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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The basic pathology in all forms of thalassemia results from the presence of excess unstable globin chains within the pathological RBC, but the pattern and rate of their precipitation is different. Consequently, their effects on the RBC membrane components are not the same and may account for the different rheological properties that have been found. It is possible that the damage incurred by excess beta chains in Hb H disease is primarily due to the direct interaction of the large inclusions with some cytoskeletal proteins such as spectrin, ankyrin, and band 3. In beta-thalassemia, where excess unstable alpha chains have already precipitated in young erythroblasts, the main damage might be caused by an excess of free oxygen radicals, which affect in particular protein 4.1. A search for additional changes and for potential differences in the membrane and cellular properties between the different thalassemic syndromes is warranted in order to understand better the different clinical expression in the various types of the disease. Moreover, when there is a better elucidation of the mechanisms by which the RBC are destroyed, one may look for possible ways and means to prevent these changes, with a consequent extension of the current short life span of the affected RBC.
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PMID:Differences in the pathophysiology of hemolysis of alpha- and beta-thalassemic red blood cells. 229 41

We believe that on the basis of all available data, severe oxidative damage occurs in alpha- and beta-thalassemic RBCs, as depicted schematically in Fig 6. The differences in the severity and pattern of the oxidative damage may be related to the type and, perhaps, quantity of precipitated globin chains. The detrimental effect of the excess chains is multifold. In the process of globin-chain precipitation, free radicals are generated. The end product of the precipitated hemoglobin chains is heme, from which eventually iron and globin are liberated. Globin chains have been found to interact and disrupt the RBC membrane, damaging the cytoskeleton. The role of heme has not yet been studied in detail in thalassemic RBCs. However, there is some evidence that it participates in damaging RBCs in other types of hemoglobinopathies. Excess of iron is known to be a catalyst of peroxidation via the Fenton reaction, causing damage to the various RBC membrane components (lipids, proteins, etc). The denatured hemaglobin, in the form of hemichromes, aggregates with protein 3, forming Actual proof of excessive free radical production in thalassemia is still warranted. It will not be easy to document since the amount of superoxide dismutase in RBCs is above and beyond that required for neutralizing excess amount of superoxide. The more active radicals, particularly hydroxyl free radical, are difficult to measure because they are so active an interact immediately with any given substrate in their vicinity. In addition, we have to better understand the finding of excess membrane lipids in thalassemic RBCs and whether there are changes in the formation and propagation of lipid peroxidation in these cells compared with normal RBCs. Regarding the proteins, further understanding is required concerning the exact type and sites of oxidation that occurs in the beta-thalassemia 4.1 protein, and whether the damage found in alpha-thalassemia is due to oxidation of ankyrin itself or its entrapment within the complex of the precipitated hemichromes of beta chains. What is the role of the different globin chain oxidation and precipitation in generating such different cytoskeletal protein alterations? Another point that needs to be elucidated is the role of different kinds of antibodies that are attached to the newly exposed antigenic sites on the thalassemic RBC membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Oxidative denaturation of red blood cells in thalassemia. 240 97

Although functional abnormalities of the sickle erythrocyte membrane skeleton have been described, there is little quantitative data on the function of the proteins that compose the skeleton. We have examined the association of spectrin, the major skeletal protein, with ankyrin, its high-affinity membrane binding site, and found sickle erythrocytes to have markedly reduced binding. Binding is assayed by incubation of purified 125I-spectrin with spectrin-depleted inside-out vesicles (IOVs) and measurement of the label bound to IOVs. Sickle IOVs bind approximately 50% less ankyrin than do controls IOVs (P less than 0.001). Control experiments show that this reduced binding is not a function of faulty composition or orientation of sickle IOVs, or of reticulocytosis per se. Our least symptomatic patient has the highest binding capacity, suggesting that this abnormality may be related to clinical severity. This trend is supported by experiments showing that asymptomatic subjects with sickle trait, sickle cell anemia and high fetal hemoglobin, and sickle beta +-thalassemia have normal binding, whereas a symptomatic patient with sickle beta zero-thalassemia has abnormal binding. In contrast to what we see with ankyrin in situ on the IOV, when isolated and studied in solution, sickle ankyrin binds normally to spectrin. This discrepancy may be related to preferential purification of the normal ankyrin species or to an abnormal topography of the membrane near the spectrin attachment site. We hypothesize that sickle hemoglobin or perhaps the metabolic consequences of sickling damage the protein skeleton. This damage may alter the surface of the erythrocyte and result in abnormal cell-cell interactions which may be related to clinical severity.
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PMID:Molecular defect in the sickle erythrocyte skeleton. Abnormal spectrin binding to sickle inside-our vesicles. 257 38

