Alpha thalassemia. A modifier of sickle cell disease.
Explore the source record for details and available documents.
Anemia, Sickle Cell↗
Biomedical subjects
S H Embury
Publications and source records attributed to S H Embury.
Human embryonic zeta-globin chains in fetal and newborn blood.
A sensitive and specific radioimmunoassay (RIA) for human embryonic zeta-globin chains was used to study normal fetal blood and newborn cord blood as well as cord blood from newborns with alpha-thalassemias. From 17 weeks until 37 weeks of gestation, zeta-globin chains were present in almost all fetal and cord blood samples (0.27% +/- 0.15% in samples of weeks 17 through 30; 0.14% +/- 0.11% in samples of weeks 31 through 37). zeta-Globin chains were present in greater than 80% of cord blood hemolysates from normal, full-term newborns (0.15% +/- 0.11%) as well as from 16 near-term newborns of diabetic mothers (0.13% +/- 0.13%). zeta-Globin chains were not detected in normal infants aged 3 months to 2 years. In cord blood hemolysates from alpha-thalassemic newborns, the levels of zeta-globin chain content varied from very high to undetectable levels. Gene mapping of the zeta-alpha-globin gene cluster was performed in 12 newborns in whom cord blood zeta-globin chains had been determined. Newborns who were carriers of alpha-thalassemia-1 due to the (--SEA/) deletion had very high levels of zeta-globin chains (greater than 1.5%).
Aging↗
The effect of speed of deoxygenation on the percentage of aligned hemoglobin in sickle cells. Application of differential polarization microscopy.
We have used differential polarization microscopy, which provides images of linear dichroism, to measure the percentage of aligned hemoglobin (Hb) in 1086 deoxygenated red blood cells from subjects with sickle cell anemia. The percentage was found to be only slightly dependent on the speed of deoxygenation, thus showing that the percentage of aligned Hb was thermodynamically controlled (as has been found previously for the percentage of polymerized Hb in vitro). A slight decrease in the percentage of aligned Hb due to increasing speed of deoxygenation is primarily due to the increase in the number of cells containing no detectable aligned Hb. This class of cells was also the most variable between the different subjects studied. We were able to identify two other groups of cells that contain different numbers of domains of aligned Hb and show that these groups contain statistically different percentages of aligned Hb. The differences between these classes of cells was shown to be primarily due to different numbers of initial nucleation sites within each cell. It appears that the presence of preformed nucleation sites within cells at ambient oxygen tensions results in the thermodynamic control of aligned Hb polymer.
Algorithms↗
Oxygen-induced marrow red cell hypoplasia leading to transfusion in sickle painful crisis.
The benefit of oxygen (O2) therapy in non-hypoxic sickle cell patients in painful crisis is uncertain. We report a case of a non-hypoxic sickle cell patient in painful crisis who developed marrow red cell hypoplasia requiring transfusion support after O2 therapy. The uncertain benefits of O2 use in such cases must be weighed against the serious and underrecognized risks of transfusion. In patients who develop O2-induced marrow red cell hypoplasia, cessation of O2 therapy may reverse the anemia and obviate the need for transfusion.
Adult↗
Preservation of sickle cell blood-flow patterns during MR imaging: an in vivo study.
Magnetic fields and RF energy have been shown to affect sickle erythrocytes in vitro. Because both strong magnetic fields and RF energy are used in MR imaging, it has been suggested that capillary blood flow in patients with sickle cell disease may be altered during MR imaging. In order to examine sickle cell blood flow during MR imaging in vivo, laser-Doppler velocimetry was performed in normal control subjects and in sickle cell subjects before, during, and after MR imaging at 0.35 and 1.5 T. Mean blood flow and patterns of blood-flow variability were compared by two hematologists. No differences were found on the recordings from each subject made before, during, and after MR imaging were compared. Blood-flow patterns generally differed between control and sickle cell subjects. Periodic oscillatory blood flow, reportedly a specific finding in sickle cell subjects, was observed in one control subject and was not consistently found in sickle cell subjects. Although energies employed during MR imaging have effects on sickle erythrocytes in vitro, our data show no changes in sickle cell blood flow during MR imaging in vivo.
Anemia, Sickle Cell↗
The different types of alpha-thalassemia-2: genetic aspects.
The alpha-thal-2 haplotype is the most common cause of alpha-thal and is found in a great many of the world's populations. It is most commonly due to the deletion of a single alpha-globin structural gene, and the deletion of a single alpha locus using gene mapping methods provides objective diagnostic evidence for this haplotype. Seven varieties of nondeletion syndromes have also been described, but these seem to be responsible for a small minority of alpha-thal in all populations studied. Detailed structural analyses of the deletional types have revealed that they were caused by a wide variety of DNA recombinant events, the racial difference of which remain poorly understood.
