Amelioration of clinical severity through raised fetal hemoglobin in sickle cell anaemia

In the present study, the levels of fetal hemoglobin (HbF) in sickle cell anemia patients were compared with sickle cell trait, beta thalassemia major and control. The mean HbF levels in beta thalassemia major and sickle cell anemia were 51.62 and 19.63% respectively. However, when the amount of HbF was expressed in terms of gram hemoglobin per deciliter whole blood, the mean values were 2.88 and 1.81 respectively between the two groups, suggesting that the genetic mechanism controlling the different threshold levels of increased HbF in these disorders could probably be similar. The elevated. HbF level in sickle cell anemia along with moderate hematologic profile observed in the present study is suggested to provide amelioration of the clinical severity unlike in beta thalassemia major where despite raised HbF levels, the severe clinical implications are attributed to marked imbalance in the globin chain synthesis.     

Sickle cell anemia from central India: A retrospective analysis

Although sickle cell anemia in India is believed to have a mild clinical presentation, few studies report severe disease in many patients from central India. Hence, we have retrospectively studied 316 children with SCA who were followed up for a period of 5.8±5.7 years. There were 55.4 blood transfusions, 43.3 episodes of vaso-occlusive crises requiring hospitalization, and 108.9 hospitalizations per 100 person years. Ninety six (30%) patients had severe disease whereas 74 patients also fulfilled the criteria for hydroxyurea therapy. Significant proportion of children with sickle cell anemia from central India present with severe clinical presentation and require regular medical attention.     

Gallstones in sickle cell disease: observations from The Jamaican Cohort study

The prevalence, incidence, risk factors, clinical associations, and morbidity of gallstones were studied in 311 patients with homozygous sickle cell disease and 167 patients with sickle cell-hemoglobin C disease in a cohort study from birth. Gallstones developed in 96 patients with homozygous sickle cell disease and 18 patients with sickle cell-hemoglobin C disease; specific symptoms necessitating cholecystectomy occurred in only 7 patients with homozygous sickle cell disease.     

Sickle cell disease: from membrane pathophysiology to novel therapies for prevention of erythrocyte dehydration

Sickle cell anemia is characterized by the presence of dense dehydrated erythrocytes that have lost most of their K content. Due to the unique dependence of Hb S polymerization on intracellular Hb S concentration, preventing this dehydration should markedly reduce polymerization. The erythrocyte intermediate conductance Ca-activated K channel (hSK4 or KCNN4), first described by Gardos, has been shown to be a major pathway for sickle cell dehydration. Studies with the imidazole antimycotic clotrimazole have shown reduction of sickle cell dehydration in vivo in a small number of patients with sickle cell disease; dose-limiting gastrointestinal and liver toxicities were observed. Based on the chemical structure of clotrimazole metabolites, a novel Gardos channel inhibitor, ICA-17043, has been developed. It has shown substantial activity both in vitro and in vivo in transgenic sickle mice. ICA-17043 is currently in phase 2 human trials. Another potential therapeutic target is the K-Cl cotransport. When sickle erythrocytes are exposed to relatively acidic conditions, they undergo cell shrinkage via activation of this pathway. K-Cl cotransport can be blocked by increasing the abnormally low erythrocyte Mg content of sickle erythrocytes. Oral Mg supplementation has been shown to reduce sickle cell dehydration in vivo in transgenic sickle mice and in patients in two separate clinical trials. Oral Mg pidolate is being tested in clinical trials in homozygous sickle cell disease and in Hb S/HbC (SC) disease, either as a single agent or in combination with hydroxyurea. The ongoing trials will determine the clinical effectiveness of therapies aimed at preventing sickle erythrocyte dehydration.     

Transcranial Doppler, MRA, and MRI as a screening examination for cerebrovascular disease in patients with sickle cell anemia: an 8-year study

