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

Our earlier studies suggested an association between alpha-thalassemia and hypertension. We postulated that this association might involve trapping of the vasodilator nitric oxide (NO) by hemoglobin (Hb). Hb A has recently been shown to carry NO on its sulfhydryl groups in addition to its hemes. In this report we studied the interaction of purified Hb H as well as Hb A with NO. The number of reactive sulfhydryls were determined spectrophotometrically with bis-dithionitrobenzoate. Spectral studies and nitrosothiol measurements after treatment with NO or nitrosothiols indicated that all eight reactive sulfhydryls of Hb H were capable of binding NO. Hb A, however, was only able to bind and transfer two molecules of NO per tetramer. These findings support the biochemical basis for the association between alpha-thalassemia and hypertension.
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PMID:Binding of nitric oxide to thiols and hemes in hemoglobin H: implications for alpha-thalassemia and hypertension. 926 26

Iron is a crucial element for many central metabolic pathways of the body. Lack of iron leads to growth arrest and anaemia while increased accumulation of this metal, as it occurs in highly frequent inherited diseases such as hereditary haemochromatosis and thalassaemia, is associated with toxic radical formation and progressive tissue damage. As shown by several groups, iron also modulates immune effector mechanisms, such as cytokine activities (IFN-gamma effector pathways towards macrophages), nitric oxide (NO) formation or immune cell proliferation, and thus host immune surveillance. Therefore, gaining control over iron homeostasis is one of the central battlefields in deciding the fate of an infection with intracellular pathogens or a malignant disease. Thus, the reticulo-endothelial system has evoked sophisticated strategies to control iron metabolism in general and especially the handling of the metal within immune cells.
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PMID:Iron and immunity: a double-edged sword. 1188 35

Pulmonary hypertension is a common complication of sickle cell disease (SCD). In spite of the mild elevations in pulmonary artery pressures in these patients, the associated morbidity and mortality is high. In fact, in adult patients with SCD, pulmonary hypertension is emerging as the major independent risk factor for death. The aetiology of pulmonary hypertension is probably multifactorial, including haemolysis, impaired nitric oxide bioavailability, chronic hypoxaemia, thromboembolism, parenchymal and vascular injury because of sequestration of sickle erythrocytes, chronic liver disease and asplenia. Interestingly, pulmonary hypertension is emerging as a common, and probably, invariant sequella of lifelong haemolytic anaemia in other hereditary and acquired haemolytic diseases, such as thalassaemia, stomatocytosis and spherocytosis. There are currently limited specific data on the effects of any treatment modality for pulmonary hypertension in patients with SCD. It is likely that maximization of SCD therapy, in all patients, and treatment with selective pulmonary vasodilators and antiproliferative agents, in patients with severe disease, would be beneficial. A large trial evaluating the effects of therapy for pulmonary hypertension in the SCD population is clearly indicated.
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PMID:Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. 1587 28

Medical advances in the management of patients with sickle cell disease, thalassemia, and other hemolytic anemias have led to significant increases in life expectancy. Improved public health, neonatal screening, parental and patient education, advances in red cell transfusion medicine, iron chelation therapy, penicillin prophylaxis for children, pneumococcal immunization, and hydroxyurea therapy have all likely contributed to this effect on longevity. Importantly, as a generation of patients with sickle cell disease and thalassemia ages, new chronic complications of these hemoglobinopathies develop. In this context, pulmonary hypertension is emerging as one of the leading causes of morbidity and mortality in adult sickle cell and thalassemia patients, and likely in patients with other hemolytic anemias. A common feature of both sickle cell disease and thalassemia is intravascular hemolysis and chronic anemia. Recent data suggest that chronic intravascular hemolysis is associated with a state of endothelial dysfunction characterized by reduced nitric oxide (NO) bioavailability, pro-oxidant and pro-inflammatory stress and coagulopathy, leading to vasomotor instability and ultimately producing a proliferative vasculopathy, a hallmark of which is the development of pulmonary hypertension in adulthood. In conclusion, pulmonary hypertension is common in patients with hereditary hemolytic anemias and is associated with a high risk of death in patients with sickle cell disease. New therapies targeting this vasculopathy and aimed at normalizing the vasodilator:vasoconstrictor balance are discussed.
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PMID:Cardiopulmonary complications of sickle cell disease: role of nitric oxide and hemolytic anemia. 1630 59

Free radicals are a one of damaging factors in diseases associated with iron overload. This review considers two principal questions: the mechanisms of free radical-mediated damage in cells and tissue and findings concerning the discovery of iron-stimulated free radical cascades in thalassemia and Fanconi anemia. There are two major precursors of all reactive oxygen and nitrogen species formed in living organism - superoxide (O(2)( -)) and nitric oxide (NO). However, it has been shown that in addition to well-known mechanisms of the formation of reactive hydroxyl radicals and peroxynitrite from superoxide and NO, there are signal pathways by which these "physiological" radicals directly induce apoptosis, proton leak in mitochondria and an increase in oxygen consumption leading to cell death. In present review the mechanisms of free radical damage are considered with the particular emphasis of iron-induced free radical formation in thalassemia and Fanconi anemia. Furthermore free radical reactions leading to lipid peroxidation, LDL oxidation, the stimulation of apoptosis and other damaging processes are discussed. An importance of the chelating and antioxidant treatments of thalassemic and Fanconi anemia patients is also considered within the context of free radical damage and its prevention.
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PMID:Superoxide and nitric oxide in pathological conditions associated with iron overload: the effects of antioxidants and chelators. 1630 68

