Ácido úrico en las gestantes con diagnóstico de drepanocitosis y preeclampsia / Uric acid in pregnant women diagnosed with sickle cell disease and preeclampsia

RESUMEN Introducción: El ácido úrico es el producto final del ciclo de las purinas y es fundamental como marcador de enfermedad renal, la gota y la preeclampsia. Este biomarcador ejerce efectos potenciales en la placenta y el feto de la gestante con drepanocitosis. Objetivo: Describir los efectos potenciales que produce el ácido úrico en las gestantes con drepanocitosis. Métodos: Se revisó literatura en inglés y en español, a través del sitio web PubMed y el motor de búsqueda Google académico, en artículos publicados en los últimos cinco años. Se utilizaron como términos de búsqueda: preeclampsia, ácido úrico y riesgos en las embarazadas con drepanocitosis. Se analizaron los aspectos más relevantes del tema en la bibliografía revisada. Análisis y síntesis de la información: El incremento del ácido úrico añadido a la vasoclusión, la hipoxia y la necrosis tisular a nivel de la placenta son mecanismos invocados en el desarrollo de la preeclampsia y los índices de partos prematuros que presentan. Es de destacar que no tiene una trayectoria uniforme en todas las pacientes, sobre todo se observa una mejor evolución (con menor presencia de estas complicaciones) en aquellas pacientes que muestran genotipo, niveles de hemoglobina fetal y haplotipo de la hemoglobina S más favorable. Conclusiones: El ácido úrico constituye un biomarcador útil y de alarma en el diagnóstico de la preeclampsia, una de las peores complicaciones tanto para la vida materna como para su descendencia, al ser la gestante con drepanocitosis una paciente de muy alto riesgo de parto pretérmino, prematuridad, bajo peso al nacer, nacidos muertos e infarto placentario.

ABSTRACT Introduction: Uric acid is the end product of the purine cycle and is essential as a marker of kidney disease, gout and pre-eclampsia. This biomarker has potential effects on the placenta and fetus of a pregnant woman with sickle cell disease. Objective: To describe the potential effects of uric acid in pregnant women with sickle cell disease. Methods: Literature in English and Spanish was reviewed, through the PubMed website and the academic search engine Google, in articles published in the last five years. The search terms were: pre-eclampsia, uric acid and risks in pregnant women with sickle cell disease. The most relevant aspects of the subject were analyzed in the reviewed bibliography. Analysis and synthesis of information: The increase in uric acid added to vasoocclusion, hypoxia and tissue necrosis at the level of the placenta are mechanisms invoked in the development of pre-eclampsia and the rates of premature births they present. It is noteworthy that it does not have a uniform trajectory in all patients, especially a better evolution is observed, with less presence of these complications in those patients who show a more favorable genotype, fetal hemoglobin levels and hemoglobin S haplotype. Conclusions: Uric acid constitutes a useful and alarm biomarker in the diagnosis of pre-eclampsia, one of the worst complications both for maternal life and for her offspring, as the pregnant woman with sickle cell disease is a patient at a very high risk of preterm delivery. prematurity, low birth weight, stillbirths and placental infarction.

Association of HMIP1 C-893A polymorphism and disease severity in patients with sickle cell anemia

Abstract Introduction: Sickle cell anemia (SCA) is a Mendelian disorder with a heterogeneous clinical course. The reasons for this phenotypic diversity are not entirely established, but it is known that high fetal hemoglobin levels lead to a milder course of the disease. Additionally, genetic variants in the intergenic region HBS1L-MYB promote high levels of fetal hemoglobin into adulthood. Objective: In the present study, we investigated the HMIP1 C-839A (rs9376092) polymorphism, located at the HBS1L-MYB intergenic region block 1, in SCA patients. Method: We analyzed 299 SCA patients followed in two reference centers in Brazil. The HMIP1 C-839A (rs9376092) genotypes were determined by allele specific polymerase chain reactions. Clinical and laboratory data were obtained from patient interviews and medical records. Results: The median fetal hemoglobin levels were higher in patients with the HMIP1 C-839A (rs9376092) AA genotype (CC = 6.4%, CA = 5.6% and AA = 8.6%), but this difference did not reach significance (p = 0.194). No association between HMIP1 C-839A (rs9376092) genotypes and other clinical and laboratorial features was detected (p > 0.05). Conclusion: In summary, our data could not support the previously related association between the HMIP1 C-893A (rs9376092) polymorphism and differential fetal hemoglobin levels.

Droga antimetabolítica en pacientes con enfermedad de células falciformes en el centro hematológico del hospital de capacitación de Kerbalaa / Antimetabolite drug in patients with sickle cell diseases in hematological center of Kerbalaa training hospital