Humans↗
The interaction of alpha-thalassemia with sickle cell anemia.
The coinheritance of alpha-thalassemia (alpha-thal) and sickle cell anemia provides a most interesting example of how separate globin gene mutations influence clinical manifestations of abnormal gene expression. Early reports in the literature contained conflicting opinions as to whether alpha-thal ameliorated the clinical consequences of sickle cell disease. With the discovery that the concentration of sickle hemoglobin (Hb S) had a profound influence on both the kinetics and extent of deoxy Hb S polymerization, it was predicted that the lower intraerythrocytic concentration of Hb S associated with alpha-thal would mitigate the clinical severity of sickle cell anemia. Moreover, the use of alpha-globin gene mapping for objectively diagnosing alpha-thal revealed that one in three Black Americans were silent carriers of alpha-thal. Thus, it followed that a great many sickle cell patients may be affected by this potentially modifying influence.
Anemia, Sickle Cell↗
The incidence of painful crisis in homozygous sickle cell disease: correlation with red cell deformability.
To determine whether the vasoocclusive severity of homozygous sickle cell (SS) disease is influenced by cellular dehydration, we correlated the incidence of painful crisis with steady-state measurements of red cell hydration. Sixteen children with SS disease were followed for 3.3 to 8 years (mean, 6.8 years), and a single crisis rate was calculated for each patient. At the time of well visits, cellular hydration was assessed by measuring cell deformability, the percentage of red cells with a density greater than or equal to 1.1056 g/mL, and the percentage of irreversibly sickled cells (ISC). The incidence of painful crisis showed a strong positive correlation with Omax, a deformability measurement reflecting cellular hydration (r = .84, P less than .002), and with hemoglobin concentration (r = .59, P = .04). That is, higher crisis rates were observed in patients with less dehydrated, more deformable red cells and also in patients with higher hemoglobin concentrations. Furthermore, cell deformability and hemoglobin concentration were independent predictors of the incidence of painful crisis, which is consistent with separate effects of these two red cells parameters on vasoocclusive severity.
Anemia, Sickle Cell↗
Rapid prenatal diagnosis of sickle cell anemia by a new method of DNA analysis.
We have used a new method of DNA analysis for the rapid prenatal diagnosis of sickle cell anemia in two fetuses at risk for this disease. This method of detecting the sickle gene is a modification of standard restriction-enzyme techniques and requires only a small amount of DNA. The first step involves a 200,000-fold enzymatic amplification of the specific beta-globin DNA sequences that may carry the sickle mutation. This provides a sufficient quantity of DNA for the analysis. Next, a short radiolabeled synthetic DNA sequence homologous to normal beta A-globin gene sequences is hybridized to the amplified target sequences. The hybrid "duplexes" are then digested sequentially with two restriction endonucleases. The presence of beta A- or beta S-globin gene sequences in the amplified target DNA from the patient determines whether the beta A-hybridization probe anneals perfectly or with a single nucleotide mismatch. This difference affects the restriction-enzyme digestion of the DNA and the size of the resulting radiolabeled digestion products, which can be distinguished by electrophoresis followed by autoradiography. This method is sufficiently sensitive and rapid that the prenatal diagnosis of sickle cell anemia can be made on the same day that the fetal DNA is made available. It can also be applied to the diagnosis of hemoglobin C disease.
Anemia, Sickle Cell↗
Advances in the prenatal diagnosis of sickle cell anemia.
These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs Homer A. Boushey, Professor of Medicine, and David G. Warnock, Associate Professor of Medicine, under the direction of Dr Lloyd H. Smith, Jr, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143.
Anemia, Sickle Cell↗
The role of fluctuating populations of blood cells in the acute painful episodes of sickle cell disease.
Explore the source record for details and available documents.
Anemia, Sickle Cell↗
Alpha-thalassemia in blacks: interactions with the sickle hemoglobin gene.
Explore the source record for details and available documents.
Anemia, Sickle Cell↗
Hematologic malignancy in sickle cell disease: report of four cases and review of the literature.
