Sickle cell syndromes. I. Hemoglobin SC-alpha-thalassemia.

Hematologic and globin synthesis studies were performed in a black American family in which the genes for alpha-thalassemia and hemoglobins (Hb) S and C were segregating. The following distribution of these abnormalities was found: father, sickle cell trait + alpha-thalassemia; mother, HbC trait + alpha-thalassemia, propositus, HbSC + alpha-thalassemia; older sibling, alpha-thalassemia trait; and younger sibling, hemoglobin H disease. The child with HbSC-alpha-thalassemia demonstrated more severe anemia and a more hemolytic picture than is typical of HbSC disease. Her erythrocytes exhibited decreased osmotic fragility in comparison with HbSC erythrocytes, but had an indistinguishable oxygen equilibrium curve and 2, 3-diphosphoglycerate (2, 3-DPG) level. Erythrocyte sickling in the patient, however, was significantly reduced, with less than 35% sickle forms observed at nearly complete oxygen desaturation. The sibling with hemoglobin H disease exhibited 26% Bart's (gamma4) hemoglobin at birth, a level comparable with that seen in infants with HbH disease in Far Eastern populations. At age 5 months typical findings of mild hemoglobin H disease appeared, with HbH making up 6.5% of the total hemoglobin.     

Iron burden in sickle cell anemia

Total body iron burden was estimated by two indirect methods in 23 patients with sickle cell anemia. Concentrations of serum ferritin correlated directly and significantly with age of the patients. Eleven of 15 patients under 20 years of age had normal levels of serum ferritin. Deferoxamine-induced urinary excretion of iron was considerably less than that reported in patients with thalassemia major who were receiving regular blood transfusions. These data imply that patients with sickle cell anemia generally do not acquire excessive iron burdens during the first two decades of life. The risks of transfusional hemosiderosis in patients with sickle cell anemia who are included in hypertransfusion programs are discussed.     

Newborn screening for sickle cell disease: effect on mortality

Newborn screening for sickle cell disease has been recommended as a method of decreasing patient mortality. However, its effectiveness in accomplishing this has not been reliably measured. To help determine the effectiveness, 10 years of experience in newborn screening have been summarized. The effects of early patient enrollment in a comprehensive treatment program on long-term morbidity and mortality are reported. From 1975 to 1985, 84,663 newborns were screened regardless of race or ethnic background. Bart's hemoglobin was present in 5%, hemoglobin AS in 2.6%, and hemoglobin AC in 0.75%. Excluding Bart's, approximately 3.6% of all newborns were carriers for hemoglobinopathy. Sickle cell disease occurred in 1:951 births (58 hemoglobin SS, 25 hemoglobin FSC, three hemoglobin S-beta +-thalassemia, and three hemoglobin S-beta O-thalassemia). In addition, one in every 4,233 newborns had a clinically significant thalassemia syndrome (eight hemoglobin FE, ten hemoglobin F only, two hemoglobin H). Compared with other newborn screening programs in California, (congenital hypothyroidism, 1:3,849; phenylketonuria 1:22,474, galactosemia 1:74,103), hemoglobinopathies are the most prevalent congenital disease. Eighty-one newborns with sickle cell disease were followed for 7.2 years. Patients experienced 513 hospitalizations, including 13 episodes of sepsis with or without meningitis and ten acute sequestration crises. The overall mortality rate for patients with sickle cell anemia diagnosed in the newborn period was 1.8%. In comparison, the clinical course of 64 patients with sickle cell anemia diagnosed after 3 months of age and followed for an average of 9.4 years was analyzed. Five of these patients died. In two of these, sickle cell anemia was diagnosed at the time of the death.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transfusion therapy for cerebrovascular abnormalities in sickle cell disease.

Cerebral angiograms were performed in patients with sickle cell disease and symptoms of stroke to evaluate transfusion therapy for cerebrovascular accidents. Three patients who were transfused repeatedly for one year to maintain less than 30% hemoglobin S were compared to two patients who were not transfused. All patients had abnormal angiograms initially. After one year the angiographic abnormalities resolved in two and improved in one transfused child. The two children who were not transfused showed progressive vascular disease. For all arteriograms, the patients were prepared by transfusion with normal red cells and careful hydration.     