Antecedentes: el fármaco antimetabolito aumenta el nivel de hemoglobina fetal y reduce la frecuencia de crisis en pacientes con anemia de células falciformes. Objetivo: Evaluar el efecto de los antimetabolitos (hidroxiurea) en casos con crisis falciforme frecuente de anemia de células falciformes y talasemia no dependiente de transfusiones en el hospital de formación de Karbala desde abril de 2016 hasta diciembre de 2020. Pacientes y métodos: de 81 pacientes realizados en este estudio de casos y controles, cuarenta recibieron hidroxiurea y los otros cuarenta y un pacientes no. Se realizaron monitoreos cada dos semanas en los primeros tres meses mediante el envío para análisis (Hb, WBC, recuento de plaquetas y urea en sangre y creatinina sérica) LA PRENSA MÉDICA ARGENTINA Antimetabolite drug in patients with sickle cell diseases in hematological center of kerbalaa training hospital 161 V.107/Nº 3 además de la evaluación de los efectos secundarios de los medicamentos. Los cuarenta y un pacientes restantes que rechazaron la terapia con medicamentos los consideramos un grupo de control. Resultado: el grupo de casos que recibió hidroxilurea tuvo crisis principalmente después de 12 semanas desde la última crisis, mientras que el grupo de control tuvo crisis principalmente cada 3 a 7 semanas con un valor P=0,0001. No hubo efectos secundarios en el 77,5% de los casos que recibieron hidroxiurea. El 22,5% restante de los casos tuvo efectos secundarios menores o inespecíficos. Conclusión: En pacientes con drepanocitosis que sufrieron episodios recurrentes de crisis, la terapia con Hidroxiurea disminuye significativamente la frecuencia de la crisis dolorosa, con un bajo nivel de efectos secundarios en comparación con el grupo control.

Background: the antimetabolite drug increase fetal hemoglobin level and reduce the frequency of crisis in sickle cell disease patients. Aim: To evaluate the effect of antimetabolites (hydroxyurea) in cases with frequent sickling crisis of sickle cell disease and non-transfusion dependent thalassemia in Karbala training hospital from APRIL 2016 till December 2020. Patient and methods: from eighty-one patients conducted in this case control study, forty were received hydroxyurea and the other forty-one patients were not. Monitoring every two weeks in the first three months by sending for investigations (Hb, WBC, platelet count and blood urea and serum creatinine) in addition to assessment of drug side effects. The remaining forty-one patients who refused drug therapy we consider them as a control group. Result: the case group who received hydroxylurea had crisis mostly after 12 weeks from last crisis, whereas the control group had crisis mostly each 3 to 7 weeks in P value 0.0001. There was no side effect in 77.5% of cases received hydroxyurea.The remaining 22.5% of cases had less or nonspecific side effects. Conclusion: In patient with sickle cell diseases who suffered from recurrent episodes of crisis, Hydroxyurea therapy significantly decreases the frequency of the painful crisis, with low level of side effects in comparison with control group

Anemia neonatal grave secundaria a transfusion feto-materna: a proposito de un caso / Severe neonatal anemia due to fetomaternal hemorrhage: an ilustrative case

La transfusión feto-materna es el paso de eritrocitos fetales a la circulación materna. Cuando es masiva, tiene una incidencia aproximada del 0,2-0,9 %. Generalmente, se desconoce el agente desencadenante, pero, en ocasiones, se pueden identificar factores de riesgo. En el embarazo, suele ser asintomática; el síntoma más frecuente es la disminución de los movimientos fetales (el 26 %) en relación con la anemia grave. Se diagnostica mediante la detección de hemoglobina fetal en la sangre materna (test de Kleihauer o citometría de flujo). Se presenta a un recién nacido con anemia crónica secundaria a la transfusión fetomaterna, que, después del tratamiento con transfusión de concentrado de hematíes, tuvo como complicación síntomas de sobrecarga de volumen y empeoramiento clínico. Tras la realización de una exanguinotransfusión, evolucionó favorablemente, sin secuelas.

Fetomaternal transfusion (FMT) is defined by the transfer of fetal blood into the maternal circulation. The incidence of massive FMT is estimated to be approximately 0.2-0.9 % of births. Although a number of etiologies have been associated with FMT, most causes remain unidentified and the pregnancy is usually asymptomatic. The most frequent symptom is the decrease in fetal movements (26 %) in relation to severe anemia. Several diagnostic modalities for FMT are described (Kleihauer stain, flow cytometry). We describe a case of a newborn with chronic anemia secondary to FMT who, after treatment with transfusions of red blood cells, presented volume overload and clinical worsening as a complication. In this case, our patient needed exchange transfusion for definitive improvement without disability.

Genetic variants associated with fetal hemoglobin levels show the diverse ethnic origin in Colombian patients with sickle cell anemia / Las variantes genéticas asociadas con niveles de hemoglobina fetal señalan diversos orígenes étnicos en pacientes colombianos con anemia falciforme.

Introduction: Fetal hemoglobin is an important factor in modulating the severity of sickle cell anemia. Its level in peripheral blood underlies strong genetic determination. Associated loci with increased levels of fetal hemoglobin display population-specific allele frequencies. Objective: We investigated the presence and effect of known common genetic variants promoting fetal hemoglobin persistence (rs11886868, rs9399137, rs4895441, and rs7482144) in 60 Colombian patients with sickle cell anemia. Materials and methods: Four single nucleotide polymorphisms (SNP) were genotyped by restriction fragment length polymorphisms (RFLP) and the use of the TaqMan procedure. Fetal hemoglobin (HbF) from these patients was quantified using the oxyhemoglobin alkaline denaturation technique. Genotype frequencies were compared with frequencies reported in global reference populations. Results: We detected genetic variants in the four SNPs, reported to be associated with higher HbF levels for all four SNPs in the Colombian patients. Genetic association between SNPs and HbF levels did not reach statistical significance. The frequency of these variants reflected the specific ethnic make-up of our patient population: A high prevalence of rs7482144-'A' reflects the West-African origin of the sickle cell mutation, while high frequencies of rs4895441-'G' and rs11886868-'C' point to a significant influence of an Amerindian ethnic background in the Colombian sickle cell disease population. Conclusion: These results showed that in the sickle cell disease population in Colombia there is not a unique genetic background, but two (African and Amerindian). This unique genetic situation will provide opportunities for a further study of these loci, such as fine-mapping and molecular-biological investigation. Colombian patients are expected to yield a distinctive insight into the effect of modifier loci in sickle cell disease.

