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E Vichinsky

Publications and source records attributed to E Vichinsky.

At least 55 records · Page 3Linked to original sources
PubMed1994

Universal screening for hemoglobinopathies using high-performance liquid chromatography: clinical results of 2.2 million screens.

In screening for hemoglobinopathies, high-performance liquid chromatography (HPLC) achieves excellent sensitivity and specificity, while adding the very important quantitative element to the analysis. Due to the development of a rapid, automated HPLC system, California began screening 600,000 births per year in 1990 using this method. Based on confirmatory testing for 97% of the initial positive results resulting from 2.2 million screens, HPLC has proven to be clinically accurate. In conjunction with the availability of quantitative data, HPLC provides a complete screening system, eliminating the need for a second screening test, and accurately discriminating beta thalassemia compound conditions. The large degree of ethnic diversity and high birth rate in California have produced detailed and reliable birth prevalence rates for most conditions and ethnicities.

Blood↗
PubMed1994

Availability of related donors for bone marrow transplantation in sickle cell anemia.

PURPOSE: To determine who might qualify for allogeneic bone marrow transplantation (BMT), we reviewed the medical records of all 143 patients with sickle cell anemia under the age of 16 years who were registered at our center. PATIENTS AND METHODS: A total of 135 records were complete and were used to estimate donor availability and disease severity. The mean number of siblings per patient was two, but this number decreased to 0.73 if half-siblings and siblings who had sickle cell anemia were excluded. Probability calculations indicated that a human leukocyte antigen (HLA)-matched sibling donor would be available for only 18% of patients with sickle cell disease. RESULTS: With regard to clinical severity, if only stroke and chronic debilitating pain are considered criteria for bone marrow transplantation, only 16% of sickle cell patients would qualify, but with use of the broader criteria of the National Collaborative Study, 38% of patients would qualify. However, not all parents will consent to have bone marrow transplantation for their child, and only a minority of patients (18%) will have an HLA-matched sibling donor. Thus, as few as 1-2% of the total population of children with sickle cell anemia will ultimately qualify for marrow transplantation. Increasing the number who can undergo transplantation will require increasing the size of the donor pool. CONCLUSIONS: Search for other therapies not based on marrow transplantation should continue. For the majority of patients with sickle cell disease, these nontransplant treatments offer the best chance for enabling patients to achieve greater longevity and a better quality of life.

Adolescent↗
PubMed1994

New advances in the pathophysiology and management of sickle cell disease.

The formation of the sickle cell hemoglobin polymer associated with deoxygenation of the sickle erythrocyte is a complex process. There are also many intracellular, extracellular, and erythrocyte membrane changes that are recognized to play important roles in the pathophysiology of this disease. The variability among these components accounts for the diversity observed in the phenotypic expression of sickle cell disease. This article reviews some of the recent developments in the understanding of the variables involved in the pathophysiology of sickle cell disease. Some of the new developments regarding clinical complications of sickle cell disease and their management are presented. New therapeutic options are reviewed. Finally, a discussion regarding transgenic models of sickle cell disease is presented.

Anemia, Sickle Cell↗
PubMed1993

F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study.

Studies on baboons and preliminary observations in three patients with sickle cell anemia (SS) suggested that high doses of pulse administered recombinant human erythropoietin (rHuEPO) stimulate F-reticulocyte production. We now report on the administration of rHuEPO in a double-blind format to ascertain frequency of response and potential precipitation of side effects. Ten patients were enrolled, but one was discontinued due to the indication of a blood transfusion. Of the other nine, five received rHuEPO in escalating doses (from 400 to 1,500 U per kg twice daily [BID] per week), alternating with a placebo, in blinded fashion. The second group, consisting of four patients, followed an identical protocol (except starting dose was 1,000 U/Kg, BID per week) and were iron supplemented during treatment. The criterion of response was a transient doubling (as a minimum) of the steady-state F-reticulocyte level. We found that none of the five patients in the first group responded to rHuEPO, and two of them became iron deficient, as judged by a significant decrease in ferritin. Of the second group, four patients responded with F-reticulocyte increases. In three patients, open label administration of rHuEPO confirmed the effect. We observed seven painful episodes during this study, two during the EPO administration and five during the placebo arm. Three patients were phlebotomized because the hemoglobin level increased 1.5 g/dL more than steady-state levels. Of the six patients followed-up by percent dense cell determinations, one exhibited increased levels during periods of the treatment, whereas the other five showed no change. No anti-rHuEPO antibodies were detected. We conclude that rHuEPO can stimulate F-reticulocyte response in some patients with sickle cell anemia, without apparent negative clinical side effects. The state of iron stores may be critical. Whether higher doses of rHuEPO and/or a different regimen might induce sustained F cells and fetal hemoglobin increases remains to be determined.

