Premature Atherosclerosis in Non-Transfusion-Dependent β-Thalassemia Intermedia

Hahalis, George; Καλογερόπουλος, Ανδρέας; Terzis, George; Tselepis, Alexandros D.; Kourakli, Alexandra; Mylona, Panagiota; Grapsas, Nikos; Alexopoulos, Dimitrios

doi:10.1159/000327997

Cited by 20 publications

(21 citation statements)

References 30 publications

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“…Free radicals act directly on the endothelial cells and have a close interaction with lipid peroxidation, causing a modification of lowdensity lipoprotein and facilitating its deposition, with the consequent formation of atherosclerotic plaques (Aessopos et al 2009). Thus, iron-mediated endothelial dysfunction and a secondary atherosclerotic process may explain arterial disease in TI patients and echo recent studies supporting the idea that TI patients show a pro-atherogenic biochemical phenotype (Hahalis et al 2011;Lai et al 2011). Moreover, iron overload may aggravate ineffective erythropoiesis and the secondary release into the circulation of damaged red blood cells (RBC) with thrombogenic potential, thus putting patients at risk of venous thrombosis (Borenstain-Ben Yashar et al 1993;Gardenghi et al 2010).…”

Section: Iron Overload and Target Organ Toxicitymentioning

confidence: 79%

-Thalassemia Intermedia: A Clinical Perspective

Musallam

Taher²,

Rachmilewitz

2012

Cold Spring Harbor Perspectives in Medicine

116

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Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with b-thalassemia intermedia has substantially increased over the past decade. Earlier studies observed that patients with b-thalassemia intermedia experience a clinical-complications profile that is different from that in patients with b-thalassemia major. In this article, a variety of clinical morbidities are explored, and their associations with the underlying disease pathophysiology and risk factors are examined. These involve several organs and organ systems including the vasculature, heart, liver, endocrine glands, bone, and the extramedullary hematopoietic system. The effects of some therapeutic interventions on the development of clinical complications are also discussed.

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Section: Iron Overload and Target Organ Toxicitymentioning

confidence: 79%

-Thalassemia Intermedia: A Clinical Perspective

Musallam

Taher²,

Rachmilewitz

2012

Cold Spring Harbor Perspectives in Medicine

116

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Section: Discussionmentioning

confidence: 99%

“…11 The composition and pathogenic roles of MP have been extensively studied in various diseases, such as ischemia, diabetes and atherosclerosis, revealing complex pathogenic roles in modulating nitric oxide and prostacyclin production, stimulating cytokine release, inducing tissue factor expression, as well as monocyte chemotaxis and adherence to the endothelium. [12][13][14][15][16][17][18] Recent studies on the mechanisms of redox regulation of RBC membrane stability 19,20 indicate that oxidative stress induces a phosphorylative response that specifically involves two tyrosine residues located in the cytoplasmic domain of band 3. 20 Band 3 is the most abundant RBC membrane protein, and represents one of the major components of the junctional complexes that connect the lipid bilayer to the cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

“…10,12,36,39,40 MP originating from RBC membranes have also been considered a major cause of premature atherosclerosis described in TI patients. 13 The mechanisms responsible for the generation of MP appear very complex in different cell types 32 and very little is known about thalassemic RBC.This report describes the first study on the mechanism of generation of MP in thalassemia and the first comprehensive analysis of the composition of MP released from TI-RBC. We found that in TI patients the number of circulating MP was correlated with the capability of TI-RBC to release MP in vitro.…”

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confidence: 96%

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Thalassemic erythrocytes release microparticles loaded with hemichromes by redox activation of p72Syk kinase

Ferru

Pantaleo

Carta³

et al. 2013

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o ndifferent genetic and clinical status provided new insights into the pathogenic role of circulating MP and possible interventions to control their amount in thalassemia. MethodsUnless otherwise stated, all materials were obtained from Sigma-Aldrich, St. Louis, MO, USA. Additional information about the methods are provided in the Online Supplementary Data. Treatment of red blood cellsVenous blood was drawn from 12 healthy individuals, eight non-splenectomized TI patients and six splenectomized TI patients. All subjects provided written, informed consent before entering the study. The study was approved by the local Ethics Committee and conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.Clinical analyses were performed by routine laboratory tests at the Policlinico Hospital (Milan, Italy). Blood anti-coagulated with heparin was stored in citrate-phosphate-dextrose with adenine (CPDA-1) prior to its use. RBC were washed three times with phosphate-buffered saline (PBS: 137mM NaCl, 2.7mM KCl, 8.1mM K 2 HPO 4 , 1.5mM KH 2 PO 4 , pH 7.4) containing glucose 5 mM to obtain packed RBC.To stimulate HMC formation, RBC from healthy donors were suspended at a hematocrit of 30% and incubated with different concentrations (0, 0.25, 0.5, 1, 1.5, 2 mM) of phenylhydrazine at 37 °C for 4 h. To test the antioxidant effect in MP release we incubated 200 μM of 2-mercaptoethanol in the presence of 1 mM phenylhydrazine. When necessary, RBC were pretreated with Syk kinase inhibitors (10 μM Syk inhibitors II and 10 μM Syk inhibitors IV, Calbiochem, Darmstadt, Germany), for 1 h at 37 °C in the dark. Each reaction was terminated by three washes with PBS-glucose. For all protocols described, untreated controls were processed identically except that the stimulant/inducer was omitted from the incubation. Red blood cell membrane preparationStandard hypotonic membranes were prepared, as previously described, 20 and stored frozen at -80°C until use. Membrane protein content was quantified using the DC Protein assay (Biorad, Hercules, CA, USA). Analysis of microparticlesThe MP in plasma were analyzed by flow cytometry using a modification of a previously described method:22 25 μL of plasma diluted 1:1 with PBS-glucose 5mM were analyzed using anti-CD41 (BD, Franklin Lakes, NJ, USA) and anti-glycophorin-A (Dako, Denmark), both diluted 1:10. Assay of hemichromesHMC were quantified by measuring heme absorbance (Abs) using the following equation:HMC= -133xAbs577 -114xAbs630 + 233xAbs560, and expressed as nMoles/mL of solubilized membranes. 23 Microparticle isolationTo induce MP release in vitro, RBC from each volunteer and phenylhydrazine-treated RBC in PBS (30% hematocrit) were incubated as previously described. 24 Electrophoresis and immunoblottingMembrane and MP proteins were solubilized in Laemmli buffer 25 under reducing [2% (w/v) dithiothreitol] or non-reducing conditions at a volume ratio of 1:1. Sodium dodecylsulfate polyacrylamide gel electropho...

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“…Decrease in hemoglobin levels in anemia has been reported as an independent risk factor for cardiovascular disease. Severe iron overload in patients with beta-thalassemia major may actually be a risk factor for atherosclerosis [1][2][3][4]. An increase in PF3 activity in thassaemic patients due to abnormal erythrocytes leads to activation of the coagulation mechanisms.…”

Section: Introductionmentioning

confidence: 99%