Introducción. La hemoglobina fetal es un importante factor modulador de la gravedad de la anemia falciforme, cuya expresión está muy condicionada por el factor genético. Los loci asociados con el incremento de la hemoglobina fetal pueden presentar frecuencias alélicas específicas para cada población. Objetivo. Investigar la presencia y el efecto de las variantes genéticas rs11886868, rs9399137, rs4895441 y rs7482144 asociadas con la persistencia de hemoglobina fetal, en 60 pacientes colombianos con anemia falciforme. Materiales y métodos. Se hizo la genotipificación de los polimorfismos de nucleótido simple ( Single Nucleotide Polymorphisms, SNP) mediante la técnica de polimorfismos de longitud de fragmentos de restricción ( Restriction Fragment Length Polymorphisms, RFLP) y el procedimiento TaqMan. La hemoglobina fetal (HbF) se cuantificó utilizando la técnica de desnaturalización alcalina de la oxihemoglobina. Las frecuencias genotípicas se compararon con las reportadas en poblaciones de referencia global. Resultados. Se observaron variantes genéticas ya reportadas para aumento de HbF en los cuatro SNP. La asociación genética entre los SNP y el incremento de la HbF no alcanzó significancia estadística. La frecuencia de estos alelos reflejó la siguiente composición específica en esta muestra de pacientes colombianos: una gran prevalencia de rs7482144-'A', lo que indica que el origen de la mutación para la anemia falciforme es África occidental, y una gran frecuencia de rs4895441-'G' y rs11886868-'C', lo que denota la influencia significativa del origen genético amerindio. Conclusión. Los resultados evidenciaron que la población con anemia falciforme de Colombia no tiene un único origen genético, sino que existen dos (africano y amerindio). Esta situación genética única ofrece la oportunidad de llevar a cabo un estudio más amplio de estos loci a nivel molecular. Se espera que el estudio de pacientes colombianos permita una visión diferente del efecto de los loci modificadores en esta enfermedad.

Pattern of hemolysis parameters and association with fetal hemoglobin in sickle cell anemia patients in steady state

This study aimed to evaluate the influence of fetal hemoglobin (Hb F) on hemolysis biomarkers in sickle cell anemia patients. Methods: Fifty adult sickle cell anemia patients were included in the study. All patients were taking hydroxyurea for at least six months and were followed at the outpatient clinic of a hospital in Fortaleza, Ceará, Brazil. The control group consisted of 20 hemoglobin AA individuals. The reticulocyte count was performed by an automated methodology, lactate dehydrogenase and uric acid were measured by spectrophotometry and arginase I by enzyme-linked immunosorbent assay (ELISA). The presence of Hb S was detected by high-performance liquid chromatography. The level of significance was set for a p-value <0.05. Results: A significant increase was observed in the reticulocyte count and lactate dehydrogenase, uric acid and arginase I levels in sickle cell anemia patients compared to the control group (p-value <0.05). Patients having Hb F levels greater than 10% showed a significant decrease in the reticulocyte count, arginase I and lactate dehydrogenase. A significant decrease was observed in arginase I levels in patients taking hydroxyurea at a dose greater than 20 mg/kg/day. Conclusion: The results of this study show that sickle cell anemia patients have increases in the hemolysis biomarkers, lactate dehydrogenase, reticulocyte count, arginase I, uric acid and increases in Hb F can reduce the reticulocyte count and arginase I and lactate dehydrogenase levels.

Socioeconomic and demographic characteristics of sickle cell disease patients from a low-income region of northeastern Brazil

To characterize the socioeconomic and demographic aspects of sickle cell disease patients from the state of Rio Grande do Norte (RN), Northeast Brazil, and their adherence to the recommended treatment. Methods: This cross-sectional descriptive study was performed at referral centers for the treatment of hematological diseases. One hundred and fifty-five unrelated individuals with sickle cell disease who went to these centers for outpatient visits were analyzed. All the patients, or their caregivers, were informed about the research procedures and objectives, and answered a standardized questionnaire. Results: The patients were predominantly younger than 12 years old, self-declared as mulatto, lived in small towns fairly distant from the referral center, and had low education and socioeconomic levels. Individuals who were ten or younger were diagnosed at an earlier age. Almost 50% of the patients were taking hydroxyurea, 91.4% reported having received pneumococcal/meningococcal vaccinations and 76.1% received penicillin as antibiotic prophylaxis. However, the majority of them reported having difficulties following the recommendations of the physicians, mainly in respect to attaining the prescribed medications and transportation to the referral centers. Conclusion: These individuals have a vulnerable socioeconomic situation that can lead to an aggravation of their general health and thus deserve special attention from the medical and psychosocial perspectives. Thus, it is necessary to improve public policies that provide Brazilian sickle cell disease patients with better access to medical treatment, living conditions, and integration into society.

