores de células tronco. Nos dias de hoje, poucos estudos, utilizando registros locais, avaliaram a probabilidade de encontrar potenciais doadores não aparentados para pacientes com DF. Este estudo teve por objetivo avaliar o papel de genes inflamaórios que codificam receptores Toll-like (TLR) na ocorrência de infecções bacterianas em pacientes com DF, visto que infecção é uma das principais causas de mortalidade em DF, e os TLR reconhecem diversos tipos de bactérias. Os pacientes incluídos no estudo tinham amostras de DNA e dados clínicos disponiveis. Os SNPs foram genotipados por reação em cadeia de polimerase em tempo real (RT-PCR). Quatrocentos e trinta pacientes, a maioria de orgem brasileira ou africana subsaariana, foram divididos em dois grupos, infectados (n=235, pacientes que apresentaram ao menos um episodio de infecção bacteriana), e não infectados (n=195, pacientes que nunca tiveram tais infecções). O genótipo T/A do SNP rs4696480 foi menos frequente em pacientes infectados (50% versus 67%, OR=0.50, 95% CI 0.34-0.75, p<0.001). Além disso, o genótipo T/T do mesmo SNP foi mais frequente em pacientes infectados (15% versus 5%, OR=0.50, 95% CI 0.34-0.75, p<0.001). Estudos prévios mostraram que indivíduos com genótipo A/A apresentavam mais secreção de marcadores inflamatórios, enquanto o alelo T foi associado a menor ocorrência e menor gravidade de doenças inflamatórias

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11

Hays, Mary Margaret. "Stem cell transplant for sickle cell disease." Thesis, Boston University, 2013. https://hdl.handle.net/2144/12117.

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Thesis (M.A.)--Boston University
Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. As SCD can cause significant morbidity and decrease in life expectancy, further research on curative options is of great interest. Hematopoietic stem cell transplant (HSCT) is the only treatment option offering a chance of cure, but the risks of treatment are not negligible. Because the outcomes of HSCT are best when the procedure is performed at a younger age, understanding what parents know about transplant, their opinion on this option and the risks they are willing to take to achieve a cure is of great value. As sickle cell disease has changed in the United States from a life-threatening condition of childhood to a chronic condition with most of the burden of morbidity and mortality shifted towards adulthood, it is necessary for parents to be fully aware of long term risks and educated on all therapeutic options, so the optimal decision can be made. Objectives: (i) To learn about parents’ recollection and pursuit of further information after undergoing an educational session on risks and benefits of HSCT. (ii) To learn about their worries about transplant and the highest mortality and infertility risks they are willing to accept in order to achieve a cure for their child. (iii) To learn about parents’ readiness to proceed to transplant based on a hypothetical scenario. [TRUNCATED]

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12

Gavlak, J. C. D. "Sleep in children with sickle cell disease." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1528622/.

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BACKGROUND: Sickle Cell Anaemia (SCA) or homozygosity for the sickle haemoglobin gene (HbSS) is the most common genetic condition in the UK. A high prevalence of Sleep Disordered Breathing (SDB) in SCA is widely accepted but there is a lack of unselected population based studies. As Polysomnography (PSG) is expensive, screening for SDB using a robust tool, e.g. the Delta 12 (Δ12) index and 3% Oxygen Desaturation Indices (ODI) calculated from home pulse oximetry, should be validated. Elevated Cerebral Blood Flow Velocity (CBFV) is a predictor of stroke in SCA, and may be associated with SDB. METHODS AND RESULTS: Prevalence of OSA was assessed and compared with the general paediatric population from Polysomnography (SCA n=195) analysed using the American Academy of Sleep Medicine (AASM) criteria. Interobserver reliability between two observers was excellent. At all ages, the prevalence of OSA was higher in SCA. OSA prevalence was highest in young children, with 50% of 4-6 year olds having an obstructive apnoea hyopnoea index (OAHI) of >1. A zero inflated model was fitted for prediction of OAHI from Δ12 or ODI; for predicting OAHI zero or >1, 3% ODI alone had the best fit. In 83 London patients, OSA was associated with elevated CBFV. Mean SpO2, ODI and CAI were predictors of basilar velocity independent of age. In the final model, mean SpO2 remained a predictor (B-3.1, beta -0.41, t -4.2, p < 0.0005) independent of age (B- 2.9, beta -0,453, t -4.7, p < 0.0005). CONCLUSION: Despite the difficulties in comparing across populations, there is a higher prevalence of OSA in unselected children with SCA than in typically developing children with no SDB symptoms, screening with overnight pulse oximetry to select those with OAHI>1 is feasible, and this may be important as there is an association between OSA and basilar CBFV in this population.

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13

Gardner, Catherine Joanne. "Genotype-phenotype correlation in sickle cell disease." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/genotypephenotype-correlation-in-sickle-cell-disease(07a190be-c88a-41f2-8e74-e063d85919a3).html.

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Sickle cell disease (SCD) has a complex pathophysiology initiated by the polymerisation of deoxy-sickle-haemoglobin. The single nucleotide change underpinning SCD does not account for the vast range and severity of SCD complications. This clinical heterogeneity is only partly explained by the genetic variability of fetal haemoglobin gene levels and co-inheritance of α- thalassemia. Although environmental factors also contribute to the clinical complexity of SCD, further genetic modifiers of SCD severity exist but are yet to be determined. Genetic association studies have been boosted recently not only with the advent of new genotyping tools, but also with the development of increasingly sophisticated analytical methods. New developments in phenotyping, genotyping and genotype-phenotype association approaches allow us to disentangle true genetic associations from hits due to chance. This thesis seeks to investigate biomarkers of sickle severity and to use these clinical markers in genotype-phenotype correlation studies. I have investigated three key markers of disease severity: haemolysis, frequency of acute pain episodes and mortality. Estimated median survival of 67 years in HbSS disease in our UK cohort is a significant improvement in survival compared to other recent estimates in the USA and Jamaica. I have undertaken genome-wide micro-array scanning and created an imputed genotype dataset of over 15,000,000 genetic variants. I have used these phenotype and genotype datasets to conduct genetic association studies, both genome-wide and candidate gene association studies. These analyses are based on linear mixed modelling to account for relatedness (including population stratification) within the cohort. In addition to the severity outcomes, I have also evaluated the known genetic loci for HbF and created a genetic “summary statistic” to quantify the effects of these three loci. Finally, I have also assessed the role of the erythroid regulator KLF1 in HbF levels in SCD with two laboratory-based projects.