Objective. The authors previously reported five transcranial Doppler ultrasonography (TCD) findings as significant in detecting clinical cerebrovascular disease in a 4-year study in patients with sickle cell disease. This is a follow-up to evaluate the validity of the original findings over another 4-year period during which the study population doubled. A clinical follow-up of the original asymptomatic sickle cell patients with positive TCD, MRA, and MRI was also made. Materials and methods. Over an 8-year period TCD, MRI, and MRA were prospectively performed in 90 sickle cell patients who were clinically asymptomatic for stroke and in 27 sickle cell patients with clinical stroke. Results. Of the 4 out of original 46 control patients in 1992 who had positive MRA and TCD, 3 have subsequently had clinical stroke. None of the 9 original patients with positive TCD and positive MRI but negative MRA have developed stroke. All five original TCD indicators of disease were still significant (P < 0.05) for detecting clinical disease: maximum velocity in ophthalmic artery (OA) > 35 cm/s, mean velocity in middle cerebral artery (MCA) > 170 cm/s, resistive index (RI) in OA < 50, velocity in OA greater than in MCA, and velocity in posterior cerebral (PCA), vertebral, or basilar arteries greater than in MCA. Four additional factors were also significant: turbulence, PCA or ACA without MCA, RI < 30, and maximum velocity in MCA > 200 cm/s. Conclusion. Positive MRA with a positive TCD in an asymptomatic patient in long-term follow-up suggests a trend for developing clinical stroke. A 4- to 8-year follow-up of nine patients with positive TCD, positive MRI, but not positive MRA did not show development of clinical stroke. Nine Doppler findings are significant in screening for clinically symptomatic vascular disease in sickle cell patients. It is recommended that children with sickle cell disease be screened for cerebrovascular disease with TCD. If one or two indicators of abnormality are present, MRA is recommended. If the MRA is positive, the patient may be considered for transfusion therapy or other treatment for prevention of stroke. Received: 17 April 1997 Accepted: 7 July 1997     

Sickle cell screening practice in pediatric emergency departments.

Management of black children who present to a pediatric emergency department (ED) commonly requires knowledge of their sickle cell status. To determine the practice of sickle cell screening, 32 pediatric EDs were surveyed. Twenty-eight (88%) completed the survey, and, of these, 22 (79%) included sickle cell screening (differential solubility test for hemoglobin S) in the management of a black febrile six-month-old infant. To determine the method of screening for sickle cell disease, 60 consecutive black children less than two years of age, who presented to a pediatric ED, were reviewed prospectively. In 51 patients (85%), their condition warranted knowledge of their sickle cell status. Of these, parents of only nine (18%) children knew their child's sickle cell status. Thirty-five (69%) patients had a presumptive newborn screening test for sickle cell disease, but only 15 presented between 8 AM and 5 PM on a weekday, the time during which the newborn screening laboratory could be telephoned for test results. For these same 15 patients, 13 had private physicians, but only three physicians had results of newborn sickle cell screening tests. The patients' hospital records were reviewed, and nine (18%) patients had prior sickle cell screening tests, but five of these tests were performed before the child was six months of age. To determine sickle cell status, 30 (59%) patients required a sickle cell screening test in the ED. ED screening detected three (6%) newly diagnosed sickle cell trait patients. In summary, sickle cell screening is recommended for young black children who present to an ED with fever or signs and symptoms supportive of sickle cell disease complications.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sickle cell anemia in the newborn

The clinical presentation of homozygous sickle cell disease is unusual in the neonatal period. Recently, we have encountered a newborn infant whose disease was apparent at birth and who died at 5 days of age. The findings at autopsy suggested a sickle cell crisis with multisystem involvement that was present prior to birth. Laboratory findings confirmed homozygous sickle cell disease without the presence of elevated levels of hemoglobin S. The cause of the unusually severe clinical course of the disease in our patient is the object of the discussion.     

Asthma and chronic sickle cell lung disease: a dynamic relationship

Chronic lung disease is a significant source of morbidity and mortality in patients with sickle cell disease. Asthma and sickle cell lung disease share many of the same clinical features and pathophysiological mechanisms. Though there is growing evidence of an association between sickle cell disease and airway hyper-reactivity, there is still no consensus on the definition of asthma in sickle cell lung disease. This review will explore what we know about asthma and airway hyper-reactivity in sickle cell disease and whether currently available asthma therapies may be beneficial in delaying or averting the progression of sickle cell lung disease.     

Sickle cell anemia in two White American children: essential laboratory criteria for diagnosis.

A number of hematologic disorders share diagnostic and clinical features of sickle cell anemia but have significantly different genetic implications and prognosis. Because of these differences, the establishment of a precise diagnosis is essential for the child in whom any form of sickle cell disease is identified. To illustrate the requirements for a definitive laboratory diagnosis of sickle cell anemia, this report presents the approach to establishing this diagnosis in two white American patients. From a review of the literature, these patients appear to be the only white Americans with sickle cell anemia in whom the diagnosis has been unequivocally established.     

STEM CELL TRANSPLANTATION FOR SICKLE CELL DISEASE: CAN WE REDUCE THE TOXICITY?

Since the genetic basis of sickle cell anemia was discovered over 50 years ago, many therapies have been developed for the treatment of this disorder. Hematopoietic cell transplantation offers curative potential, but it is associated with a 5-10% risk of dying. Patients who undergo allografting but develop stable donor-host hematopoietic chimerism appear to experience a significant clinical benefit. Our paper discusses the risks and benefits of hematopoietic cell transplantation in patients with sickle cell disease and summarizes the outcome of 147 patients who received allografts for sickle cell disease. We also review the development of new approaches to establish stable mixed chimerism after transplantation for sickle cell disease.     