Análisis de pacientes drepanocíticos tratados con hidroxiurea en el Hospital Nacional de Niños / Evaluation of sickle cell patients treated with hidroxyurea at the National Children's Hospital

Antecedentes: desde 1984 estudios comprobaron que la hidroxiurea aumentaba los niveles de hemoglobina fetal y del volumen corpuscular medio, por esta razón a partir de 1998 fue el primer fármaco aprobado para el tratamiento en la drepanocitosis. El objetivo de este estudio fue describir la respuesta y complicaciones de los pacientes drepanocíticos en tratamiento con hidroxiurea en el Hospital Nacional de Niños. Métodos: estudio transversal y retrospectivo, realizado en pacientes con drenopacitosis atendidos en el servicio de Hematología del Hospital Nacional de Niños de enero 2006 a diciembre 2009; se incluyeron pacientes cuyo expediente clínico reunía los criterios de inclusión...

Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: a single-center experience in Brazil / Efeitos clinicos e hematologicos do tratamento com hidroxiureia em pacientes falciformes: experiencia de um centro no Brasil

CONTEXT AND OBJECTIVES Sickle cell disease (SCD) is the most common genetic disorder among people of African descent, affecting approximately 3,500 newborns each year in Brazil. Hydroxyurea (HU) is the only effective drug to treating patients with SCD, thereby reducing morbidity and mortality. The objective was to analyze the effects of HU on SCD patients at our institution. DESIGN AND SETTING Retrospective study conducted at a sickle cell centre in Ribeirão Preto, São Paulo, Brazil. METHODS We analyzed clinical and laboratory data on 37 patients. The hematological parameters and clinical events that occurred during the year before and the first year of treatment with HU were analyzed. The mean dose of HU was 24.5 ± 5.5 mg/kg/day. RESULTS There were rises in three parameters: hemoglobin (8.3 g/dl to 9.0 g/dl, P = 0.0003), fetal hemoglobin (HbF) (2.6% to 19.8%, P < 0.0001) and mean cell volume MCV (89 to 105 fl, P = 0.001); and reductions in the numbers of leukocytes (10,050/µl to 5,700/µl, P < 0.0001), neutrophils (6,200/µl to 3,400/µl, P = 0.001), platelets (459,000/µl to 373,000/µl, P = 0.0002), painful crises (1.86 to 0.81, P = 0.0014), acute chest syndromes (0.35 to 0.08, P = 0.0045), infections (1.03 to 0.5, P = 0.047), hospitalizations (1.63 to 0.53, P = 0.0013) and transfusions (1.23 to 0.1, P = 0.0051). CONCLUSION The patients presented clinical and hematological improvements, with an increase in HbF and a reduction in the infection rate, which had not been addressed in most previous studies. .

CONTEXTO E OBJETIVO A doença falciforme (SCD) é o distúrbio genético mais comum entre afrodes-cendentes, afetando aproximadamente 3.500 recém-nascidos a cada ano no Brasil. A hidroxiureia (HU) é a única droga efetiva para o tratamento dos pacientes com SCD, reduzindo a morbidade e a mortalidade da doença. O objetivo do estudo foi analisar os efeitos da HU em pacientes com SCD em nossa instituição. TIPO DE ESTUDO E LOCAL Estudo retrospectivo realizado em um centro de anemia falciforme em Ribeirão Preto, São Paulo, Brasil. MÉTODOS Nós analisamos os dados clínicos e laboratoriais de 37 pacientes. Os parâmetros hematológicos e eventos clínicos que ocorreram no ano anterior e durante o primeiro ano de tratamento com HU foram analisados. A dose média de HU foi 24.5 ± 5.5 mg/kg/dia. RESULTADOS Houve aumento em três parâmetros estudados: hemoglobina (8,3 g/dl para 9,0 g/dl, P = 0,0003), hemoglobina fetal (HbF) (2,6% para 19,8%, P < 0,0001) e volume corpuscular médio (VCM) (89 para 105 fl, P = 0,001); e redução do número de leucócitos (10.050/µl para 5.700/µl, P < 0,0001), neutrófilos (6.200/µl para 3.400/µl, P = 0,001), plaquetas (459.000/µl para 373.000/µl, P = 0,0002), crises dolorosas (1,86 para 0,81, P = 0,0014), síndrome torácica aguda (0,35 para 0,08, P = 0,0045), infecções (1,03 para 0,5, P = 0,047), hospitalizações (1,63 para 0,53, P = 0,0013) e número de transfusões (1,23 para 0,1, P = 0,0051). CONCLUSÃO Os pacientes apresentaram melhora clínica e hematológica, com aumento da HbF e redução da taxa de infecção, dado este não explorado na maioria dos estudos clínicos já publicados. .