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14

Kawadler, J. M. "Neuroimaging biomarkers in paediatric sickle cell disease." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1464063/.

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Sickle Cell Disease (SCD) is a collection of genetic haemoglobinopathies, the most common and severe being homozygous sickle cell anaemia. In the UK, it has been estimated that 1 in 2000 children are born with SCD. The disease is characterised by chronic anaemia, recurrent pain crises and vascular occlusion. Neurologically, there is a high incidence of stroke in childhood, as well as cognitive dysfunction. Newborn screening programmes and preventative treatments have allowed a much longer lifespan; however recently, neurological research has shifted to characterising subtler aspects of brain development and functioning that may be critically important to the individual’s quality of life. This thesis overviews the neurological and neurocognitive complications of SCD, and how magnetic resonance imaging (MRI) can provide biomarkers for severity of disease. During the PhD, retrospective and prospective cognitive and MRI data were collected and analysed. Diagnostic clinical MRI sequences and advanced MRI sequences were applied, as well as a neuropsychological test battery aimed at intelligence and executive function. First, this thesis reviews the intelligence literature in SCD and includes previously unreported data, finding patients, regardless of abnormality seen on conventional MRI, have lowered full-scale intelligence quotient than controls. Then, to determine imaging biomarkers, volumetric differences and diffusion characteristics were identified. Patients were found to have decreased volumes of subcortical structures compared to controls, in groups corresponding to disease severity. Results from a three-year longitudinal clinical trial suggest evidence of atrophy in paediatric patients, with no apparent protective effect of treatment. Diffusion tensor imaging revealed reduced white matter integrity across the brain, correlating with recognised markers of disease severity (i.e. oxygen saturation and haemoglobin from a full blood count). Overall, the four experiments bridge a gap in the cognitive and neuroimaging literature of the extent of neurological injury in children with SCD.

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15

Edmond, A. M. "The spleen in sickle cell disease in childhood." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598759.

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16

Singhal, Atul. "Growth and metabolism in homozygous sickle cell disease." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288009.

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17

Wu, Li-Chen. "Correction of sickle cell disease by homologous recombination." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008p/wu.pdf.

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18

JÃnior, Geraldo Bezerra da Silva. "Renal abnormalities in patients with sickle cell disease." Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=10491.

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nÃo hÃ
ABSTRACT Background - Kidney abnormalities are one of the main chronic complications of sickle cell disease (SCD). The aim of this study is to investigate the occurrence of renal abnormalities among patients with SCD. Methods - This is a cohort study with 26 SCD patients followed in a medical center in Fortaleza, CearÃ, Brazil. Urinary acidification and concentration tests were performed using calcium chloride (CaCl2), and after a 12h period of water and food deprivation. Fractional excretion of sodium (FENa), transtubular potassium gradient (TTKG) and solute free water reabsorption (TcH2O) were calculated. The SCD group was compared to a group of 15 healthy volunteers (control group). Aquaporin-2 (AQP2) and renal outer medullary K+ channels (ROMK) were quantified through exosomes search in urine. Results - Patient`s average age and gender were similar to controls. Urinary acidification deficit was found in 5 SCD patients (19.2%), who presented urinary pH > 5.5 after CaCl2 test. Urinary osmolality was significantly lower in SCD patients (355Â60 vs. 818Â202mOsm/kg, p=0.0001, after 12h period water deprivation). Urinary concentration deficit was found in all SCD patients (100%). FENa was higher among SCD patients (0.75Â0.3 vs. 0.55Â0.2%, p=0.02). The TTKG was higher in SCD patients (5.5Â2.5 vs. 3.0Â1.5, p=0.001), and TcH2O was lower (0.22Â0.3 vs. 1.1Â0.3L/day, p=0.0001). The search for AQP2 did not show significant difference between SCD patients and control group (102Â6.0 vs. 100Â7.2%, p=0.874), as well as for ROMK (172Â38 vs. 100Â25%, p=0.207). Conclusions - SCD is associated with important kidney dysfunction. The main abnormalities found were urinary concentrating and incomplete distal acidification defect. There was also an increase in the potassium transport and decrease in water transport, evidencing the occurrence of distal tubular dysfunction.
RESUMO IntroduÃÃo - AlteraÃÃes renais representam uma das complicaÃÃes crÃnicas principais da doenÃa falciforme (DF). O objetivo deste estudo Ã investigar a ocorrÃncia de alteraÃÃes renais em pacientes com DF. MÃtodos - Foi realizado estudo de coorte com 26 pacientes com DF acompanhados em um ambulatÃrio de Fortaleza, CearÃ, Brasil. Testes de acidificaÃÃo e concentraÃÃo urinÃrias foram realizados usando cloreto de cÃlcio (CaCl2) e apÃs perÃodo de 12h de jejum e privaÃÃo hÃdrica. Foram calculados fraÃÃo de excreÃÃo de sÃdio (FENa), transporte transtubular de potÃssio (TTKG) e transporte de Ãgua livre de solutos (TcH2O). O grupo de pacientes com DF foi comparado com um grupo de 15 voluntÃrios sadios (grupo controle). Os transportadores aquaporina-2 (AQP2) e canal de K+ apical (ROMK) foram quantificados pela pesquisa de exossomas na urina. Resultados - A mÃdia de idade e a distribuiÃÃo de gÃnero foi similar entre os dois grupos. DÃficit de acidificaÃÃo urinÃria foi encontrada em 5 pacientes com DF (19,2%), que apresentaram pH urinÃrio > 5,5 apÃs o teste com CaCl2. A osmolaridade urinÃria foi significativamente menor entre os pacientes com DF (355Â60 vs. 818Â202mOsm/kg, p=0,0001, apÃs perÃodo de 12h de jejum e privaÃÃo hÃdrica). DÃficit de concentraÃÃo urinÃria foi encontrado em todos os casos de DF (100%). A FENa foi maior entre os pacientes com DF (0,75Â0,3 vs. 0,55Â0,2%, p=0,02). O TTKG tambÃm foi maior nos pacientes com DF (5,5Â2,5 vs. 3,0Â1,5, p=0,001), e o TcH2O foi menor (0,22Â0,3 vs. 1,1Â0,3L/dia, p=0,0001). A pesquisa de AQP2 nÃo mostrou diferenÃa significativa em relaÃÃo ao grupo controle (102Â6,0 vs. 100Â7,2%, p=0,874), bem como a do canal ROMK (172Â38 vs. 100Â25%, p=0,207). ConclusÃo - A DF Ã associada a importantes alteraÃÃes renais. As principais alteraÃÃes encontradas foram dÃficit de concentraÃÃo e acidificaÃÃo urinÃria. Foi ainda observado aumento no transporte

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19

Indik, Julia H., Vineet Nair, Ruslan Rafikov, Iwan S. Nyotowidjojo, Jaskanwal Bisla, Mayank Kansal, Devang S. Parikh, et al. "Associations of Prolonged QTc in Sickle Cell Disease." PUBLIC LIBRARY SCIENCE, 2016. http://hdl.handle.net/10150/622120.