Effect of G-6 PD deficiency on sickle cell disease in Saudi Arabia

High incidence of G6PD deficiency has been reported in areas of the eastern province of Saudi Arabia where sickle cell gene is also prevalent. This study was conducted to assess the co-incidence of this enzymopathy with Hb S and its influence upon the clinical and hematological expression of sickle cell disease. Eighty three children with SS disease, 145 patients with sickle cell trait and 100 random cord blood as samples with normal Hb AF, and an FS electrophoretic pattern respectively were examined. The frequency of interaction of G6PD deficiency with Hb S was found significantly increased but no effect of this enzyme defect was discerned on the clinical and hematological status of homozygous sickle cell disease.     

Sickle cell syndromes. II. The sickle cell anemia-alpha-thalassemia syndrome

Five American black patients, ages 1 to 16 years, with the sickle cell anemia-alpha-thalassemia syndrome are described. Each patient had persistent microcytosis not explained by iron deficiency, and in each family the presence of alpha-thalassemia in combination with sickle cell trait was demonstrated in one of the parents. In one patient, in whom the diagnosis of sickle cell anemia was established at birth, an elevated level of Barts (gamma4) hemoglobin was also found. In these patients levels of alkali-resistant hemoglobin and reticulocyte counts were similar to those of sickle cell anemia patients of comparable age; however, stained smears of their peripheral blood rarely showed the presence of irreversibly sickled cells. No major ameliorative effect of the alpha-thalassemia on the clinical expression of the sickle cell disease of these patients was evident.     

Sudden-onset blindness in sickle cell disease due to retinal artery occlusion

Central retinal artery occlusion (CRAO) is a rare and potentially devastating cause of acute blindness in sickle cell disease (SCD) that is unique compared to classic sickle retinopathy. Few details related to this complication in SCD are known, including its risk factors, pathogenesis, presentation, treatment and outcomes. We present three patients with SCD and retinal artery occlusion. The overall variability in clinical presentation, treatment and prognosis reported in the literature underscores the need for a greater understanding of these factors as they relate to this complication in SCD.     

Massive splenic infarction in an adolescent with hemoglobin S‐HPFH

Hemoglobin sickle‐hereditary persistence of fetal hemoglobin (S‐HPFH) is a condition in which there is compound heterozygosity for the Hb S mutation and the HPFH deletion. These patients have no anemia, little evidence of hemolysis and generally have a benign clinical course compared to other types of sickle cell anemia. We describe a 19‐year‐old male with HbS‐HPFH who had no history of anemia or vaso‐occlusive crisis, who presented with a massive splenic infarct. We conclude that patients with HbS‐HPFH can occasionally present with severe complications and require a high level of clinical suspicion for complications when presenting to the hospital. Pediatr Blood Cancer 2013; 60: E49–E51. © 2012 Wiley Periodicals, Inc.     

Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia

Sickle hemoglobin is the product of one mutated gene, but the disease phenotype is the product of many genes. Polymorphism among the genes responsible for the pleotropic effects can be epistatic (or modifier) genes contributing to interindividual variation that characterizes sickle cell anemia patients. Modulation in the hemoglobin F levels is associated with the beta-globin gene cluster haplotypes and to gender and chromosomal sites different from chromosome 11 influencing the severity of the disease. Coexistence of alpha thalassemia with sickle cell disease produces hematologic and clinical consequences that are beneficial in some complications but deleterious in others. There is little if any modulation of the phenotype of sickle cell anemia by coexistence of G6PD deficiency. Mutations that favor blood coagulation or thrombosis may influence the phenotype of the disease. Improved understanding of the influence of genes involved in modulating the complex pathophysiology of sickle cell disease may allow prediction of the phenotype of sickle cell patients and aid in management decisions.     

Effect of alpha-globin genotype on the pathophysiology of sickle cell disease

The clinical picture of sickle cell disease is heterogeneous and varies tremendously among patients and in the same patient from time to time. The level of HbF, alpha-genotype, beta-haplotype, age, sex, and the environment are important factors that modify the clinical picture of sickle cell disease. My paper focuses on the effect of alpha-globin genotype on the pathophysiology of sickle cell anemia, HbSC disease, and sickle beta-thalassemia. The data indicate that the coinheritance of alpha-thalassemia results in some beneficial effects and in some harmful effects. Thus, there are trade-offs involved in this interaction in which the salutary effects are undermined by harmful ones.     