Excretion of iron in response to deferoxamine in sickle cell anemia

Iron chelation with deferoxamine was studied in ten patients with sickle cell anemia who had received 2 to 37 liters of red blood cells. Urinary excretion of iron in response to 1.5 gm of deferoxamine administered intravenously ranged from 5.9 to 28.7 mg/24 hours and was closely related to the amount of iron acquired from transfusions. Administration of ascorbic acid did not improve deferoxamine-induced excretion of iron. Urinary excretion of iron in response to 0.75 gm of DFO intramuscularly was 4.7 to 6.9 mg/24 hours in three patients who had received 15 to 37 liters of red cells. The data indicate that measurement of DFO-induced excretion of iron is of value in detecting increased iron stores in children with sickle cell anemia who have received repeated transfusions and that chelation therapy will retard the accumulation of iron.     

Adenotonsillar hypertrophy: a precipitating factor of cerebrovascular accident in a child with sickle cell anemia

Cerebrovascular accident is one of the most serious complications of sickle cell anemia. The specific factors that predispose patients with sickle cell anemia to stroke are increased disease severity, higher baseline white blood cell count and lower baseline hematocrits. Likewise the presence of a co-existent alpha thalassemia trait and/or high fetal hemoglobin (HbF%) may reduce the risk. We report a child with sickle cell anemia and marked adenotonsillar hypertrophy resulting in obstructive sleep apnea syndrome. There was no other known risk factor for developing cerebrovascular accident in this child during her hospitalization for adenotonsillectomy.     

Acute chest syndrome in sickle cell disease: etiology and clinical correlates

Acute chest syndrome (ACS) is a new pulmonic process in a clinically ill patient with sickle cell disease. We prospectively analyzed 102 episodes of ACS in patients in our hospital during a 2-year period to study cause and clinical correlates. In 12% of the episodes, ACS was judged to be secondary to bacterial pneumonia (including only 3% secondary to Streptococcus pneumoniae), 8% was associated with uncomplicated viral pneumonias, and 16% with mycoplasmal pneumonias. The clinical course and seasonal variations in these groups were compared with those in the remaining 64% of episodes. In comparison with episodes of ACS of undetermined origin (presumably secondary to pulmonary infarct, atelectasis, or missed infections), patients with bacterial pneumonia were sicker, as shown by fever and hospitalization of longer duration, the percent of those requiring red blood cell transfusion, and the presence of pleural effusions. The lower incidence of bacterial pneumonias among our patients compared with that previously reported may reflect our use of penicillin prophylaxis and pneumococcal immunization to prevent S. pneumoniae infections.     

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.     

Obesity--does it occur in Nigerian children with sickle cell anemia

Children with sickle cell anemia are vulnerable to growth deficits; thus, it would be thought that obesity would be rare among them. The objective of the study is to examine the prevalence of obesity in a sickle cell anemia population in Lagos. A random sample of children with sickle cell anemia aged 2-15 years was interviewed and anthropometric measurements including weight and height were taken. Their body mass index (BMI) was calculated. Participants were classified as obese or not obese by their BMI or weight-for-height-for-age using World Health Organization standard definitions. The overall prevalence of obesity was 2.5% and 3.8% among hemoglobin genotype SS subjects and hemoglobin genotype AA controls, respectively. The age-specific prevalence for obesity was highest among the adolescent age category in hemoglobin genotype AA controls and the childhood age category in subjects with sickle cell anemia. All the obese subjects with sickle cell anemia were from upper socioeconomic strata, while two and one of the three subjects with hemoglobin genotype AA were from upper and middle socioeconomic strata, respectively. Obesity does exist among children with sickle cell anemia in Lagos, Nigeria. Public health programs aimed at prevention and control of obesity must include children with sickle cell anemia.     

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.     

Chemotherapy to increase fetal hemoglobin in patients with sickle cell anemia

The obvious beneficial effects of hemoglobin F on sickling have motivated numerous investigators to increase this type of hemoglobin artificially in patients with sickle cell anemia. Various chemotherapeutic agents including 5-azacytidine, hydroxyurea, and cytosine arabinoside, have been used successfully in patients. All of these drugs can increase the level of hemoglobin F in sickle cell anemia (SS) patients, but the kinetics and magnitude of the responses are highly individual and variable. The mechanism or mechanisms responsible for the increased synthesis of hemoglobin F remain unknown. Further controlled studies in a limited number of patients with severe sickle cell disease will be necessary in order to work out a rational, safe treatment program suitable for wider use.     