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Sudden death is a leading cause of mortality in sickle cell disease, implicating ventricular tachyarrhythmias. Prolonged QTc on an electrocardiogram (ECG), commonly seen with myocardial ischemia, is a known risk for polymorphic ventricular tachycardia (VT). We hypothesized that prolonged QTc is associated with mortality in sickle cell disease. ECG were analyzed from a cohort of 224 sickle patients (University of Illinois at Chicago, UIC) along with available laboratory, and echocardiographic findings, and from another cohort of 38 patients (University of Chicago, UC) for which cardiac MRI and free heme values were also measured. In the UIC cohort, QTc was potentially related to mortality with a hazard ratio (HR) of 1.22 per 10ms, (P = 0.015), and a HR = 3.19 (P = 0.045) for a QTc>480ms. In multivariate analyses, QTc remained significantly associated with survival after adjusting for inpatient ECG status (HR 1.26 per 10ms interval, P = 0.010) and genotype status [HR 1.21 per 10ms interval, P = 0.037). QTc trended toward association with mortality after adjusting for both LDH and hydroxyurea use (HR 1.21 per 10ms interval, P = 0.062) but was not significant after adjusting for TRV. In univariate analyses, QTc was related to markers of hemolysis including AST (P = 0.031), hemoglobin (P = 0.014), TR velocity (P = 0.036), higher in inpatients (P<0.001) and those with an SS compared to SC genotype (P<0.001) in the UIC cohort as well as to free heme in the UC cohort (P = 0.002). These findings support a relationship of prolonged QTc with hemolysis and potentially mortality in sickle cell disease.

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20

Mackey, Michelle Noble. "Understanding Parents' Disease-Managing Strategies for Children With Sickle Cell Disease." ScholarWorks, 2019. https://scholarworks.waldenu.edu/dissertations/6610.

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Sickle cell disease (SCD) is one of the most difficult and stressful chronic diseases for parents of afflicted children to manage. Managing SCD can be traumatic for parents particularly if they have no specific coping strategies for managing the disease or ensuring the child visits the doctor as scheduled. The use of certain coping strategies may affect the parents' and patients' perceptions of the illness and influence their decisions regarding treatment, which can have a lasting impact on their lives. Effective parental strategies such as positive thinking can aid in disease management, but there is limited research on the coping strategies used by parents of children with SCD specifically. The purpose of this phenomenological study, which was guided by Thompson and Gustafson's transactional stress and coping model, was to describe parents' coping strategies in managing their young child's SCD as it relates to use of health services. Data collection included one-to-one, open-ended interviews with 10 parents of children with SCD. Colaizzi's method of phenomenological data analysis was used to identify themes. Five themes emerged from data analysis and they are: parental methods of coping with SCD, participants' understanding of SCD, SCD family and support, managing SCD with hydration and medication, and experience accessing healthcare. These results indicated the participants' coping strategies varied according to their individual situations. Insight from this study could lead to positive social change by helping to identify specific coping strategies parents can use to better manage their child's disease and effectively access available health services.

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Matthie, Nadine. "Sickle Cell Disease: The Role of Self-Care Management." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4538.

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Abstract Sickle cell disease is the most common genetic disorder in the United States. Approximately 90% of the hospitalizations in this patient population occur due to the most common complication, pain crises. Prevention of these crises is therefore essential and requires the patient to assume an active role in his or her disease management. Studies suggest that further research is needed to examine the self-care management process and to identify factors influencing self-care behaviors. The relationships among these factors must be clearly defined before interventions to improve self-care management can be determined. The aims of the study were threefold. The first aim was to evaluate the relationships among psychosocial variables (SCD self-efficacy and social support) and socio-demographic variables (age, gender, education, employment status, income, and living situation) in understanding individual differences in self-care management variables (perceived self-care ability and self-care actions). It was hypothesized that higher SCD self-efficacy, greater social support, being employed, living with family or friends, increased age, more years of education, higher income, and being male are each associated with having higher perceived self-care ability and more frequent self-care actions. The second aim was to evaluate the relationships among psychosocial variables (SCD self-efficacy and social support), socio-demographic variables (age, gender, education, employment status, income, and living situation), and self-care management variables (perceived self-care ability and self-care actions) in understanding hospital visits for crises. It was hypothesized that higher perceived self-care ability and more frequent self-care actions are associated with fewer hospital visits for crises. The third aim was to evaluate the mediational role of perceived self-care ability and self-care actions in the relationships among psychosocial variables (SCD self-efficacy and social support), socio-demographic variables (age, gender, education, employment status, income, and living situation), and the number of hospital visits for crises. It was hypothesized that SCD self-efficacy, social support, and the socio-demographic variables have both a direct and an indirect relationship with the number of hospital visits for crises. In 103 young Black adults (ages 18-30) with sickle cell disease (SCD), an exploratory , correlational study was conducted, via secondary analysis of data, to examine the relationships among SCD self-efficacy, social support, socio-demographic variables, self-care management (self-care ability and self-care actions), and the number of hospital visits for crises. Bivariate correlations and regression analyses were conducted to evaluate the relationships among the variables and to examine the mediational role of self-care management. Sickle cell disease self-efficacy, social support, years of education, and income were significantly related to perceived self-care ability and self-care actions. Social support accounted for the majority of the variance in each self-care management variable. The hypothesis that higher SCD self-efficacy and greater social support are associated with higher perceived self-care ability and more frequent self-care actions was supported. Education was also associated with higher perceived self-care ability and self-care actions as hypothesized. The overall model with SCD self-efficacy, social support, years of education, income, perceived self-care ability, and self-care actions was not significant in predicting the number of hospital visits for crises. There were no significant associations noted among age, annual household income, living situation, employment status, and the self-care management variables. The hypothesis that higher perceived self-care ability and more frequent self-care actions are associated with fewer hospital visits for crises was not supported. Further, there was no adequate evidence to support a direct relationship between SCD self-efficacy, social support, years of education, and the number of hospital visits for crises. The indirect relationship, through self-care management, among the variables was also non-significant. There was however a significant direct relationship noted between income and the number of hospital visits for crises. The outcomes of the study may be important for clinical care, patient education, and health outcomes in the SCD population. Findings may be used to conduct larger confirmatory studies and to develop interventions that may be used to supplement therapy in the clinical setting and to enhance patient self-care management at home. Additional studies are needed, however, to clarify what additional variables may affect the number of hospital visits for crises and to identify specific pain prevention and management strategies used by SCD patients.