Adolescent↗
PubMed1993

Detection of Hb E/beta-thalassemia versus homozygous EE using high-performance liquid chromatography results from newborns.

The influx of Southeast Asian immigrants into California over the past few years has resulted in a dramatic increase of Hb E disorders detected in newborn screening. Initial hemoglobin patterns of FE do not distinguish between homozygous EE, a benign state, and E/beta-thalassemia, a clinically significant disorder which is frequently transfusion-dependent. Since language and cultural customs frequently prevent parent testing which can rule out the thalassemic disorder, and diagnosis in the neonate is not possible by traditional red cell indices and is relatively expensive by DNA methodology, an alternate screening method is proposed. This study investigated the Hb F and Hb E relative percentages obtained in the newborn's high-performance liquid chromatography result, and found that the percentage of Hb E was markedly lower in neonates with Hb E/beta-thalassemia versus those which were homozygous EE. Likewise, the F/E ratios were different in the E/beta-thalassemia group versus the EE group. This analysis can at least minimize the number of DNA tests required, and with more E/beta-thalassemia case data, may prove to be a reliable substitute.

Chromatography, High Pressure Liquid↗
PubMed1992

Differentiation of homozygous hemoglobin E from compound heterozygous hemoglobin E-beta O-thalassemia by hemoglobin E mutation analysis.

OBJECTIVES: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia). METHODS: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation. RESULTS: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months. CONCLUSIONS: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.

Asian↗
PubMed1991

Pain in sickle cell disease. Rates and risk factors.

BACKGROUND AND METHODS: Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. RESULTS: There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit. CONCLUSIONS: The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.

Adolescent↗
PubMed1990

Vitamin C deficiency in patients with sickle cell anemia.

Because peroxidative damage to red cell membranes may contribute to the pathophysiology of sickle cell disease, deficiency of fat- and water-soluble antioxidants could be a determinant in the pathogenesis of this disease. We have previously reported a deficiency of vitamin E in sickle cell disease. The present study was undertaken to see if a deficiency in vitamin C might also be detected. Leukocyte vitamin C, which reflects total body vitamin C reserve, was measured by a modified 2,4-dinitrophenylhydrazine method. Sickle cell patients (N = 18) had lower leukocyte vitamin C levels (18.3 +/- 9.4 micrograms/10(8) cells) than normal controls (N = 12; 30.3 +/- 7.5 micrograms/10(8) cells; p less than 0.01). Furthermore, 50% of the patients had vitamin C levels below 15 micrograms/10(8) cells, a value consistent with vitamin C deficiency. A statistically significant correlation (r = -0.62 with 0.01 less than p less than or equal to 0.025) was found between leukocyte vitamin C levels and serum ferritin concentration. Because dietary vitamin C intake appeared to be adequate, increased vitamin C utilization may account for this deficiency. However, the mechanisms for this deficiency as well as its pathophysiologic consequences remain to be established.

Anemia, Sickle Cell↗
PubMed1989

Elevated fasting breath hydrogen and abnormal hydrogen breath tests in children with sickle cell disease: a preliminary report.

Hydrogen breath tests were performed in eight children with sickle cell disease (Hgb S-S), four of whom were growth retarded. Average base-line breath H2 values after an overnight fast were elevated (22.4 +/- 10.8 ppm; normal = 7.1 +/- 5.0). Breath H2 concentrations increased significantly above base line within 30-40 min after lactulose ingestion in the four growth-retarded children whereas a negligible rise was observed in the four with normal growth indices. Breath H2 production for each time interval in the first 120 min was greater in all Hgb S-S then in normal children (p less than 0.01 for each time interval measured before 60 min). The results indicate that children with sickle cell disease have intestinal abnormalities favoring excess production of H2 in the fasted state combined with early elevations in postlactulose breath H2 in those with growth retardation. The possible role of disordered gastrointestinal motility and/or anomalously distributed intestinal flora in growth retardation of children with Hgb S-S requires further investigation.