Accumulating evidence supports the existence of a condition involving hemolysis-associated pulmonary hypertension (PHT). Hemolysis-induced release of cell-free hemoglobin and red blood cell arginase, resulting in impaired nitric oxide bioavailability, endothelial dysfunction, and PHT, has been reported in sickle cell disease. Since thalassemia is also a condition of chronic hemolysis, these patients are at risk. The data demonstrate that hemolysis-induced dysregulation of arginine metabolism and PHT also occurs in thalassemia. Erythrocyte release of arginase during hemolysis contributes to the development of PHT. Therapies that maximize arginine and nitric oxide bioavailability may benefit patients with thalassemia.
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PMID:Hemolysis-associated pulmonary hypertension in thalassemia. 1633 2

Thalassemia (thal) and Fanconi's Anemia (FA) are genetic disorders associated with iron-catalyzed free radical damage. Therefore, the contemporary and most successful treatment of thalassemic patients depends on the application of iron (Fe) chelators. However, there is another pathway of free radical-mediated damaging processes in these pathologies, depending on the interplay between physiological free radicals superoxide and nitric oxide (NO). In the present study, we have considered the major routes of superoxide damaging effects in mitochondria: the initiation of apoptosis through the reduction of cytochrome c, the activation of uncoupled proteins by superoxide, and the mitochondrial damage due to the competition between superoxide and nitric oxide at the Complex IV site (cytochrome oxidase). The application of the effective scavengers superoxide dismutases and flavonoids for the treatment of thalassemic and FA patients, is discussed.
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PMID:Interplay between superoxide and nitric oxide in thalassemia and Fanconi's anemia. 1654 Apr 23

Cutaneous leg ulcers are common in sickle cell anaemia and their risk might be genetically determined. Sickle cell anaemia patients were studied to examine the relationship of leg ulcers with haemolysis and with single nucleotide polymorphisms (SNPs) in candidate genes that could affect sickle vasoocclusion. Leg ulcer patients had lower haemoglobin levels and higher levels of lactate dehydrogenase, bilirubin, aspartate transaminase and reticulocytes than did control patients with sickle cell anaemia but without leg ulcers. Age-adjusted comparisons showed that sickle cell anaemia-alpha thalassaemia was more frequent among controls than cases. These results strongly suggested that the likelihood of having leg ulcers was related to the intensity of haemolysis. 215 SNPs in more than 100 candidate genes were studied. Associations were found with SNPs in Klotho, TEK and several genes in the TGF-beta/BMP signalling pathway by genotypic association analyses. KL directly or indirectly promotes endothelial nitric oxide (NO) production and the TEK receptor tyrosine kinase is involved in angiogenesis. The TGF-beta/BMP signalling pathway modulates wound healing and angiogenesis, among its other functions. Haemolysis-driven phenotypes, such as leg ulcers, could be improved by agents that reduce sickle erythrocyte density or increase NO bioavailability.
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PMID:Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. 1668 47

Blood transfusion therapy is life-saving for patients with beta-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although alpha-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, gamma-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and gamma-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.
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PMID:Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. 1701 49

Priapism occurs in 30-45% of male patients with sickle cell disease (SCD), but the possible influence of genetic risk factors on the incidence of priapism is not well understood. We examined genetic polymorphisms in 199 unrelated, adult (>18 years), male patients with Hb SS and Hb Sbeta(0)-thalassaemia, 83 (42%) of whom reported a history of priapism. Candidate genes for association with priapism were identified based on their involvement in adhesion, coagulation, inflammation and cell signalling. Additionally, we examined genes involved in nitric oxide biology (NOS2, NOS3, SLC4A1), as well as polymorphisms in the klotho (KL) gene, which has previously been associated with priapism. Strong evidence of association was found for single nucleotide polymorphisms in transforming growth factor-beta receptor, type III (TGFBR3) (rs7526590; P = 0.00058), aquaporin (AQP1) (rs10244884; P = 0.00068), integrin alphav (ITGAV) (rs3768780; P = 0.00090), and the A1 subunit of coagulation factor XIII (F13A1) (hcv1860621; P = 0.00156). Associations with TGFBR3, AQP1, and ITGAV remained significant after adjusting for multiple testing, using the Benjamini-Hochberg procedure. Our data suggest that genes involved in the TGFbeta pathway, coagulation, cell adhesion and cell hydration pathways may be important in risk for priapism.
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PMID:Genetic polymorphisms associated with priapism in sickle cell disease. 1740 68


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