Hemoglobin disorders and endothelial cell interactions

Conran, Nicola; Costa, Fernando Ferreira

doi:10.1016/j.clinbiochem.2009.06.024

Cited by 57 publications

(47 citation statements)

References 190 publications

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“…It was associated with more blood transfusions, possibly augmented by increased ineffective erythropoiesis [33], and a possible role of the spleen in the iron regulation [40]. Besides being toxic to the heart, liver and endocrine organs, chronic iron overload causes inflammation and oxidative stress to EC [41,42,43], RBCs, platelets and neutrophils [30], which could lead to more hemolysis and hypercoagulability [30]. …”

Section: Discussionmentioning

confidence: 99%

Intravascular Hemolysis, Vascular Endothelial Cell Activation and Thrombophilia in Splenectomized Patients with Hemoglobin E/β-Thalassemia Disease

Atichartakarn

Chuncharunee²,

Archararit³

et al. 2014

Acta Haematol

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The relationship between asplenia and thrombophilia in β-thalassemia disease patients is not yet completely understood. One hundred and ten adult hemoglobin (Hb) E/β-thalassemia (E/β-Thal) disease outpatients, dichotomized according to the presence or absence of the spleen, were prospectively studied for evidence of intravascular hemolysis (IVH) and vascular endothelial cell (EC) activation. Biomarkers of IVH (serum cell-free Hb), EC [soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule 1 (sVCAM-1)], platelet and EC [soluble P-selectin (sP-selectin)], inflammation [high-sensitivity C-reactive protein (hs-CRP)], and coagulation [thrombin-antithrombin complexes (TAT)] activation, as well as other selected blood tests were determined. The 61 splenectomized patients had a more severe hemolytic disease and higher levels of cell-free Hb and ferritin (p = 0.003), sE-selectin, sP-selectin, hs-CRP, and TAT (p < 0.05). However, serum levels of sVCAM-1 were not different between the two groups. The findings suggested IVH and EC activation. Together with chronic iron overload and chronic low-grade inflammation activation, the findings extend our understanding of the mechanism of thrombophilia in splenectomized E/β-Thal disease patients.

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Section: Discussionmentioning

confidence: 99%

Intravascular Hemolysis, Vascular Endothelial Cell Activation and Thrombophilia in Splenectomized Patients with Hemoglobin E/β-Thalassemia Disease

Atichartakarn

Chuncharunee²,

Archararit³

et al. 2014

Acta Haematol

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“…Enhanced Hb binding to RBC membrane fragments, yielded upon hemolysis, could result in a more potent trigger of inflammation and increased levels of potentially toxic nontransferrin-carried iron. Inflammation and non-heme iron overload are clinical features of HbE/␤-thalassemia (108,109). Thus, the novel finding of HbE as an altered nitrite reductase, coupled with the known enhanced binding of HbE to the RBC membrane in consideration of the aforementioned caveats, provides a new model to explain the severe pathophysiological consequences of HbE/␤-thalassemia.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E

Roche

Malashkevich

Balazs

et al. 2011

Journal of Biological Chemistry

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Hemoglobin (Hb) E (␤-Glu26Lys) remains an enigma in terms of its contributions to red blood cell (RBC) pathophysiological mechanisms; for example, EE individuals exhibit a mild chronic anemia, and HbE/␤-thalassemia individuals show a range of clinical manifestations, including high morbidity and death, often resulting from cardiac dysfunction.The purpose of this study was to determine and evaluate structural and functional consequences of the HbE mutation that might account for the pathophysiology. Functional studies indicate minimal allosteric consequence to both oxygen and carbon monoxide binding properties of the ferrous derivatives of HbE. In contrast, redoxsensitive reactions are clearly impacted as seen in the following: 1) the ϳ2.5 times decrease in the rate at which HbE catalyzes nitrite reduction to nitric oxide (NO) relative to HbA, and 2) the accelerated rate of reduction of aquometHbE by L-cysteine (L-Cys). Sol-gel encapsulation studies imply a shift toward a higher redox potential for both the T and R HbE structures that can explain the origin of the reduced nitrite reductase activity of deoxyHbE and the accelerated rate of reduction of aquometHbE by cysteine. Deoxy-and CO HbE crystal structures (derived from crystals grown at or near physiological pH) show loss of hydrogen bonds in the microenvironment of ␤Lys-26 and no significant tertiary conformational perturbations at the allosteric transition sites in the R and T states. Together, these data suggest a model in which the HbE mutation, as a consequence of a relative change in redox properties, decreases the overall rate of Hb-mediated production of bioactive NO.

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“…The pathophysiology of cardiovascular involvement in thalassemia appears to be multifactorial, with a central role of iron overload and a significant contribution of immunoinflammatory mechanisms [25]. It is reported that free heme and the red cell membrane elements that are producedduring hemolysis have a negative effect on nitric oxide and arginine availability and therefore thatimpaired nitric oxide bioavailability may represent the central feature of endothelial dysfunction, and pervasively contributes to the overlapping mechanisms of vasculopathies observed in β-TI [6,26]. In addition, high HDL-associated phospholipase A 2 levels, attributed to increased enzyme secretion from monocytes/macrophages and to the predominance of small dense LDL particles in plasma, have been observed in β-TI [27].…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Proatherogenic Biochemical Phenotype in Beta Thalassemia Minor and Intermedia

Lai

Vacquer²,

Carta³

et al. 2011

Acta Haematol

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The purpose of this study was to focus on pathophysiological mechanisms linking β-thalassemia intermedia (β-TI) and minor (β-TMI) with cardiovascular risk. Iron status, prooxidant-antioxidant balance and lipid profiles in serum, and lipid content in peripheral blood mononuclear cells (PBMCs) were evaluated in 20 β-TMI subjects, 22 β-TI patients and in 30 nonthalassemic blood donors. The mRNA levels of some genes involved in the regulation of iron and cholesterol metabolism were also determined. In β-TI and in β-TMI, serum iron, prooxidant-antioxidant ratio, transferrin saturation and erythropoietin levels were higher, while transferrin and hepcidin were lower compared to controls. Hepcidin and interleukin-1α mRNA levels were found to be reduced in β-TI- and β-TMI-PBMCs, while those of tumor necrosis factor alpha were increased. A reduction in high-density lipoprotein cholesterol in serum and an accumulation of neutral lipids coupled with increased mRNA levels of acetyl-coenzyme A:cholesterol acyltransferase and decreased neutral cholesterol ester hydrolase in PBMCs were also observed in β-TI and β-TMI compared to controls. Taken together, these findings provide experimental support for the idea that not only β-TI patients but also β-TMI have a proatherogenic biochemical phenotype which may contribute to increase their cardiovascular disease risk.

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Hemoglobin disorders and endothelial cell interactions

Cited by 57 publications

References 190 publications

Intravascular Hemolysis, Vascular Endothelial Cell Activation and Thrombophilia in Splenectomized Patients with Hemoglobin E/β-Thalassemia Disease

Intravascular Hemolysis, Vascular Endothelial Cell Activation and Thrombophilia in Splenectomized Patients with Hemoglobin E/β-Thalassemia Disease

Structural and Functional Studies Indicating Altered Redox Properties of Hemoglobin E

Evidence for a Proatherogenic Biochemical Phenotype in Beta Thalassemia Minor and Intermedia

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