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22

Riddington, Ceri Joanne. "Systematic reviews and clinical trials in sickle cell disease." Thesis, University of Liverpool, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399217.

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23

Sylvester, Karl Peter. "Pulmonary function abnormalities in children with sickle cell disease." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424442.

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Lunt, Alan Charles. "Development of pulmonary function abnormalities in sickle cell disease." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/development-of-pulmonary-function-abnormalities-in-sickle-cell-disease(00af4d47-32d5-4145-9964-63ef4654f3b4).html.

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Sickle cell disease (SCD) is one of the commonest inherited disorders worldwide. Acute chest syndrome (ACS) is the commonest cause of death in young adults and pulmonary dysfunction is a major contributor to morbidity in aging adults with SCD, but the aetiology is poorly understood. The first four studies presented in this thesis test the hypothesis that pulmonary vascular abnormalities are involved in the pathogenesis of SCD-related lung disease. Significant associations were found between small vessel pulmonary vascular dimensions, lung function abnormalities and echocardiographic estimates of ventricular function and cardiac output in adults with SCD; the decline in lung function observed in a subset of patients with longitudinal measurements correlated with changes in vascular dimension. Increased pulmonary capillary blood volume was shown to be related to the airways obstruction seen in SCD children. Respiratory system resistance and pulmonary capillary blood volume were significantly correlated in the SCD children, but not in the controls, suggesting the raised respiratory system resistance in the SCD children was, at least partly, explained by their increased pulmonary capillary blood volume. Additionally, fluid loading by means of blood transfusion in SCD children was found to acutely increase pulmonary capillary blood volume resulting in an increase in respiratory system resistance and worsening lung function. Furthermore, alveolar nitric oxide production was elevated in SCD children compared to controls and in the SCD children was correlated with pulmonary blood flow, but airway nitric oxide flux was similar to that of the controls and did not correlate with biomarkers of airways obstruction. Lung function appears to deteriorate over time in children with SCD, but prospective longitudinal data with appropriate control groups were lacking. The study presented in chapter five tested the hypothesis that lung function in SCD children, assessed longitudinally, would decline relative to controls and was related to ACS, and that restrictive abnormalities would increase in prevalence. In SCD children, but not controls, lung function declined significantly, and was significantly associated with ACS. Restrictive abnormalities were significantly more common at follow up.

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Alexander, Helen. "Coping with Sickle Cell Disease Using Cognitive Behavior Therapy." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/5157.

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This project focused on identifying the best evidence available on the use of cognitive behavior therapy (CBT) for pediatric patients and families with sickle cell disease (SCD) to improve their coping skills with pain management. This resulted from an identified gap in nursing practice regarding psychosocial support for this subset of hospitalized pediatric patients. The practice-focused question was whether there was evidence in the literature on the use of CBT techniques to improve parental coping skills with children who have chronic and life-threatening illness that could be utilized with sickle cell disease. The theory of stress and coping guided the underpinnings of the study process. The Johns Hopkins Nursing evidence-based practice model (JHNEBP) was the framework for this project. A systematic review was conducted utilizing research-based articles from the major healthcare databases. The original search resulted in over 12,000 articles. This pool was further refined based upon a link between the pediatric population with chronic or life-threatening conditions and family coping skills. This was further narrowed down based on the use of social-cognitive therapy and coping skills. This process resulted in 6 research articles on the use of CBT with the target population. An evaluation of these studies found evidence that CBT can improve parental coping skills. Nursing support for parental coping with SCD has the positive social impact of decreased parental stress and improved quality of life for both the child and the family unit.

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26

Garrett, Kevin C. "Sickle cell disease and the family: a phenomenological study." Diss., Kansas State University, 2014. http://hdl.handle.net/2097/17328.

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Doctor of Philosophy
Department of Family Studies and Human Services
Joyce A. Baptist
Sickle cell disease (SCD) is a prevalent, pervasive chronic illness. It is a hereditary condition that affects those of African, Mediterranean, Indian, Middle Eastern, and Hispanic/Latino descent. It causes extreme pain for patients and a myriad of other symptoms and complications. The medical issues associated with and the very nature of SCD has the potential to cause psychological distress and related problems for patients. Parents, caregivers, significant others, and family members are similarly affected by a family member with SCD. Applying the Vulnerability-Stress-Adaptation Model, this qualitative study used heterogeneous sampling and explored the experience of three families with SCD. Three main themes emerged from the data, analyzed using thematic analysis: Stress and Challenges, Adapting to and Coping with the Demands of SCD, and Individual and Family Strengths. The pervasiveness and unpredictability of SCD as well as the strengthening effects of having experienced SCD were shared across families, despite their heterogeneity. Clinical implications for families with SCD are discussed.

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27

AlJuburi, Ghida. "Sickle cell and the burden of disease in England." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/28116.

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Background Sickle cell disorders (SCD) are the most common inherited blood disorders in England. Without prompt diagnosis and proper treatment, they can be a serious source of morbidity and mortality. Sickle cell diseases affect mainly black minority and ethnic populations, and have so far received relatively low priority from a health policy perspective. Antenatal and newborn screening, the development of minimum standards, antibiotic prophylaxis, comprehensive immunisations, and preventive diagnostic tests have positively influenced SCD management. There remains an unclear picture as to the trends and health care utilization of patients with SCD in England. Aims This study looks at the burden of disease in England by assessing hospital admissions, readmissions and related costs. It also aims to identify gaps in care and prevention which may identify possible contributors to avoidable admissions. Findings Using Hospital Episode Statistics (HES) data, trends for SCD hospital admissions in England showed a rise in 50% of hospital admissions over a 10 year period. The most deprived areas had a higher rate of readmission and in-patient mortality among those with SCD. Adolescents had a higher rate of readmission possibly identifying a gap in health care access. Local findings in a high prevalence area showed that the majority of admissions were for a short length of stay and 74% of patients accounted for multiple admissions. A patient focus group and questionnaire both identified potential gaps in care and prevention. Conclusion Through the use of 6 studies which showed the SCD admission rates in England, the readmission rates, local admissions, costs associated with admission and patient perspectives in both care and prevention, there is a clearer picture as to the trends and health care utilization of patients with SCD in England. The studies suggest that ascertaining the prevalence of at-risk groups in England as well as addressing inequalities in health care access among minority groups and areas of high disease prevalence can further aid in disease management. Shifting diagnostic and follow-up care from acute care facilities to primary care facilities and promoting preventive care measures and adherence to standards and guidelines may possibly decrease the cost burden, reduce avoidable hospital admissions and increase the timeliness and effectiveness of disease management. Investing in training and education of primary care physicians for sickle cell diseases may also improve quality of care.