Cholelithiasis in children with sickle cell disease: experience of a French pediatric hospital]

BACKGROUND: Gallstones are frequently encountered in sickle cell disease. Their complications are difficult to distinguish from vaso-occlusive abdominal pain and they can sometimes threaten the patient's life. The aim of this study was to describe our local experience with cholelithiasis in children with sickle cell disease. PATIENTS AND METHODS: We analyzed the follow-up records and abdominal sonography results of 185 children with sickle cell anemia, aged zero to 18 years, followed up in Trousseau Children's Hospital (Paris) from 1982 to 1998. RESULTS: Cholelithiasis was detected in 26 patients. The youngest patient was five years old. Cholelithiasis was discovered because of clinical manifestations in 12 patients. Asymptomatic cholelithiasis patients developed clinical manifestations in 28% cases in a maximum delay of two and a half years after its diagnosis. Laparoscopic cholecystectomy was performed in nine cases and open cholecystectomy in 17 cases. The mean postoperative length of stay was significantly shorter in the group of patients with laparoscopy in comparison with the group with open cholecystectomy. Histologic analysis of the gallbladders noted 85% of acute or chronic cholecystis. CONCLUSION: We suggest that cholelithiasis should be carefully sought in the presence of abdominal manifestations in sickle cell patients. We recommend that annual abdominal sonography be performed in sickle cell patients as early as seven years of age and elective cholecystectomy be performed on patients with cholelithiasis.     

Splenic function in sickle cell disease in the Eastern Province of Saudi Arabia

The sickle cell disease that occurs in the Eastern Province of Saudi Arabia is reported to be clinically benign. It is biochemically characterized by high levels of fetal hemoglobin. Twenty-four Saudi patients with sickle cell disease were compared with 22 American patients. As a group, the Saudi patients were less anemic and had less hemolysis, microcytic RBC, and much higher levels of Hb F. Splenic function was assessed by enumeration of pocked RBC. Seventeen Saudi patients had low numbers of Pk RBC, indicating normal or nearly normal splenic function, whereas all American patients had markedly decreased splenic function and high numbers of Pk RBC. Low levels of Pk RBC were strongly associated with high levels of Hb F. The genetic basis of the milder sickle cell disease in Saudi Arabia has not been elucidated, but may involve multiple genetic factors. Although the sickle cell disease in Arab patients of eastern Saudi Arabia is often less severe than that in America, it is far from "benign," and some patients have severe clinical courses similar to those in patients in the West.     

Paediatric priapism—treatment conundrum

Priapism is a rare condition in childhood. The majority of reported cases are boys with sickle cell disease, in whom nonoperative management may be successful when patients present early. We report a 14-year-old boy with sickle cell disease who presented with priapism of 72-h duration and was successfully treated by bilateral saphenocorporal shunts.     

Fetal outcome and childhood mortality in offspring of mothers with sickle cell trait and disease

The sickle cell hemoglobinopathy is a major public health problem which causes high morbidity and mortality in India. Although the hematological and clinical profile of the patients is extensively studies. The reproductive outcome of mothers afflicted with sickle cell trait and disease is still unknown in India. In a retrospective study, we have examined the reproductive profile of 190 mothers afflicted with sickle cell, attending Medical Out-Patient Department at V.S.S. Medical College Hospital, Burla in Western Orissa, India during the year 1991–1992. Seventy-three mothers who were found normal after medical examination and were free from hemoglobinopathic disorders, anemia, jaundice, iron deficiency, etc. constituted the control group and 66 mothers with sickle cell trait and 51 with sickle cell disease formed the study group. The reproductive history was recorded for number of conceptions, fate of offspring, live birth, surviving children and childhood mortality. Hematological investigations and hemoglobin electrophoresis were done as per the standard procedure. There was no difference in mean number of livebirths per mother between controls and sickle cell trait mothers. But between the controls and sickle cell homozygotes (p<0.01), and sickle cell trait and disease (p<0.01) mothers, this mean number was significant. For abortions/miscarriages, the difference between controls and sickle cell homozygotes (p<0.001), and sickle cell trait and disease (p<0.01) mothers was highly significant. The number of stillbirths per mother in homozygous sickle cell mothers was higher (p<0.01) as compared to controls. There were significantly higher childhood deaths in sickle cell trait (p<0.05) and disease (p<0.05) mothers than in the controls. It seems that the sickle cell heterozygote and hemoglobin E heterozygote mothers are genetically better fit than the sickle cell homozygotes. Further, the sickle cell disease is clinically severer than the hemoglobin E disease in India probably due to molecular diversity.