Homozygous sickle cell disease in Uganda and Jamaica a comparison of Bantu and Benin haplotypes / La anemia de células falciformes homocigóticas en Uganda y Jamaica comparación de haplotipos Bantú y Benin

OBJECTIVE: To compare the haematological and clinical features of homozygous sickle cell (SS) disease in Bantu and Benin haplotypes in a cross-sectional study of 115 Ugandan patients attending the Sickle Cell Clinic at Mulago Hospital, Kampala, Uganda, with 311 patients in the Jamaican Cohort Study. METHODS: This involved comparison of clinical features and haematology with special reference to genetic determinants of severity including fetal haemoglobin levels, beta-globin haplotype and alpha thalassaemia status. RESULTS: The Bantu haplotype accounted for 94% of HbS chromosomes in Ugandan patients and the Benin haplotype for 76% of HbS chromosomes in Jamaica. Ugandan patients were marginally more likely to have alpha thalassaemia, had similar total haemoglobin and fetal haemoglobin levels but had higher reticulocyte counts and total bilirubin levels consistent with greater haemolysis. Ugandan patients had less leg ulceration and priapism, but the mode of clinical presentation, prevalence of dactylitis, features of bone pain and degree of delay in sexual development, assessed by menarche, were similar in the groups. In Ugandan patients, a history of anaemic episodes was common but these were poorly documented. CONCLUSION: The haematological and clinical features of the Bantu haplotype in Uganda were broadly similar to the Benin haplotype in Jamaica except for less leg ulceration and priapism and possibly greater haemolysis among Ugandan subjects. Anaemic episodes in Uganda were treated empirically by transfusion often without a clear diagnosis; better documentation including reticulocyte counts and observations on spleen size is necessary to evolve appropriate models of care.

OBJETIVO: Comparar los rasgos clínicos de la anemia de células falciformes homocigóticas (SS) en los haplotipos Bantú y Benin en un estudio transversal de 115 pacientes ugandeses que asisten a la Clínica de la anemia de células falciformes en el Hospital de Mulago, Kampala, Uganda, con 311 pacientes en un estudio de cohorte jamaicano. MÉTODOS: El estudio conllevó la comparación de los rasgos clínicos y hematológicos con referencia especial a los determinantes genéticos de la severidad, incluyendo los niveles de la hemoglobina fetal, haplotipos del gen de la globina beta, y el estado de la alfa talasemia. RESULTADOS: El haplotipo Bantú dio cuenta del 94% de los cromosomas HbS en los pacientes ugandeses, en tanto que los haplotipos Benin dieron cuenta del 76% de los cromosomas de HbS en Jamaica. Los pacientes de Uganda presentaron una probabilidad marginalmente mayor de alfa talasemia, tenían niveles similares de hemoglobina total y hemoglobina fetal, pero en cambio presentaban conteos más altos de reticulocitos así como niveles mayores de bilirrubina total, en correspondencia con una mayor hemólisis. Los pacientes ugandeses presentaban menor ulceración de las piernas y priapismo, pero el modo de presentación clínica, la prevalencia de dactilitis, los rasgos de dolor óseo, y el grado de retraso en el desarrollo sexual, evaluado por la menarquia, fueron similares en todos los grupos. Los pacientes de Uganda se caracterizaron comúnmente por una historia de episodios de anemia, pobremente documentados. CONCLUSIÓN: Los rasgos clínicos y hematológicos del haplotipo Bantú en Uganda fueron considerablemente similares al haplotipo Benin en Jamaica, salvo por una menor presencia de ulceración de las piernas y priapismo, así como posiblemente mayor hemólisis entre los sujetos de Uganda. Los episodios de anemia en Uganda fueron tratados empíricamente mediante transfusión, a menudo sin un diagnóstico claro. Se necesita una mejor documentación - incluyendo conteos de reticulocitos - así como observaciones del tamaño del bazo, a fin de desarrollar modelos de cuidado apropiados.

Haplotipos del gen de la globina beta en portadores de hemoglobina S en Colombia / Beta globin haplotypes in hemoglobin S carriers in Colombia

Introducción. La mutación de la hemoglobina S (HbS) va acompañada por otras mutaciones en la región del cromosoma 11, conocida como conjunto de la globina beta(beta globin cluster). El patrón de combinación de estos polimorfismos da lugar a los haplotipos que se heredan junto con la mutación de la hemoglobina S, se denominan haplotipos de la mutación bs y revisten gran importancia epidemiológica y clínica. Objetivo. Determinar la frecuencia de los principales haplotipos asociados al gen HBB en pacientes colombianos heterocigotos para hemoglobina S. Materiales y métodos. En la Clínica Colsanitas se han estudiado a la fecha 1.200 muestras de sangre periférica de niños en busca de hemoglobinopatías, y se ha encontrado el rasgo falciforme como la hemoglobinopatía más frecuente. Se determinaron los haplotipos del gen HBB que presentaron la mutación beta-S en 33 niños con patrón electroforético de hemoglobina AS, mediante reacción en cadena de la polimerasa (PCR) y enzimas de restricción. Se determinaron el patrón electroforético de la hemoglobina, el nivel de hemoglobina fetal y los parámetros hematológicos de cada individuo. Resultados. Los haplotipos de la hemoglobina S encontrados con mayor frecuencia en la muestra analizada son de origen africano y su orden de aparición fue mayor para el haplotipo Bantú (36,4 %), seguido por Senegal (30,3 %), Benín (21,2 %) y Camerún (12,1 %). La electroforesis de hemoglobina confirmó el fenotipo AS; la dosificación de hemoglobina fetal mostró niveles por debajo de 1 % y los parámetros hematológicos analizados mostraron valores normales en el 100 % de los individuos. Conclusión. Los haplotipos de la HbS encontrados con mayor frecuencia en la muestra estudiada eran de origen africano y su distribución variaba de acuerdo con el lugar de prodedencia del individuo. La mayor frecuencia correspodió al haplotipo Bantú.