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Nakakawa, Juliet. "Modelling malaria and sickle cell gene." Thesis, Stellenbosch : Stellenbosch University, 2011. http://hdl.handle.net/10019.1/17989.

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Thesis (MSc)--Stellenbosch University, 2012.
ENGLISH ABSTRACT: The high sickle cell gene frequency has been hypothesised to be related to the protective advantage against malaria disease among heterozygous individuals. In this thesis, we study the interaction between the dynamics of malaria and sickle cell gene. The main aim is to investigate the impact of malaria treatment on the frequency of sickle cell gene. For this, we develop a mathematical model that describes the interactions between malaria and sickle cell gene under malaria treatment. The model includes both homozygous for the normal gene (AA) and heterozygous for sickle cell gene (AS) and assumes that AS individuals are not treated since they do not show clinical symptoms. We first analyse the model without malaria treatment, using singular perturbation techniques, basing on the fact that epidemiological and demographical dynamics occur on two different time scales (fast and slow dynamics). Our analysis on the fast time scale shows that high sickle cell gene frequency leads to high endemic levels for longer duration of parasitemia among heterozygous individuals. However, if the duration of parasitemia is reduced then high sickle cell gene frequency is associated with low endemic levels. We also note that on the slow time scale, the invasion ability of sickle cell gene is dependent on the malaria epidemiological parameters. The invasion coefficient given as the difference in the weighted death rates of AA and AS individuals is used as a measure to determine the establishment of sickle cell gene in the population. Results show that, the gene may establish itself if the weighted death rate of AA individuals is greater than that of AS individuals otherwise it fails. We note that, high mortality of AA individuals leads to establishment of sickle cell gene in the population. Then we analysed the model with treatment, our results indicate that the frequency of sickle cell gene decreases with an increase in the recovery rate of AA individuals. We thus conclude that eradication of malaria disease will lead to a reduction in sickle cell gene frequency.
AFRIKAANSE OPSOMMING: Daar word veronderstel dat die hoë sekelsel geenfrekwensie onder heterosigotiese individue verwant is aan die beskermende voordeel teen malaria siekte. In hierdie verhandeling ondersoek ons die wisselwerking tussen die dinamika van malaria en die sekelsel geen. Die hoofdoel is om die invloed van malaria behandeling op die frekwensie van die sekelsel geen te ondersoek. Hiervoor het ons ‘n wiskundige model ontwikkel, wat die wisselwerking tussen die dinamika van malaria en die sekelsel geen met malaria behandeling, beskryf. Die model sluit beide homosigotiese vir die normale geen (AA) en heterosigotiese vir die sekelsel geen (AS) in, en neem aan dat AS individue nie behandel is nie omdat hulle nie die eerste kliniese simptome getoon het nie. Ons ontleed eers die model sonder malaria behandeling, deur gebruik te maak van enkelvoudige pertubasie tegnieke, wat gegrond is op die feit dat epidemiologiese en demografiese dinamika plaasvind op twee verskillende tydskale (vinnige en stadige dinamika). Ons ontleding op die vinnige tydskaal dui dat hoë sekelsel geenfrekwensie onder heterosigotiese individue lei tot hoë endemiese vlakke vir ‘n langer duur van parasitemie. Nietemin, as die duur van parasitemie afneem, dan word hoë sekelsel geenfrekwensie verbind met lae endemiese vlakke. Ons neem ook waar dat op die stadige skaal die indringingsvermoë van die sekelsel afhanklik is van malaria se epidemiologiese parameters. Die indringingskoëffisiënt wat bereken word as die verskil van die geweegde sterftekoerse van AA en AS individue, word gebruik as ‘n maatstaf om die vestiging van die sekelsel geen in die bevolking te bepaal. Resultate toon dat die geen homself kan vestig as die geweegde sterftekoers van AA individue groter is as di e van die AS individue, andersins misluk dit. Ons let op dat hoë mortaliteit van AA individue lei tot die vestiging van die sekelsel geen in die bevolking. Daarna het ons die model wat behandeling insluit ge-analiseer en ons resultate toon dat die frekwensie van die sekelsel geen afneem met ‘n toename in die herstelkoers van AA individue. Ons kom dus tot die gevolgtrekking dat die uitwissing van malaria siekte sal lei tot die afname in sekelsel geenfrekwensie.

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29

Barach, Ilana. "Disease Management and Psychosocial and Health Outcomes in Pediatric Sickle Cell Disease." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1337716279.

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30

Eiymo, Mwa Mpollo Marthe-Sandrine. "Pulmonary Complications of Sickle Cell Disease Resulting from Erythroid Cell-Driven Signalling." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406901116.

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31

Cooper, LaQuita Nichelle. "Sickle Cell Disease Pain Burden and Quality of Life Among Black Children in Mississippi." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/6000.

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Acute and chronic pain is a common hallmark of sickle cell disease (SCD) in children and adolescents, which can have a profound effect on their quality of life (QOL). However, this relationship is not well quantified. The purpose of this quantitative study was to examine the relationship between SCD pain burden and QOL among Black children ages 8-17 in Mississippi with SCD. The secondary aim was to compare children and caregiver reports of SCD pain burden and QOL with SCD. The social ecological model was used to identify personal factors that influence SCD pain burden and QOL of children with SCD. Eighty-five children and caregiver pairs completed paper surveys on demographics, pain burden, and QOL. Hierarchical linear regression results indicated that increased child SCD pain burden was statistically associated with decreased child's QOL (P

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32

Stewart, Kai Anika Djenaba. "An examination of African American college students' knowledge and attitudes regarding sickle cell disease and sickle cell disease carrier testing a mixed methods study /." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/stewart.pdf.

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33

Mara, Prengler. "Magnetic resonance perfusion and cerebrovascular studies in sickle cell disease." Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418098.