Sickle cell trait/hereditary persistence of fetal hemoglobin trait. Misdiagnosis as sickle cell anemia by newborn screening

A black female infant, reported as a result of mandatory newborn screening to have sickle cell anemia, was found at 8 months of age to have instead the entirely benign disorder sickle cell trait/hereditary persistence of fetal hemoglobin trait. The finding of hemoglobin S without Hb A does not suffice for the diagnosis of homozygous Hb S. Screening programs that diagnose sickle cell aneimia without first demonstrating sickle hemoglobin in both parents will consistently misdiagnose several more benign hemoglobin states as sickle cell anemia.     

Anxiety, self-concept, and personal and social adjustments in children with sickle cell anemia.

The psychologic effect of sickle cell anemia, a life-long chronic illness, on the self-concept, anxiety level, and personal and social adjustments of school-aged children was investigated by using a battery of standard psychologic tests. Two groups of children were evaluated: a study group of 29 children with sickle cell anemia (hemoglobin SS) and a comparison group of 26 black inner city schoolchildren without sickle cell disease or other known chronic illness. The youngsters with sickle cell anemia did not differ from a peer group of schoolchildren in personal, social, and total adjustments. The self-concept scores of the patient group were lower than those of the comparison group. An unexpected finding of the study was the observation that the anxiety scores (measuring acute anxiety) were significantly lower in the study group than those in the comparison group.     

Echocardiographic aspects in pediatric patients with sickle cell disease]

BACKGROUND: Cardiovascular involvement is not well studied in children with sickle cell disease. The aim of this study was to evaluate the echocardiographic parameters of children with sickle cell disease. PATIENTS AND METHODS: We performed a transversal and case-control study including 80 subjects of six months to 16 years of age divided into four groups of 20 children each: heterozygous sickle cell disease, homozygous sickle cell anemia, anemia of other causes than sickle cell, and healthy children. All children had a complete physical examination, biological screening including hemogram and hemoglobin electrophoresis, chest x-ray, electrocardiogram, and Doppler echocardiogram. Data were compared using the chi 2 method and the Student's t-test. RESULTS: The mean age was 8.5 years and the sex-ratio was 1. Echocardiographic abnormalities were observed in seven patients with anemia unrelated to sickle cell, 15 children with heterozygous anemia and all the homozygous patients. The main abnormalities were: left ventricular enlargement (ten homozygous patients, one heterozygous subject, five of the patients with another cause of anemia), increased contractility of the heart (18 homozygous patients, seven heterozygous patients, five in the anemia group) and mild to moderate mitral or tricuspid regurgitation (12 homozygous, five heterozygous and five patients in the anemia group). One homozygous child had a dilated and hypokinetic cardiomyopathy with pulmonary hypertension. The parameters of left ventricular systolic function and left heart chamber dimensions were lower in the control group (P < 0.04). DISCUSSION: This study shows the frequency of heart chamber dilatation with left ventricular hyperkinesis usually described in the literature. The lack of case of chronic cor pulmonale may be due to the young age of our patients. One case of dilated and hypokinetic cardiomyopathy suggests that other causes than anemia should be considered, particularly myocardial ischemia, which could not be demonstrated because of our limited investigative methods. CONCLUSION: These results emphasize the frequency of the heart involvement in sickle cell disease, particularly in the homozygous type, and point out the importance of the cardiologic screening of these patients.     

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.     

Splenic function in Omani children with sickle cell disease: correlation with severity index,hemoglobin phenotype,iron status,and alpha-thalassemia trait

The prevalence of functional asplenia in Omani children with sickle cell disease (SCD) has not been previously defined. In this study, the authors aim to compare the natural history of splenic dysfunction in their patients to other reports. The splenic function was studied in 72 Omani patients with sickle cell disease (50 homozygous for hemoglobin S (HbS-S), 11 double heterozygotes for HbS and beta(0)-thalassemia (HbS-beta(0)-thal), 5 HbS-beta(+)-thal, 5 patients with hemoglobin S-D disease, and 1 child with hemoglobin S oman trait) aged 4.8-16 years, using (99m)Tc-labeled tin colloid scintigraphy. The study revealed 4 groups according to their colloid uptake: group I included 20 patients (28%) with normal splenic function; group II, 6 patients (8%) with mild hyposplenism; group III, 20 (28%) with severe hyposplenism; and group IV, 26 (36%) patients with functional asplenia. Overall, more than 60% of them had preserved splenic function. Except for HbS-beta(+) patients, the developmental pattern of hyposplenism was not different among the different Hb phenotypes. Factors associated with preservation of spleen function in these patients were larger splenic size (p < .01), less clinical severity (p < .05), lower MCH (p < .01), higher HbF (p < .001), and presence of alpha-thalassemia trait (p < .05).     