Introduction. The hemoglobin S (HbS) mutation is accompanied by other mutations in the region of chromosome 11 known as "beta globin cluster". The pattern of combination of these polymorphisms giving rise to the haplotypes that co-inherit the HbS mutation, are called haplotypes bs, and are of great epidemiological and clinical significance. Objective. The frequencies of major haplotypes associated with S beta-globin gene was determined in Colombian patients heterozygous for hemoglobin S. Materials and methods. As part of the national neonatal screening program at Clínica Colsanitas, located in major cities of Colombia, nearly 1,200 children from different areas of the country were examined for hemoglobinopathies. The sickle cell trait was identified as the most common. S beta-globin gene haplotypes were determined by PCR and restriction enzymes in 33 children with AS hemoglobin electrophoretic patterns (carrier state). In addition, electrophoretic patterns of hemoglobin, fetal hemoglobin levels and hematologic parameters of each individual were identified. Results. The most frequent haplotypes in Colombia were the Bantú haplotype (36.4 %), followed by Senegal (30.3 %), Benin (21.2 %) and Cameroon (12.1 %) haplotypes. Hemoglobin electrophoresis confirmed the AS phenotype in all patients, and fetal hemoglobin levels below 1%. Other hematological parameters were normal in all cases. Conclusion. The HbS haplotypes found more frequently in the sample were of African origin, and their distribution varied according to the place of origin of the individual. The most frequent corresponded to the Bantu haplotype.

What influences Hb fetal production in adulthood?: [review]

Human hemoglobin genes are located in α and β globin gene clusters in chromosomes 16 and 11, respectively. Different types of hemoglobin are synthesized according to the stage of development with fetal hemoglobin (α2γ2) (Hb F) being the main hemoglobin in the fetal period. After birth, there is a reduction (to about 1 percent) in Hb F levels and adult hemoglobin, Hb A (2α2β2), increases to more than 96 percent of total hemoglobin. However, some genetic conditions whether linked to the β-globin gene cluster or not are associated with high Hb F levels in adults. Among those linked to β-globin are hereditary persistence of fetal hemoglobin, delta-beta thalassemia (δβ-Thalassemia) and the XmnI polymorphism (-158 C > T). Other polymorphisms not related to β-globin gene cluster are known to influence the γ-globin gene expression in adulthood. The most relevant polymorphisms that increase concentrations of Hb F are the HMIP locus on chromosome 6, the BCL11A locus on chromosome 2, the Xp22.2 region of the X chromosome and the 8q region on chromosome 8. Findings from our research group studying genetic factors involved in γ-globin gene regulation in adults without anemia in the northwestern region of São Paulo State showed that high Hb F levels are influenced by the presence of hereditary persistence of fetal hemoglobin mutations and the XmnI polymorphism, suggesting that both genetic alterations characterize the molecular basis of the evaluated population.

Hemoglobina fetal em indivíduos com anemia falciforme e persistência hereditária da hemoglobina fetal / Fetal hemoglobin in patients with sickle cell anemia and hereditary persistence of fetal hemoglobin