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34

Drasar, Emma Rachel. "Genetic and biological markers of severity in sickle cell disease." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/genetic-and-biological-markers-of-severity-in-sickle-cell-disease(7c1f16a0-0862-4311-ae7f-7842a85e915e).html.

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Sickle cell disease (SCD) is remarkable for the variability of its phenotype despite its genetic simplicity, with family and population studies indicating a strong genetic influence. The best characterised genetic modifiers are genes controlling HbF levels and co-inheritance of alpha-thalassaemia. Other genetic and biological factors may also influence disease severity and the development of complications. King’s Health Partners have the largest adult cohort of SCD patients in the United Kingdom, approximately 2400 patients. Characterising this group (using laboratory variables, evidence of clinical complications and admission data) has formed the basis for my studies. Telomere length and Duffy antigen receptor for chemokines (DARC) status and two complications, sickle nephropathy and sickle hepatopathy were investigated. Relative telomere length (measured using qPCR) was significantly longer in patients with SCD than controls and positively correlates with white blood count. Shorter telomeres were found in patients on hydroxycarbamide treatment and those with Hb SC. We hypothesise that longer telomeres result from up-regulation of telomerase due to inflammation. Polymorphisms in DARC have a high prevalence in people of African ancestry and explain benign ethnic neutropenia. We found positive associations with Duffy positive phenotype and a reduced time to readmission and the development of leg ulcers. We investigated if sickle-related renal impairment was associated with the APOL1, DARC and HMOX1 genes. Duffy positive phenotype was associated with the development of macroalbuminuria and the presence of 1 or more APOL1 risk alleles was associated with the development of renal impairment (as measured by MDRD eGFR). We assessed the prevalence of liver disease in our population using Enhanced Liver Fibrosis score (a combination of serum markers associated with liver fibrosis) and transient elastography (Fibroscan®). Using this approach we found that transfusional iron overload and haemolysis appear to play a key role in the pathogenesis of sickle hepatopathy.

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35

Janse, van Rensburg P. J. "Paediatric cardiac anaesthesia in sickle cell disease : a case series." Master's thesis, University of Cape Town, 2015. http://hdl.handle.net/11427/13790.

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Sickle cell disease (SCD) is the most common inherited haematological disorder, producing a mutation of the haemoglobin molecule known as haemoglobin S (HbS). The presence of HbS in the erythrocyte makes it prone to sickling - a process which may lead to vaso-occlusive injury, haemolysis and a hypercoagulable state. Sickling is precipitated by dehydration, hypoxia, hypothermia, acidosis and low flow states. Over time, multi-organ damage develops with significant morbidity and mortality. Paediatric patients with SCD and congenital heart defects may require anaesthesia for corrective cardiac surgery on cardiopulmonary bypass (CPB). During the perioperative period these high-risk patients may suffer significant complications when exposed to the conditions that favour erythrocyte sickling. This case series details our experience of four paediatric patients with SCD patients who underwent corrective cardiac surgery at Red Cross War Memorial Childrenâ€™s Hospital. The pathophysiology is discussed and the perioperative management of transfusion, cardiopulmonary bypass and temperature regulation is highlighted.

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Ola, Bolanle. "Living with sickle cell disease and depression in Lagos, Nigeria." Thesis, De Montfort University, 2016. http://hdl.handle.net/2086/12266.

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Sickle cell disease (SCD) and depression are each major public health issues globally. Nigeria currently has the largest proportion of people with SCD worldwide, with up to 150,000 annual births. This study highlights the limitations of previous studies, which only utilize the biomedical model in explaining SCD, and which pay insufficient attention to the lived experiences of people with SCD. Extant literature reports strong associations between SCD and depression, and locates the problem ‘only’ in terms of disease severity, levels of service utilization or alleged psychological maladjustment to SCD condition. Biomedical research tends to treat stigma as a predicament that automatically correlates with SCD. Data collected was guided by a modified three-staged theoretical framework derived from Arthur Kleinman, with the use of questionnaires (incorporating Patient Health Questionnaire) to describe depression in persons with SCD; 15 in-depth interviews to explore the illness experience of SCD, and a series of six focus groups to examine depression and stigma in SCD as a form of ‘societal sickness’. In the first stage, questionnaires were administered to 103 outpatients at an SCD clinic in Lagos, Nigeria, and findings revealed an association of depression with age, and severity of SCD as indicated by symptoms such as leg ulcers. The first stage enabled those with moderate depression to be identified and invited into the subsequent stages (two and three) of the research. In the second stage, fifteen in-depth interviews with adults living with SCD were conducted and analysed using interpretive phenomenological analysis (IPA), also drawing on the influences of Herbert Blumer and Erving Goffman. Testimonies suggested that people with SCD face overwhelmingly negative criticisms from a wide range of significant others, including close family members; that the discrimination they face arises not from their condition per se but from the societal norms and expectation that they are assumed to break; and that they themselves identify pathways from the negative experience they endure to their own depression and mental distress. In the third stage, a series of three focus groups, each with five participants, found that people with SCD began to reject negative labels, identify challenges in their own terms, gain a sense of confidence and identity from their participation in groups, and began to identify social barriers to their full participation in society that they wished to challenge. The overall findings of the research suggest that by coming together in groups, people with SCD themselves suggest that rigorously researched social interventions may be considered an important adjunct to medical interventions in improving the lives of those living with SCD in Nigeria and throughout sub-Saharan Africa.

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Salmon, Anderson Tricia. "Sickle Cell Trait and Genetic Counseling." ScholarWorks, 2017. https://scholarworks.waldenu.edu/dissertations/4020.

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Sickle cell trait (SCT) is a very prevalent disorder in the United States, especially among African Americans or people of African descent. However, even with the prevalence of the disorder, there are no standardized guidelines for providing patients with information about SCT and the implications of the disorder at physicals and well-check visits. The purpose of this evidence-based project was to increase awareness for African American patients 18-44 years old in the practice setting about SCT and to provide options for testing and genetic counseling. Kotter's contemporary change theory was used as a guide to implement the new practice approach. A quasi-experimental, single-group, pretest-posttest-only design was used to explore the relationship between providing consistent SCT education and the impact on the rate of SCT screening and genetic counseling. A total of 71 patients participated in the program. The analysis showed a significant (p < 0.001) mean difference of 18.16 points from the preintervention SCT and genetics test mean, which indicated that the intervention was successful in raising SCT and genetics knowledge scores among the target population. The results demonstrated that the implementation of SCT education in the practice setting can enhance social implications related to SCT awareness and opportunities for SCT testing and genetic counseling. The implementation of SCT clinical guidelines can help to increase awareness about SCT and improve the overall population health and reduce the financial burden affiliated with care of those with sickle cell disease and SCT complications.

