Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Repeated injections of large doses of erythropoietin (Epo) have been shown to be of benefit in the treatment of murine and human beta-thalassemia. To determine whether Epo gene therapy could replace this treatment for long-term periods, lethally irradiated beta-thalassemic (Hbbd3th haplotype) and normal DBA/2J (Hbbd haplotype) mice were grafted with syngeneic bone marrow cells infected with a retroviral vector carrying the Epo cDNA. In normal mice, dysregulated Epo production induced elevated serum Epo levels (176 +/- 68 mU/mL), high hematocrit levels (73% +/- 8%), and elevated beta-minor globin chain synthesis. In contrast, in thalassemic mice, moderate increases in the hematocrit levels (from 33% +/- 1% to 43% +/- 9%), associated with limited increases in the initially elevated Epo levels (from 83 +/- 22 to 190 +/- 230 mU/mL), were recorded 2 months after transplantation. In mice in which the hematocrit increased most, from 33% +/- 1% before transplantation to 49% +/- 10%, the retroviral Epo gene expression induced a striking improvement of the beta-thalassemic syndrome. These mice exhibited normal or near-normal beta/alpha-globin chain synthesis ratios, induced by the activation of the beta-minor chain. This led to the elimination of the high amounts of unpaired alpha chains in erythrocytes and finally reduced the reticulocyte count despite the permanent Epo stimulation. These results show that efficient Epo gene expression corrects the erythrocyte phenotype of the mouse beta-thalassemic syndrome. However, the incidence of lethal polycythemia or of transient improvements indicates that the present strategy is only the first step toward such indirect gene therapy.
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PMID:Retrovirus-mediated transfer of the erythropoietin gene in hematopoietic cells improves the erythrocyte phenotype in murine beta-thalassemia. 804 75

Up to the mid-1960s, beta-thalassemia was treated with blood transfusions as frequent as needed to keep symptoms under control and to prevent transfusional hemosiderosis. In the following years, high transfusion regimens and iron chelation therapy with desferrioxamine were used. Because of these different treatment modalities, skeletal findings in thalassemia have markedly changed. In the past, thalassemic patients treated with a low transfusion regimen and without chelation therapy developed osteopenia--with widened medullary spaces, cortical thinning and trabecular atrophy--secondary to chronic expansion of red marrow, due to increased erythropoietin response to chronic anemic hypoxia. Typical radiographic patterns in the skull included widened diploic space, atrophic-especially outer--tables and, in some patients, the "hair-on-end" pattern. As for the face, obliteration of the paranasal sinuses and the typical "rodent facies" were observed. In the ribs, bulbous expansion of the posterior and anterior segments and the "rib within a rib" patterns were observed. As for the spine, coarse trabecular arrangement was seen. The "cobweb" pattern was seen in the pelvis and finally the lack of the normal concave outline was observed in the long bones. In the patients treated with high transfusion regimens and iron chelation therapy over the last 30 years, both skull anomalies and disfigurement are less frequent. The skull is almost normal, with the exception of osteopenia and thickened diploic space in the frontal bone only; the paranasal sinuses are usually not obliterated. The hands and rib are normal, just like long bones, pelvis, scapulae and vertebral bodies. Nevertheless, in some adequately treated patients new skeletal features have been recently observed in the long bones, which are similar to those occurring in rickets and/or scurvy, and in the vertebral bodies, resembling platyspondylia. These abnormal features might be caused by several factors--i.e., marrow expansion, transfusion regimens, direct/indirect effects of desferrioxamine, iron load, endocrine abnormalities, deficiency of some minerals and finally dysvitaminoses. Nevertheless, osteopenia remains the main negative factor of thalassemia.
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PMID:[The evolutionary effects of therapy on the skeletal lesions in beta-thalassemia]. 819 Sep 18

Serum concentrations of erythropoietin (EPO) were determined by immunoassay in 45 patients with thalassemia intermedia (TI). The mean serum level of EPO was significantly higher in the thalassemic patients than in the controls, but transfused subjects had lower pretransfusional serum concentrations of EPO than untransfused ones. An inverse relationship between the serum values of EPO and total hemoglobin was observed only in the untransfused thalassemic patients. These data suggest that in TI, even a low transfusional regimen may cause a decrease in serum concentration of EPO, independent of the level of total Hb.
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PMID:Serum erythropoietin levels in thalassemia intermedia. 821 39