O estudo de marcadores associados à síntese de hemoglobina fetal (HbF) é de grande interesse científico, pois contribui para o entendimento dos mecanismos regulatórios dos genes envolvidos na síntese das cadeias globínicas gama, uma vez que esta Hb é importante na modulação genética da anemia falciforme (HbSS). O objetivo desse estudo foi investigar a influência de alterações em genes envolvidos na síntese de HbF e suas associações com marcadores laboratoriais e clínicos na HbSS e caracterizar o fenótipo e o genótipo de indivíduos com o perfil sugestivo de persistência hereditária de hemoglobina fetal (PHHF). Dessa forma, foi realizado um estudo de corte transversal, seguido de caso-controle com a casuística de 43 indivíduos HbSS com HbF> 3,0% e 3 indivíduos com perfil sugestivo de PHHF. O presente estudo foi aprovado pelo CEP-CpGM-Fiocruz. Os polimorfismos HBG2 -396/-391del, HBG2 SNP -369 C>G, HBG2 -309 A>G, HBG2 -157 T>C, HBG1 -499 T>A, HBG1 -369 C>G, HBG1 -271 C>T e HBG1-225/-222del foram investigados por sequenciamento automático de DNA; os haplótipos ligados ao gene da globina beta foram investigados por PCR-RFLP; os polimorfismos BCL11Ars766432, BCL11Ars6732518, OR51B5/6rs4910756, OR51B5/6rs7483122, HMIPrs11759553, HMIPrs35959442 foram investigados por PCR em tempo real; a talassemia alfa 23.7 Kb e as deleções PHHF-1, PHHF-2 e PHHF-4 por PCR. As análises hematológicas foram realizadas em contador automático de células, o perfil de hemoglobina foi confirmado por cromatografia líquida de alto desempenho e as dosagens bioquímicas foram investigadas por quimiluminescência. As concentrações de HbF foram associadas com HbS (p<0,0001), hematócrito (p=0,035), VCM (p=0,010), HCM (p=0,045), colesterol VLDL (p=0,044), ferro (p=0,001) e ferritina (p=0,042). Os polimorfismos estudados apresentaram associação com marcadores laboratoriais e clínicos no grupo estudado. O polimorfismo HBG1 -271 C>T foi associado com a concentração de HbF (p=0,027; RP=4,45; IC95%= 1,14 – 17,41) e ferro (p=0,0076); o HBG1 -499 T>A com as concentrações de glicose (p=0,007) e de alfa-1 antitripsina (p=0,008); o HBG1 -225/-222del com as concentrações de colesterol LDL (p=0,017); o HBG2 -396/-391del com as concentrações de HbS (p=0,017), creatinina (p=0,042) e bilirrubina p=0,030), sendo associado também ao quadro clínico mais grave da doença, com ocorrência frequente de crises vaso-oclusivas (p=0,046), litíase biliar (p=0,021) e o uso de hemoterápicos (p=0,009); o BCL11A rs766432 com a contagem de reticulócitos (p<0,0001) e a concentração de colesterol total (p=0,033); o BCL11Ars6736518 com concentração de glicose (p=0,049) e a contagem de eosinófilos (p=0,012); o HMIPrs35959442 com as concentrações de ferritina (p=0,035), creatinina (p=0,008) e VCM (p=0,022); o HMIPrs11759553 com as concentrações de ácido úrico (p=0,033) e ferritina (p=0,020); e os polimorfismos OR51B5/6rs7483122 e OR51B5/6 rs4910756 com as concentrações de creatinina (p=0,001). A análise multivariada mostrou associação do genótipo CAR/CAR com a concentração diminuída de HbF e o uso de hemoterápicos. A talassemia alfa 23.7 Kb apresentou efeito protetor, sendo associada com as concentrações de ALT (p=0,044), AST (p=0,039) e com a contagem de linfócitos (p=0,050). Os três casos associados ao fenótipo de PHHF não apresentaram alterações clínicas e laboratoriais significativas, inclusive o caso 3, que apresentou o genótipo HbSF. É importante salientar que esses indivíduos não eram portadores de nenhuma das formas de PHHF investigadas. Estudos adicionais devem ser conduzidos com o objetivo de validar os resultados encontrados nesse estudo e de esclarecer os possíveis mecanismos pelos quais os marcadores moleculares investigados interferem na modulação da síntese de HbF e se esses biomarcadores podem apresentar mecanismos diferenciados daqueles comumente investigado, uma vez que foram descritas associações com marcadores importantes para o acompanhamento clínico de indivíduos HbSS.

The study of markers associated with the fetal hemoglobin (HbF) synthesis is of great scientific interest, since it can contribute to understanding regulatory mechanisms of genes involved in the synthesis of globin chains, once that HbF participate in the genetic modulation of sickle cell anemia (HbSS). The aim of this study was to investigate the influence of changes in genes involved in the synthesis of HbF and their associations with clinical and laboratory markers in HbSS and characterize the phenotype and genotype of individuals with the profile suggestive of hereditary persistence of fetal hemoglobin (HPFH). Thus, we performed a cross-sectional study, followed by a case-control, in a group of 43 HbSS individuals with HbF> 3.0% and 3 individuals with a suggestive profile of HPFH. Polymorphisms HBG2 -396/-391del, the HBG2 SNP -369 C> G, HBG2 -309 A> G, HBG2 -157 T> C, HBG1 -499 T> A, HBG1 -369 C> G HBG1 the -271 C> T and HBG1-225/-222del were investigated by automated DNA sequencing; haplotypes linked to the beta globin gene were investigated by PCR-RFLP; single nucleotide polymorphisms of BCL11Ars766432, BCL11Ars6732518, OR51B5/6rs4910756, OR51B5/6rs7483122 , HMIPrs11759553, HMIPrs35959442 were investigated by real-time PCR, alpha thalassemia 2 with 3.7 Kb deletion and HPFH-1 , HPFH-2 and HPFH-4 deletions by PCR Hematological tests were performed in automatic cell counter, the profile of hemoglobin was confirmed by high performance liquid chromatography and biochemical analysis were investigated by immunochemistry assay method. Levels of HbF were associated with HbS (p <0.0001), hematocrit (p= 0.035), MVC (p= 0.010), MHC (p= 0.045), VLDL cholesterol (p= 0.044), iron (p= 0.001) and ferritin (p= 0.042)...