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Lim, Crystal Marie Stack. "Pain, Quality of Life, and Coping in Pediatric Sickle Cell Disease." Digital Archive @ GSU, 2009. http://digitalarchive.gsu.edu/psych_diss/54.

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Introduction: Sickle cell disease (SCD) affects predominately African Americans and is one of the most prevalent diseases in the United States (Schecter, 1999). Research has not sufficiently examined whether pain associated with SCD impacts quality of life or whether coping impacts this relation. The purpose of this study was to examine the relation between pain and quality of life in children with SCD and to determine whether coping moderates the relation. A secondary aim was to examine associations between age and pain, quality of life, and coping. A final exploratory aim was to examine the relation between racial identity and study variables. Method: 104 children (M = 12.93 years, SD = 3.17 years) with SCD and their parents participated during a regularly scheduled SCD-related medical visit. Parents completed a demographic form. Children completed the Pediatric Pain Questionnaire (PPQ), the Pain Coping Questionnaire (PCQ), the Pediatric Quality of Life Inventory (PedsQL), Sickle Cell Disease Quality of Life (SCD-QoL), and the Multidimensional Inventory of Black Identity (MIBI). Results: After controlling for site and gender, regression analyses revealed that pain (ƒÒ = -0.37) and emotion-focused avoidance coping (ƒÒ = -0.39) were significant predictors of overall generic quality of life (PedsQL Total Score), total R2 = 0.44, F (5, 93) = 13.88, p < 0.001. There was no significant pain x coping interactions found for overall generic quality of life. Child age was not associated with study variables. Exploratory analyses revealed the MIBI Centrality Scale was associated with PCQ Approach Coping, r (80) = -0.24, p < 0.05, and the MIBI Regard Scale was correlated with PCQ Problem-Focused Avoidance Coping, r (84) = 0.30, p < 0.01. Discussion: This study found that pain and emotion-focused avoidance coping were inversely associated with quality of life in children with SCD. Coping was not found to moderate the relation between pain and overall quality of life. The associations between racial identity and coping demonstrate the importance of further examining cultural factors in children with SCD. In addition, there continues to be a need for future research to focus on the psychosocial functioning of children with SCD.

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Perry, Angela. "Quality of life for caregivers of children with sickle cell disease." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002049.

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Coleman, Beth. "Exploring the experience of pain in adults with sickle cell disease." Thesis, Canterbury Christ Church University, 2013. http://create.canterbury.ac.uk/12486/.

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Sickle Cell Disease (SCD) is England’s most common blood disorder whereby sickled shaped red blood cells block small blood vessels causing both acute and chronic pain. Currently there is poor understanding about the experience of SCD pain. Furthermore, there is a recognised difficult relationship between SCD patients and health care professionals (HCP) which has been found to prevent patients seeking medical assistance. Seven adults with SCD participated in semi-structured interviews regarding their experience of pain and receiving medical treatment. Interviews were transcribed and analysed using Interpretative Phenomenological Analysis (Smith, Flowers & Larkin, 2009). The analysis revealed three overarching themes: experiencing unimaginable pain, the dilemma of treatment and finding a life with pain. Findings suggest describing SCD pain is extremely difficult, participants favoured using analogies to attempt to communicate the constant, agonising, limitless, inescapable pain. Participants described that normal rules do not apply in that pain medication does not always relieve pain. These factors have caused misunderstanding with staff thinking SCD patients are drug seeking. Participants wanted HCPs to listen to their own expertise when considering treatment options. Study limitations, implications for clinical practice and current models of health and illness are considered, as well as possible for future research.

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Mohammed, Samir M. M. "Calcium metabolism in sickle cell disease : possible link with sicklaemic osteoporosis." Thesis, University of Salford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292910.

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Bandeen, Timothy C. "Effects of sickle cell disease on growth of the craniofacial complexes. /." View the abstract Download the full-text PDF version View the full-text HTML version, 2005. http://etd.utmem.edu/ABSTRACTS/2005%5F001%5Fbandeen%5Findex.html.

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Thesis (M.S.)--University of Tennessee Health Sciences Center, 2005.
Spine title: Effects of sickle cell disease on growth of the craniofacial complexes. Appendices: leaves 162-414 Bibliography: leaves 145-161.

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Dahman, Bassam. "Evaluating Bilateral Phenomena: The Case of Pain in Sickle Cell Disease." VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1178.

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Gbotosho, Oluwabukola Temitope. "Novel approaches to diagnosis, prognosis and pathogenesis of sickle cell disease." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708915.

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Al-Kitani, Mahfoodha. "Physiological responses to exercise in Omani children with sickle cell disease." Thesis, University of Bath, 2013. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.577754.