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

Fifteen thalassemia intermedia patients were considered, whose clinical and radiological findings were examined and compared. Eight patients underwent regular transfusion therapy. All patients underwent total body CT: the volume of ectopic erythropoiesis foci was calculated by a digital calculation algorithm (ROI volume). This work was aimed at correlating the quantitative measures of ectopic erythropoiesis assessed by CT with serum level of erythropoietin (EPO) and of trasferrin-free receptors (TfR) in both transfused and non-transfused patients, also considering the volume changes of ectopic erythropoiesis and bone changes over 36 months' follow-up. A direct correlation was demonstrated between serum transferrin and ectopic erythropoietic masses in transfusion-dependent patients: in fact, increased values of serum transferrin correspond to the enlargement of these masses and to bone lesion worsening.
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PMID:[Clinico-radiological correlation in thalassemia intermedia]. 832 57

Thalassemia is a common genetic disorder among the South Chinese. To see if thalassemia would adversely affect the erythrocyte response to recombinant human erythropoietin (rHuEPO, Epogen) in dialysis patients, the response to rHuEPO in 4 dialysis patients with thalassemic traits (thal-t) was compared with that of 4 control patients who were matched for age, sex, mode of dialysis and baseline hemoglobin levels over a 6-month period. Patients with thal-t showed a reduced erythrocyte response to rHuEPO compared to control dialysis patients as reflected by a reduced reticulocyte index, a slower rise in hemoglobin or hematocrit levels, requirement of a higher cumulated dose of rHuEPO to achieve a target hemoglobin of 10 g/dl and a higher maintenance dose of rHuEPO. A dialysis patient with hemoglobin H disease (HbHD) was also studied. He failed to respond to rHuEPO despite that the dose was increased to 250 U/kg/week. In contrast, his matched control dialysis patient, despite a lower baseline hemoglobin level (6.1 versus 8.8 g/dl), was able to reach a target hemoglobin level of 10 g/dl by 6 weeks and could be maintained at this level with 50 U/kg/week. The patient with HbHD had splenomegaly and a higher baseline serum erythropoietin level, reticulocyte count, serum bilirubin, serum ferritin and serum iron saturation than control patients and patients with thal-t. It was concluded that thal-t reduces the erythrocyte response to rHuEPO in dialysis patients and that in the presence of active hemolysis and enhanced endogenous erythropoietin secretion, dialysis patients with HbHD are resistant to treatment with rHuEPO.
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PMID:Influence of thalassemia on the response to recombinant human erythropoietin in dialysis patients. 834 81

The primary pathophysiological event in the erythrocytes of individuals with the various sickle syndromes is the intracellular aggregation or polymerization of sickle haemoglobin (HbS). The extent of polymerization is determined by the intracellular haemoglobin composition (% HbS and % HbS A, A2 and F), concentration (MCHC and % of dense cells) and oxygen saturation, as well as minor factors such as intracellular pH and DPG concentration. Intracellular HbS polymerization leads to a marked decrease in the flexibility or rheological properties of the sickle erythrocytes and obstruction in various microcirculatory beds, as well as chronic anaemia. Other abnormalities in the properties of the sickle erythrocytes, including membrane abnormalities, changes in ion fluxes and volume and endothelial adhesion, result from acute and chronic oxygen-linked polymerization events and may, in turn, modify polymerization. However, within a good approximation, many aspects of sickle cell disease pathophysiology--for example variations in anaemia among the different sickle syndromes--can be explained in terms of differences in polymerization tendency. Thus, the effects of alpha-thalassaemia can be explained with reference to changes in MCHC and syndromes with high HbF are understandable in terms of the sparing effect of HbF on polymerization. Recent therapeutic approaches to sickle cell disease focus on attempts to reduce intracellular HbS polymerization by altering the haemoglobin molecules, erythrocyte properties, or the distribution of intracellular haemoglobin species. The last, through pharmacological elevation of HbF, has become the central focus of much laboratory and clinical research in recent years. Agents such as hydroxyurea (with or without recombinant erythropoietin) and butyrate compounds elevate HbF (and reduce HbS) in a majority of sickle erythrocytes, thus decreasing intracellular polymerization. Current prospective protocols are designed to see if these changes cause clinical improvement at acceptable doses. Other treatment strategies, including bone marrow transplantation and possible gene replacement therapies, are also under active clinical or laboratory investigation.
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PMID:Sickle cell disease pathophysiology. 835 18