To study the biogenesis of red cell membrane skeleton at various stages of erythroid differentiation, we have chosen the following model systems: a) Rauscher erythroleukemia cell line representing the early stages of differentiation, b) Friend erythroleukemia cells, and c) in vitro cultured human erythroblasts. The latter two systems represent terminally differentiated erythroblasts. Using these model systems, we have shown asynchronous synthesis of membrane proteins during erythroid differentiation. At the early stages of erythroid development, the synthesis of spectrin, ankyrin and band 4.1 proteins is initiated before that of the band 3 protein. Following erythroid induction with erythropoietin and dimethylsulfoxide (DMSO), there is a dramatic increase in the synthesis of the band 3 protein without noticeable changes in the synthesis of other membrane proteins. This increase in band 3 synthesis is accompanied by increased stability and recruitment of the skeletal proteins into the membrane skeleton, leading to increased steady state levels. The progressive increase in band 3 synthesis continues during terminal maturation of erythroblasts. This is accompanied by increased stability and assembly of spectrin and ankyrin on the membrane, despite their reduced synthesis. These results point to a key role for the band 3 protein in anchoring and stabilizing these proteins into the permanent skeletal network. Finally, to detect defects of skeletal biosynthesis, we have extended these studies to a patient with severe hereditary spherocytosis characterized by a combined deficiency of spectrin and ankyrin. We have shown that this combined deficiency is a consequence of reduced ankyrin synthesis and mRNA content representing a thalassemia-like membrane protein mutation.
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PMID:Biogenesis of erythrocyte membrane skeleton in health and disease. 831 23

Malaria, caused by members of the genus Plasmodia, is still the most prevalent parasitic disease in the world. In an attempt to understand genetic factors conferring resistance to malaria, mouse models of thalassemia, sickle trait, and ankyrin and spectrin deficiency were studied during infection with species of malaria infectious to rodents. Although growth of P. falciparum is not inhibited in thalassemic erythrocytes in culture, mice carrying a beta-thalassemia mutation were protected from Plasmodium chabaudi adami, supporting epidemiologic findings. Transgenic mice expressing beta s hemoglobin were also significantly protected from two species of rodent malaria. Importantly, a significant role for the spleen in protection in the beta s transgenic mice was found. Finally, mice deficient in spectrin and ankyrin were studied with respect to their ability to support the growth of malaria. It was found that spectrin deficient mice were almost completely refractory to P. chabaudi adami and P. berghei. These models will allow further study of host factors in resistance to malaria.
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PMID:Transgenic and mutant animal models to study mechanisms of protection of red cell genetic defects against malaria. 842 8

The recent discovery of the specific molecular defects in many patients with hereditary spherocytosis and hereditary elliptocytosis/pyropoikilocytosis partially clarifies the molecular pathology of these diseases. HE and HPP are caused by defects in the horizontal interactions that hold the membrane skeleton together, particularly the critical spectrin self-association reaction. Single gene defects cause red cells to elongate as they circulate, by a unknown mechanism, and are clinically harmless. The combination of two defective genes or one severe alpha spectrin defect and a thalassaemia-like defect in the opposite allele (alphaLELY) results in fragile cells that fragment into bizarre shapes in the circulation, with haemolysis and sometimes life-threatening anaemia. A few of the alpha spectrin defects are common, suggesting they provide an advantage against malaria or some other threat. HS, in contrast, is nearly always caused by family-specific private mutations. These involve the five proteins that link the membrane skeleton to the overlying lipid bilayer: alpha and beta spectrin, ankyrin, band 3 and protein 4.2. Somehow, perhaps through loss of the anchorage band 3 provides its lipid neighbours (Peters et al, 1996), microvesiculation of the membrane surface ensues, leading to spherocytosis, splenic sequestration and haemolysis. Future research will need to focus on how each type of defect causes its associated disease, how the spleen aggravates membrane skeleton defects (a process termed 'conditioning'), how defective red, cells are recognized and removed in the spleen, and why patients with similar or even identical defects can have different clinical severity. Emphasis also needs to be given to improving diagnostic tests, particularly for HS, and exploring new options for therapy, like partial splenectomy, which can ameliorate symptoms while better protecting patients from bacterial sepsis and red cell parasites, and perhaps from atherosclerosis (Robinette & Franmeni, 1977) and venous thrombosis (Stewart et al, 1996).
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PMID:Red blood cell membrane disorders. 1105 1