Hematologic malignancy has rarely been reported in adults with sickle cell disease. We describe four sickle cell patients (two with hemoglobin SC, two with hemoglobin SS) who developed hematologic malignancy (acute myeloblastic leukemia, multiple myeloma, malignant histiocytosis, and Hodgkin's disease). Three of the cases represent the first adult association between SC or SS hemoglobinopathy and the particular malignancy involved. Sickle hemoglobin does not appear to exert a protective effect against childhood hematologic malignancies, suggesting that better survival in sickle cell disease may be accompanied by an increased incidence of hematologic neoplasms in adulthood. Karyotypic analysis revealed alterations of chromosome 5 in two sickle cell patients with leukemia, raising the possibility of a chromosomal link between the two diseases. Further epidemiologic and cytogenetic studies are needed to define the relationship between hematologic malignancy and sickle cell disease.
Adult↗
The clinical pathophysiology of sickle cell disease.
Polymerization of deoxyhemoglobin S within sickle erythrocytes is of cardinal importance to each of the clinical complications of sickle cell anemia. Sickle gene expression, however, is modulated by a number of pathophysiological mechanisms that generate vast clinical diversity among sickle cell patients. These processes include genotypic variations, modifications of polymerization, abnormal erythrocyte hydration, membrane defects, and rheologic factors. In many cases it is possible to relate specific pathophysiological mechanisms to particular disease features or to possibilities for therapeutic intervention.
Anemia, Sickle Cell↗
Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene.
Recent advances in molecular genetics have permitted detailed study of the human alpha-globin genes and the causes of alpha-thalassemia. In this review, we examine the causes of alpha-thalassemia in the black population and the consequences of the interactions between alpha-thalassemia and structural hemoglobin variants.
Anemia, Sickle Cell↗
Reduced transglutaminase-catalyzed cross-linking of exogenous amines to membrane proteins in sickle erythrocytes.
In order to determine the capacity of sickle cells to undergo transglutaminase-catalyzed cross-linking of membrane proteins, human normal and sickle erythrocytes were incubated with [ring-2-14C]histamine in the presence of Ca2+ and ionophore A23187. The [14C]histamine incorporation into membrane components was observed in freshly prepared erythrocytes. Incorporation of radioactivity into spectrin and Band 3 membrane components was significantly (P less than 0.001) less in sickle erythrocytes than in normal cells. Transglutaminase deficiency was excluded by the finding of increased activity of this enzyme in sickle cells from patients with reticulocytosis. The incorporation of [3H]spermine into red cell membranes was also less in sickle erythrocytes than in normal cells under the same conditions of incubation used for [ring-2-14C]histamine. Sickle erythrocytes were more permeable to these amines than normal cells. It is proposed that the gamma-glutamyl sites of membrane proteins in sickle erythrocytes are less accessible for transglutaminase-catalyzed cross-linking to histamine and polyamines in vitro, perhaps due to prior in vivo activation of this enzyme by the increased calcium in sickle cells and/or shielding secondary to altered membrane organization.
Acyltransferases↗
Visualization of oriented hemoglobin S in individual erythrocytes by differential extinction of polarized light.
The distribution of oriented, polymerized sickle cell hemoglobin (hemoglobin S) in erythrocytes is visualized with a microscope that produces an image proportional to linear dichroism. Monochromatic light alternately polarized along two perpendicular directions is incident on the sample. The image is focused on a diode array, and the digital output is used to form two images. One is the usual image proportional to the average transmitted light intensity of the two incident polarizations of light; the other is a linear differential image proportional to the linear dichroism of the sample. This quantitative image can specifically reveal oriented hemoglobin molecules with a sensitivity of about 4000 oriented molecules per picture element of the image.
Anemia, Sickle Cell↗
The interaction of coexistent alpha-thalassemia and sickle cell anemia: a model for the clinical and cellular results of diminished polymerization?
Review of the studies on the interaction of alpha-thalassemia and sickle cell anemia reveals a consistently beneficial effect on the severity of anemia and the rheologic and cellular properties of sickle cells. The predominantly vaso-occlusive clinical aspects of sickle cell anemia studied are not uniformly benefited by the presence of alpha-thalassemia. These variable results may be related to the detrimental effects of higher hematocrit on whole blood viscosity. The effects of alpha-thalassemia on sickle cell anemia are probably related to a fundamental effect on MCHC and polymerization, although coexistent effects on other properties of sickle cells and the possibility that the MCHC differences may be secondary to sickling effects cannot be excluded. In total, alpha-thalassemia is an imperfect model for the effects of polymerization on the clinical consequences of sickle cell disease. An important inference from the published literature is that the severity of anemia may be a more important determinant of the ultimate clinical consequence of sickle cell anemia, life expectancy, than has previously been appreciated. Although the effect of alpha-thalassemia is an imperfect model for modified polymerization, studies of the phenotypic result of the interaction of these two genotypes will provide further insight into the causes of clinical diversity in sickle cell disease.
Anemia, Sickle Cell↗