Growth patterns by age and sex in children with sickle cell disease

We examined growth patterns by age and sex in 133 children and adolescents with sickle cell disease. These patients are estimated to be representative of the total population aged 1 to 18 years with sickle cell disease in a large metropolitan area. Median height and weight curves constructed from serial growth data available for all 133 children demonstrated impairment in height and weight at all ages and in both sexes. Analysis of growth trends by age reveals a pattern of increasing deficit with increasing age; boys are more severely affected than girls. Growth velocity curves constructed for a series of 13 adolescents with sickle cell disease illustrate the marked delay in the onset of the normal pubertal growth spurt in these patients.     

Obesity—Does It Occur in Nigerian Children with Sickle Cell Anemia

Children with sickle cell anemia are vulnerable to growth deficits; thus, it would be thought that obesity would be rare among them. The objective of the study is to examine the prevalence of obesity in a sickle cell anemia population in Lagos. A random sample of children with sickle cell anemia aged 2–15 years was interviewed and anthropometric measurements including weight and height were taken. Their body mass index (BMI) was calculated. Participants were classified as obese or not obese by their BMI or weight-for-height-for-age using World Health Organization standard definitions. The overall prevalence of obesity was 2.5% and 3.8% among hemoglobin genotype SS subjects and hemoglobin genotype AA controls, respectively. The age-specific prevalence for obesity was highest among the adolescent age category in hemoglobin genotype AA controls and the childhood age category in subjects with sickle cell anemia. All the obese subjects with sickle cell anemia were from upper socioeconomic strata, while two and one of the three subjects with hemoglobin genotype AA were from upper and middle socioeconomic strata, respectively. Obesity does exist among children with sickle cell anemia in Lagos, Nigeria. Public health programs aimed at prevention and control of obesity must include children with sickle cell anemia.     

Pitted red cell counts in sickle cell disease. Relationship to age, hemoglobin genotype, and splenic size

Splenic reticuloendothelial function, as determined by pitted red cell counts in 114 pediatric patients with sickle cell disease, was evaluated. Patients with homozygous sickle cell disease (HbSS) had a mean pit count of 11.8 +/- 7.0% and the count increased with age. Sickle cell hemoglobin C disease (HbSC) patients had a mean pit count of 4.9 +/- 9.1%, the count being unaffected by age. One patient with HbS-beta thalassemia had a count of 12%, while eight patients with HbS-beta + thalassemia had a mean count of 0.4 +/- 0.3%. There was one patient each with HbSS-alpha thalassemia, HbS-O Arab, and HbS-Lepore, and the pit counts were 4.9, 31.4, and 0.4%, respectively. In both HbSS and HbSC patients, the pit count was significantly lower in patients who had palpable spleens. The pit count may be used as a predictor of disease severity in the sickle cell disorders.     

Less intensive long-term transfusion therapy for sickle cell anemia and cerebrovascular accident.

To determine the efficacy of a less intensive transfusion regimen in preventing recurrent cerebrovascular accidents and reducing transfusion requirements in patients with sickle cell anemia, we offered to 14 patients who had been undergoing aggressive transfusion therapy (sickle hemoglobin concentration kept less than 30% of total) for a mean of 9 years the option of either diminishing or stopping transfusion therapy. Thirteen patients chose to continue a modified transfusion regimen to maintain sickle hemoglobin concentration less than 60%; 10 of these patients have now been followed for 1 year or more (12 to 27 months, mean 15.5 months). There have been no recurrent neurologic events, although two patients have died of complications of hemochromatosis. All patients had a reduction in donor exposure, and there was a mean reduction in net transfusion requirement of 31.4% during the first year after modification. The greatest reduction was achieved in the single patient managed by small-volume (5 ml/kg) simple transfusion rather than partial packed cell exchange. We conclude that although long-term consequences of less aggressive transfusion therapy are unknown, the use of such a regimen may be reasonable, particularly in patients with significant transfusional hemochromatosis.