Thrombosis is a major complication of human hemolytic anemias such as sickle cell disease, thalassemia, and severe hereditary spherocytosis (HS). Mice with severe HS and severe hereditary elliptocytosis (HE) also suffer from thrombosis, with incidences ranging from 15 and 22% in beta-spectrin- and ankyrin-deficient mice, respectively, to 85 to 100% in alpha-spectrin-deficient and band 3 knockout mice. A contributing factor to thrombosis could be loss of phospholipid asymmetry of the mutant red blood cells (RBCs), with concomitant exposure of the aminophospholipid phosphatidylserine (PS). Increased PS exposure occurs in RBCs from sickle cell and thalassemia patients and in RBCs from band 3-deficient mice. To determine if increased PS exposure correlates with thrombotic risk in HS and HE mice with ankyrin, beta-spectrin, and alpha-spectrin deficiencies, measurements of FITC-labeled annexin V binding to externalized PS on RBCs were performed. PS exposure is elevated in all mice with HS and HE, but the percentage of RBCs with exposed PS does not correlate with thrombotic risk in these mice.
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PMID:Erythroid phosphatidyl serine exposure is not predictive of thrombotic risk in mice with hemolytic anemia. 1077 78

Gene therapy for patients with hemoglobin disorders has been hampered by the inability of retrovirus vectors to transfer globin genes and their cis-acting regulatory sequences into hematopoietic stem cells without rearrangement. In addition, the expression from intact globin gene vectors has been variable in red blood cells due to position effects and retrovirus silencing. We hypothesized that by substituting the globin gene promoter for the promoter of another gene expressed in red blood cells, we could generate stable retrovirus vectors that would express globin at sufficient levels to treat hemoglobinopathies. Recently, we have shown that the human ankyrin (Ank) gene promoter directs position-independent, copy number-dependent expression of a linked gamma-globin gene in transgenic mice. We inserted the Ank/(A)gamma-globin gene into retrovirus vectors that could transfer one or two copies of the Ank/(A)gamma-globin gene to target cells. Both vectors were stable, transferring only intact proviral sequences into primary mouse hematopoietic stem cells. Expression of Ank/(A)gamma-globin mRNA in mature red blood cells was 3% (single copy) and 8% (double copy) of the level of mouse alpha-globin mRNA. We conclude that these novel retrovirus vectors may be valuable for treating a variety of red cell disorders by gene replacement therapy including severe beta-thalassemia if the level of expression can be further increased.
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PMID:Long-term expression of gamma-globin mRNA in mouse erythrocytes from retrovirus vectors containing the human gamma-globin gene fused to the ankyrin-1 promoter. 1106 98

Major membrane proteins have been quantitatively analyzed in erythrocytes and platelets from patients with homozygous (splenectomized and non-splenectomized) and heterozygous forms of beta-thalassemia depending on severity of clinical manifestation of this disease. Quantitative analysis of erythrocyte membrane proteins revealed increase in alpha- and beta-spectrin. (In non-splenectomized patients with homozygous beta-thalassemia the amount of this protein was lower than in corresponding controls.) Besides spectrin, the increase of 2.1-2.3 fractions of ankyrin, and the decrease of band 3 protein (anion-transport protein), 4.1, palladin, and glyceraldehyde-3-phosphate dehydrogenase were also found. Analysis of major platelet membrane proteins revealed significant increase in gelsolin. This increase was found in all forms of beta-thalassemia irrespective of gender. Significant changes in platelet membrane protein fractions were found in patients (especially non-splenectomized) with homozygous beta-thalassemia. These included significant decrease in myosin, profilin, and gamma-actin and increase in actin-binding protein in both male and female patients. The content of other protein fractions (alpha-actinin, tubulin, tropomyosin) remained unchanged. Changes in protein fractions of erythrocytes and platelets correlated with severity of clinical manifestation of the disease.
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PMID:Analysis of erythrocyte and platelet membrane proteins in various forms of beta-thalassemia. 1531 Feb 73

Gene analysis in Japanese patients with congenital hemolytic anemia due to red cell membrane disorders, thalassemias, unstable hemoglobinopathies and red cell enzymopathies were summarized. In hereditary spherocytosis, twenty-four mutations of band 3, five mutations of protein 4.2 and twenty mutations of ankyrin have been identified. In beta thalassemia, fourty-seven mutations of beta globin have been found, and ten mutations among them comprise 80% of beta thalassemia patients in Japan. Most common alpha0 and alpha+ thalassemia are--SEA and--alpha3.7, respectively. Fourty glucose-6-phosphate dehydrogenase mutations and twenty-three pyruvate kinase mutations have been identified, allowing a better understanding of the structure-function relationships of these enzymes.
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PMID:[Congenital hemolytic anemia]. 1577 39


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