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According to the national survey of genetic blood disorders, the prevalence of haemoglobinopathies in Oman is 9.5% with Sickle Cell Disease (SCD) and Sickle Cell Trait (SCT) representing two major public health concerns and having great impact on individuals’ lives as well as on society (Al-Riyami et al., 2001). Complications related to SCD arise owing to ischemic tissue injury and may result in organ dysfunction and premature death. Patients with SCD often experience painful crises (vaso-occlusion), renal disease, acute chest syndrome (ACS) and other lifethreatening conditions. Physical education teachers tend to exclude children with SCD from PE classes due to their health status. It is currently unknown whether exercise might have beneficial, adverse or no effect in children and adults with SCD. Consequently, the recommendation of exercise for children and adults with SCD is rare. accordingly, there were three objectives to the work within this thesis: First, to investigate physical fitness markers in SCD and SCT and compare them to normal healthy children. With no reference data available, the aim of the first study was to provide a general idea of this population’s physical fitness parameters. The results suggest that children with SCT had similar anthropometric measurements, physical fitness and exercise responses to normal healthy children. In contrast, SCD children who were shorter and had lower body mass, higher fat mass and lower physical fitness than SCT and normal healthy children. In addition, children with SCD exhibited higher heart 3 rate and blood lactate responses in response to exercise than SCT children and normal healthy children. The second study was designed to determine cardiovascular responses to exercise in children with SCD and SCT and to compare them with those of normal healthy children from the same age ranges. Normal healthy children had a significantly higher estimated maximal oxygen uptake (VO2max) than SCT and SCD children (P < 0.05), with SCD children achieving the lowest VO2max. The mean heart rate in SCD and SCT was significantly higher during sub-maximal exercise than in normal healthy children (P < 0.05). White blood cell (WBC) count was also higher (P < 0.05) in the SCD group than in the other two groups, which is suggestive of a chronic inflammatory state. The third study aimed to determine whether a single bout of exercise elicits changes in interleukin- 6 (IL-6) concentrations in children with SCD. Children with SCD exhibited higher baseline IL-6 concentrations than the normal healthy children (P < 0.05), suggesting a persistent inflammatory state. However, the exercise bout did not elicit a significant change in IL-6 concentrations in either normal healthy or SCD children. The final study investigated the effect of an acute bout of exercise on postprandial changes in triacylglycerides (TAG), glucose, insulin and total cholesterol. Postprandial TAG concentrations were reduced in the exercise trial (P < 0.05). The postprandial glucose and insulin responses were also reduced in the exercise trial (P < 0.05). In conclusion, the work in this thesis suggests that Omani children with SCD have lower physical fitness than normal healthy children, and that exercise might have beneficial effects on this population. The lower physical fitness of SCD children is associated with altered body composition and lower oxygen-carrying capacity of the blood, as these children had shorter stature, lower body mass, higher fat mass and exhibited lower VO2max. The potential benefit of exercise for this population is demonstrated by the alterations of postprandial lipaemia after an acute bout of exercise. Higher TAG has been associated with increased incidence of vaso-occlusive events in subjects with SCD, and exercise lowered postprandial TAG concentrations in children with SCD.

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Higgins, John M. (John Matthew). "Mathematical and mechanical modeling of vaso-occlusion in sickle cell disease." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/38660.

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Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007.
Includes bibliographical references.
Vaso-occlusive crises cause most of the morbidity and mortality associated with sickle cell disease. The proximal causes of these occlusive events are not well understood. The risks and consequences of vaso-occlusion however are clear. Ten percent of sickle cell disease patients will have a stroke by the age of 20. Two thirds of sickle cell disease patients require more than one hospitalization per year for treatment of pain crises. The flow behavior of blood samples from sickle cell patients was studied in an artificial microfluidic environment. This microfluidic environment allowed modulation of the hydrostatic pressure causing flow, the ambient oxygen concentration, and the vascular channel geometry. A range of blood samples was evaluated by selecting specimens with various hematocrits and concentrations of sickle hemoglobin. Velocity profiles were calculated following sudden changes in oxygen concentration. From these profiles, it was possible to create a phase space of vaso-occlusion in the artificial microfluidic environment. This phase space characterizes the environmental conditions in which sickle cell blood will stop flowing within a given interval of time.
(cont.) This work is a first step in characterizing the inter-relationships between some of the control parameters governing vaso-occlusion: pressure, oxygen concentration, channel size, hematocrit, and sickle hemoglobin concentration. This artificial device enables a quantification of the effect of a clinical therapy, red blood cell exchange, as performed on an actual sickle cell patient. Additionally, three sample small molecules known to alter rates of sickle hemoglobin polymerization were evaluated for their ability to perturb the tendency of sickle cell blood to stop flowing. These results suggest a possible application of this technique to the diagnosis and monitoring of sickle cell patients as well as to the investigation of new regimens of existing treatments and altogether novel therapies.
by John M. Higgins.
S.M.

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Al-Saqladi, Abdul-Wahab. "Sickle cell disease in Yemeni children : Clinical, biochemical and genetic aspects." Thesis, University of Liverpool, 2010. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526823.

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Owotomo, Jejelola. "The Socioeconomic and Cultural Impact of Sickle Cell Disease in Nigeria." ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2569.

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Sickle cell disease (SCD) is a genetic health condition that has continued to increase globally. SCD is prevalent in developing countries like Nigeria with 20 to 30% of the population living with SCD. The aim of this study was to explore the effect of the socioeconomic and cultural factors that affect the quality of life (QOL) of individuals with SCD in Nigeria. The framework for the study is secondary prevention. Secondary prevention allows for opportunities to improve QOL amongst people living with SCD focusing on the health beliefs, and socioeconomic wellbeing. A phenomenological approach was used to collect in-depth data on the effect of socioeconomic and cultural factors from 30 randomly selected individuals living with SCD in Nigeria. Thematic content analysis of participant responses was the qualitative methodology used for this study. Study results indicated that among individuals living with SCD in Nigeria, socioeconomic and cultural factors of the disease contributed to diminishing QOL. Common themes included limited education and awareness, financial support, and cultural beliefs as impactful on an individual's capacity to manage their SCD, leading to diminished QOL. A potential positive social change of this study is to share study results and recommendations with public health officials to promote public health policy and practices that can encourage increased awareness, and treatment of SCD to stimulate a better QOL of individuals living with SCD.

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Fowora, Muinah Adenike. "Adherence to Self-Care Management of Sickle Cell Disease Among Caregivers." ScholarWorks, 2016. https://scholarworks.waldenu.edu/dissertations/2257.

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The self-care management of sickle cell disease (SCD) improves mortality rate; however, compliance with SCD self-care management remains a problem. The purpose of this study was to examine the knowledge and factors that influence compliance with SCD self-care management recommendations among caregivers of children with SCD. The health belief model was used as the theoretical foundation of this study, theorizing that caregivers' perceived susceptibility, severity, and benefits of SCD self-care management will influence compliance. The study used a quantitative research design. A cross-sectional survey was administered to 100 caregivers of children with SCD attending sickle cell clinics in Lagos, Nigeria using convenience sampling. Information was obtained from participants using a structured interviewer-administered questionnaire, and data were analyzed using descriptive statistics, bivariate correlations, and binary logistic regression techniques. Findings confirmed a high adherence rate but low knowledge of SCD self-care management among the caregivers of children with SCD. There was no significant correlation between knowledge of SCD self-care management and adherence. However, the findings from the multivariate analysis identified knowledge as a predictor of adherence and religiosity and total number of barriers as barriers to adherence. Parental health beliefs did not influence adherence to SCD self-care management. These findings have social change implications by guiding the work of health educators, health care providers, and public health practitioners to incorporate group counseling on SCD self-care management at every sickle cell clinic.

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Goldstein, Alana L. "Transition Readiness in Adolescents and Young Adults with Sickle Cell Disease." Xavier University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=xavier1439143927.

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Dissertations / Theses on the topic 'Sickle cell disease treatment'

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