Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states

Plasma Concentration of Platelet-Derived Microparticles Is Related to Painful Vaso-Occlusive Phenotype Severity in Sickle Cell Anemia

International audienc

Fetal hemoglobin and hydroxycarbamide modulate both plasma concentration and cellular origin of circulating microparticles in sickle cell anemia children

International audienceMicroparticles are cell membrane-derived microvesicles released during cell apoptosis and activation processes. They have been described as bio-markers in various vascular diseases, including sickle cell anemia, and associated with an increased risk of thrombosis. We investigated the effects of fetal hemoglobin level, a factor known to modulate the clinical expression of sickle cell anemia, and that of hydroxycarbamide treatment which reduces the frequency of vaso-occlusive crises, the canonical clinical manifestation of the disease, on both the plasma concentration and the cellular origin of circulating microparticles. Flow cytometry was used to characterize microparticles in 62 sickle cell anemia children at steady state aged 2 months-16 years; 13 of them were treated with hydroxycarbamide. In untreated children, we observed negative correlations between fetal hemoglobin levels and the absolute plasma concentration of microparticles as well as that of microparticles specifically derived from platelets, erythrocytes, and monocytes. Compared to untreated children, those treated with hydroxyurea showed lower concentrations of total microparticles as a consequence of decreased microparticles shed by platelets and erythrocytes. In conclusion, in our sickle cell patients, neonatal decline of fetal hemoglobin coincided with an increase in circulating microparticles derived from erythrocytes, platelets, and monocytes. Hydroxyurea treatment was associated with a decrease in microparticles derived from erythrocytes and platelets

Comparison of MPs concentration between control group and SCA patients groups.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g002" target="_blank">Figure 2A</a>: Total MPs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g002" target="_blank">Figure 2B</a>: Platelet-derived MPs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g002" target="_blank">Figure 2C</a>: Erythrocyte-derived MPs.</p

Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation

International audienceBackgroundRecent evidence suggests that autonomic nervous system activity could be involved in thepathophysiology of sickle cell disease, but it is unclear whether differences in autonomic nervoussystem activity are detectable during steady state in patients with mild and severe disease.The aim of the present study was to compare the autonomic nervous system activity, bloodrheology, and inflammation in patients with sickle cell anemia according to the frequency ofacute pain crisis.Design and MethodsTwenty-four healthy volunteers, 20 patients with sickle cell anemia with milder disease, and15 patients with sickle cell anemia with more severe disease were recruited. Milder disease wasdefined as having no pain crisis within the previous year. More severe disease was defined ashaving had within the previous year three or more pain crises which were documented by aphysician and required treatment with narcotics. The autonomic nervous system activity wasdetermined by spectral analysis of nocturnal heart rate variability. Blood viscosity determinationand measurements of several inflammatory markers (interleukin-6, soluble vascular celladhesion molecule-1, soluble CD40 ligand and sL-selectin) were made on blood samples collectedin steady-state conditions.ResultsResults showed that: 1) patients who had suffered more frequent pain crises had lowerparasympathetic activity and greater sympatho-vagal imbalance than both controls andpatients with milder disease. However, when adjusted for age, no significant difference wasdetected between the two sickle cell anemia patient groups; 2) patients who had suffered morefrequent pain crises had higher blood viscosity than patients with milder disease, and this wasnot dependent on age.ConclusionsResults from the present study indicate that both the autonomic nervous system activity andblood viscosity are impaired in patients with sickle cell anemia exhibiting high frequency ofpain crisis in comparison with those who did not experience a crisis within the previous year

Hematological characteristics of the control group and the two SCA groups.

<p>All values are expressed as median and ranges. RBC: red blood cells; WBC: white blood cells; NA: not available. * different from controls (p< 0.05)</p

Representative flow cytometry analysis for quantifying microparticles originated from red blood cells and platelets.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g001" target="_blank">Figure 1A</a>: Acquisition gate set up using the fluorescent microbeads size of the megamix kit according to the manufacturer instructions. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g001" target="_blank">Figure 1B</a>: negative control using isotypic control-PE and annexin V-FITC in EDTA buffer. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g001" target="_blank">Figure 1C</a>: double fluorescence plots demonstrating MPs originated from RBCs. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087243#pone-0087243-g001" target="_blank">Figure 1D</a>. double fluorescence plots demonstrating MPs originated from platelets.</p