Patients with sickle cell disease taking hydroxyurea in the Hemocentro Regional de Montes Claros

BACKGROUND: The development of therapies for sickle cell disease has received special attention, particularly those that reduce the polymerization of hemoglobin S. Hydroxyurea is a commonly used medication because it has the ability to raise levels of fetal hemoglobin, decrease the frequency of vaso-occlusive episodes and thus improve the clinical course of sickle cell disease patients. OBJECTIVE: To study hematological data and the clinical profile of sickle cell disease patients taking hydroxyurea in a regional blood center. METHODS: From the charts of 20 patients with sickle cell anemia, the clinical outcomes and a number of hematological variables were analyzed before and during treatment with hydroxyurea. RESULTS: The patients' ages ranged from 6 to 41 years old, most were dark skinned and there was a predominance of women. The main symptom that defined whether patients were prescribed hydroxyurea was painful crises followed by hospitalizations. During treatment with hydroxyurea there were significant increases in hemoglobin, fetal hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin. The reticulocyte and white blood cell counts dropped significantly with treatment. A positive correlation was found between fetal hemoglobin and mean corpuscular volume before and during treatment. Additionally, a correlation was found between the white blood cell and reticulocyte counts before treatment with hydroxyurea. CONCLUSION: Most patients showed improvements with treatment as demonstrated by increases in hemoglobin, fetal hemoglobin and mean corpuscular volume, as well as by reductions in the reticulocyte and white blood cell counts. Clinically, more than 50 percent of patients had a significant reduction of events.

Enfermedad hemolítica perinatal: manejo de la embarazada RhD negativo / Perinatal hemolytic disease: management of RhD immunization in pregnancy

En solo 50 años la enfermedad hemolítica perinatal por isoinmunización anti D pasó de ser una enfermedad sin etiología conocida, incurable y no prevenible, a la situación actual en que por las técnicas de prevención, diagnóstico oportuno y tratamiento especializado tiene baja incidencia y altas expectativas de sobrevida, incluso en los casos más severos. Se describe la historia, las técnicas de prevención, diagnóstico, manejo y tratamiento de la enfermedad.

In just 50 years the perinatal hemolytic disease due to RhD isoimmunization went from being a disease without known etiology, untreatable and not preventable to the current situation in which the prevention techniques, opportune diagnosis and specialized treatment has low its incidence and has an expected high survival even in the more severe cases. This article describes the history, prevention techniques, diagnosis, management and treatment of the disease.

The identification of beta-thalassemia mutants in Brazilians with high Hb F levels / Identificação de mutantes de beta talassemia em grupo de indivíduos com Hb Fetal aumentada da população brasileira

Hemoglobinopathies are a heterogeneous group of genetic disorders which represent a public health problem, with significant morbidity, in countries where the prevalence is high. This study aimed at identifying molecular abnormalities that might explain the laboratorial profile obtained using electrophoresis and high performance liquid chromatography in a group of individuals without signs or clinical symptoms of anemia. Five different mutations for beta-thalassemia were found using PCR-ASO: three cases with CD 6 (-A), one CD 39, one IVI I-6, one -87 (mutations originating in the Mediterranean region) and one IVS II-654 (mutation originating in Asia). This is the first time that the CD 6 (-A), -87 and IVS II-654 mutations have been described in the Brazilian population.

As hemoglobinopatias são um grupo de afecções genéticas que representam problema de saúde pública em muitos países em que sua incidência é alta, com significativa morbidade. Objetivamos identificar defeitos moleculares que pudessem explicar o perfil laboratorial obtido por eletroforese e HPLC com Hb F elevada, em um grupo de indivíduos adultos sem sinais ou sintomas de anemia. Encontramos cinco diferentes mutações que originam beta talassemia por PCR-ASO: três casos com CD 6 (-A), um CD 39, um IVS 1-5, um -87 todas de origem mediterrânea, e um IVS II-654 de origem asiática. As mutações CD 6 (-A), -87 e IVS II-654 foram descritas pela primeira vez na população brasileira.

Estudo da correlação entre os níveis de hemoglobina fetal e o prognóstico dos pacientes com anemia falciforme / Study of the correlation between fetal hemoglobin levels and the prognosis of patients with sickle cell anemia

Os níveis de hemoglobina fetal (HbF) foram analisados em 47 pacientes com anemia falciforme, residentes em Fortaleza, capital do Ceará, com a finalidade de fornecer informações sobre a influência da HbF no prognóstico desta doença. A determinação dos valores hematológicos foi realizada em contador automático de células sanguíneas (modelo Sysmex KX-21N, Roche) e os níveis de HbF foram determinados pela técnica da desnaturação alcalina. Dentre os resultados foi demonstrada uma tendência de menor número de pacientes com crises vaso-oclusivas (p=0,0405) e úlceras de perna (p=0,0076) com o aumento dos níveis de HbF. Não houve diferença estatisticamente significativa na comparação entre os níveis de HbF e os valores de hemácias, hemoglobina, hematócrito, leucócitos e plaquetas. Os resultados demonstram que os níveis de hemoglobina fetal podem ser utilizados como fator prognóstico nos pacientes com anemia falciforme, no entanto não deve ser a única ferramenta diagnóstica para prever o quadro clínico destes pacientes.

The fetal hemoglobin (HbF) levels of 47 patients with sickle cell anemia living in Fortaleza, Brazil were analyzed to provide information on the influence of HbF on the prognosis of this disease. Measurement of hematological variables was achieved using a Sysmex KX-21N cell counter ( Roche) and the levels of HbF were determined by the alkali denaturation technique. With increased levels of HbF, there was a trend that fewer patients had painful episodes (p = 0.0405) and leg ulcers (p = 0.0076). There were no statistically significant differences between the levels of HbF and the concentrations of red blood cells, hemoglobin, hematocrit, leukocytes and platelets. The results show that levels of fetal hemoglobin can be used as a prognostic factor in patients with sickle cell anemia however they should not be the only diagnostic tool to predict the clinical status of these patients.