The present investigation was undertaken to search for soluble forms of the erythropoietin receptor in human serum using polyclonal antibody against an amino terminal peptide sequence in the extracellular domain. This sequence was located adjacent to the amino terminus at residues 25-38. When this antibody was used for Western blots of solubilized membranes from nucleated bone marrow cells, a protein consistent with native erythropoietin receptor was seen. Purified soluble ectodomain of the erythropoietin receptor displayed appropriate reactivity with this antibody. When sera from normal subjects and patients with a range of hematologic disorders were examined by Western blotting, a protein with a molecular mass of 34 Kd was detected in sera from patients with enhanced erythropoiesis including sickle cell anemia, thalassemia, and megaloblastic anemia. This protein was rarely detected in normal serum but appeared when normal subjects were treated with recombinant erythropoietin and disappeared after full treatment of patients with megaloblastic anemia due to vitamin B12 deficiency. The protein was not detected after myeloablation for bone marrow transplantation but appeared with marrow engraftment. Reactivity of this protein with the peptide antibody was competitively inhibited by the amino terminal peptide sequence. An additional 48 Kd protein was detected that showed minimal variation in intensity with differing degrees of erythropoietic activity. Detection of this protein could not be inhibited by the addition of synthetic peptide. Our findings indicate the presence of a soluble form of the erythropoietin receptor related to the extracellular domain that is highly correlated with enhanced erythropoiesis.
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PMID:Serum form of the erythropoietin receptor identified by a sequence-specific peptide antibody. 887 30

A case of a pregnant woman suffering from homozygous (delta beta) zero-thalassemia clinically running as thalassemia Intermedia is described. In this patient pregnancy could not follow its normal course and was interrupted in the 24th week, because of endouterine death of the foetus due to complications such as serious haemolytic anaemia following transfusional alloimmunisation and the presence of portal vein thrombosis. In this article the literature is reviewed and the need is shown for all thalassemic patients to be tested for the various blood antigenic systems, so that transfusional reactions can be avoided. Stress is laid on the importance of erythropoietin both in the pathogenesis of haematological and rheological modifications in thalassemic patients and also as a trigger in serious thrombotic complications.
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PMID:[Pregnancy complication in homozygous (delta beta) zero-thalassemia. A clinical case]. 850 61

High total haemoglobin levels in homozygous sickle cell (SS) disease are a risk factor for painful crises, avascular necrosis of the femoral head, proliferative sickle retinopathy, and the acute chest syndrome. Since lowering the haemoglobin level may ameliorate these features, understanding the determinants of total haemoglobin may be of practical importance. A range of possible determinants including red cell characteristics, reticulocytes, serum iron, transferrin saturation, serum ferritin, alpha thalassaemia status, red cell mass and plasma volume, oxygen affinity, red cell survival, transferrin receptor and erythropoietin levels have been measured in 62 patients selected to provide a range of total haemoglobin and fetal haemoglobin levels. There were weak negative associations of haemoglobin with mean cell volume and mean cell haemoglobin concentration, strong negative associations with proportional reticulocyte counts, oxygen affinity, plasma volume, serum transferrin receptors, and erythropoietin levels and strong positive associations with red cell mass. Weighted analysis suggested that the statistically independent determinants of haemoglobin level were alpha thalassaemia, sex, red cell mass/body weight, plasma volume/body weight, fetal haemoglobin, and red cell count. The apparent contributions of red cell survival, P50, reticulocyte count, serum transferrin receptor and erythropoietin levels were explained by the effects of these other variables. The independent determinants as a group explained 91% of the variation in haemoglobin level.
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PMID:Determinants of haemoglobin level in steady-state homozygous sickle cell disease. 856 87


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