Adolescent↗
PubMed1989

Hematopoietic hormones: from cloning to clinic.

In order to maintain adequate circulating numbers of blood cells, the bone marrow must produce billions of cells each day and must be able to rapidly increase production by 10-20-fold in response to infection and hemorrhage. The existence of circulating factors that regulate this process has been suspected for over 100 years. Recently, the genes encoding these growth factors were cloned and their functions are now identified. Interleukin-3 (IL-3) acts on the most primitive hematopoietic stem cell, driving this self-renewing cell to produce progeny of all hematopoietic lineages. Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the granulocyte-macrophage progenitor cell, as well as cells committed to the erythroid lineage, to differentiate. G-CSF and M-CSF stimulate the most differentiated myeloid progenitors to produce granulocytes and monocytes/macrophages, respectively. Erythropoietin stimulates the differentiation of late erythroid progenitors. In the lymphoid progenitor lineage, IL-2 stimulates T cell differentiation; IL-4 and IL-6 stimulate differentiation of B cells. The colony-stimulating factors also enhance function and cause activation of the mature cells whose production they induce. In clinical trials, these hormones have successfully ameliorated anemia in renal failure, chronic disease, and in prematurity. They have improved pancytopenias in aplastic anemia, myelodysplastic syndromes, and congenital cytopenias, and they have hastened recovery from chemotherapy and bone marrow transplantation.

Cloning, Molecular↗
PubMed1989

Experience with newborn screening using isoelectric focusing.

Electrophoretic techniques are used for hemoglobinopathy diagnosis. Confirmation of the hemoglobin variants is necessary. Currently, citrate agar electrophoresis is the most available, but high performance liquid chromatography is highly recommended in a reference laboratory. Thin layer isoelectric focusing is an excellent technique that can be easily adapted for large-scale newborn hemoglobinopathy screening. Although the initial instrument cost can be about twice as much as the cost for standard electrophoretic equipment, cost-effectiveness for newborn screening is considerable because repeat analysis for uninterpretable results is not necessary. Resolution of hemoglobins is much better with thin layer isoelectric focusing than for any of the other electrophoretic methods currently available, and thin layer isoelectric focusing is the best method to use to establish a definitive diagnosis using newborn blood samples. Cord blood samples may be contaminated with maternal blood, and evaluation of Hb A2 levels in such samples can serve as the method to detect contamination. Follow-up testing is required regardless of the method of blood collection.

Anemia, Sickle Cell↗
PubMed1988

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)

Anemia, Sickle Cell↗
PubMed1986

Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial.

Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S.pneumoniae in children with sickle cell anemia who were under the age of three years at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin V potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84 percent reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients vs. 2 of 105; P = 0.0025), with no deaths from pneumococcal septicemia occurring in the penicillin group but three deaths from the infection occurring in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by four months of age to decrease the morbidity and mortality associated with pneumococcal septicemia.

Administration, Oral↗
PubMed1985

Growth retardation in sickle-cell disease treated by nutritional support.

The effect of increased nutritional intake was evaluated in 5 growth-retarded children with sickle-cell disease. Growth on recommended daily calorie and protein intakes had been inadequate in all 5. Fat absorption and intestinal mucosal morphology were normal in all 5. 2 children were given nutritional supplementation by nasogastric intubation, 1 received nightly oral formula supplements, and 2 were supplemented with zinc, iron, folate, and vitamin E only. Nutritional supplementation by the nasogastric route produced a rapid sustained increase in growth rate, associated with striking reductions in pain crises and infections which had previously necessitated many hospital admissions. Oral supplementation improved the clinical course but had no effect on growth rate. Mineral and vitamin supplements influenced neither the growth rate nor the clinical course. The observations indicate that nasogastric nutritional supplementation may accelerate growth and reduce the incidence and severity of complications in growth-retarded children with sickle-cell disease.

Adolescent↗