Imbalance of erythropoiesis and iron metabolism in patients with thalassemia.

Aim: This study aimed to evaluate the imbalance of erythropoiesis and iron metabolism in patients with thalassemia. Methods: 192 patients with non-transfusion-dependent thalassemia (NTDT), 94 patients with transfusion-dependent thalassemia (TDT) and 101 healthy controls were recruited between June 2013 and December 2016 in the Hematology Department, the First Affiliated Hospital of Guangxi Medical University. The groups were compared in terms of levels of erythropoiesis biomarkers [growth differentiation factor 15 (GDF15), erythropoietin (EPO) and soluble transferrin receptor (sTfR)] and of iron overload biomarkers [serum ferritin (SF), liver iron concentration (LIC) and cardiac T2*] and hepcidin. Results: The levels of GDF15, EPO, sTfR, LIC and SF were significantly higher in patients with thalassemia. The levels of GDF15 and EPO were significantly higher in patients with TDT compared to NTDT. Those with iron overload had higher EPO, GDF15, SF and sTfR levels compared with non-iron overload patients. Hepcidin levels and ratios of hepcidin to erythropoietic activity and to iron biomarker levels were lower in patients with ß-thalassemia intermedia or hemoglobin (Hb) E/ß-thalassemia than in patients with HbH disease. The hepcidin levels were correlated negatively with the levels of EPO, GDF15 and sTfR in patients with NTDT and TDT, but correlated positively with SF and Hb levels only in patients with TDT. Conclusions: Patients with thalassemia showed iron overload, reduced hepcidin levels, and a greater extent of ineffective erythropoiesis. The hepcidin levels were more strongly related to ineffective erythropoiesis compared with iron overload. The imbalance between erythropoiesis and iron metabolism differed across different thalassemia types.

Very low doses of direct intravenous iron in each session as maintenance therapy in hemodialysis patients.

BACKGROUND: Intravenous (IV) iron supplementation is widely used in hemodialysis (HD) patients to treat their periodic losses. However, the ideal dose and frequency is unknown. The goal of the study is to see if a 20 mg dose of iron IV at the end of each session of HD as iron maintenance is better than the iron prior therapy. We analyze the erythropoiesis activity (EA) and functional iron (FI) after four weeks of treatment. METHODS: In 36 patients, we measure reticulocyte count and content of hemoglobin reticulocyte (CHr) as EA and FI markers, respectively, before and after the treatment. Before the study, 23 patients received another different therapy with IV iron as maintenance therapy. RESULTS: Reticulocyte count: 49.7 ± 23.8 × 10(3) before and 47.2 ± 17.2 × 10(3) after the treatment (p= 0.51). The CHr: 34.8 ± 3.7 pg and 34.4 ± 3.5 pg, respectively, (p= 0.35), showing an excellent correlation with the other FI markers (serum iron r = 0.6; p = 0.001; saturation transferrin r = 0.49; p = 0.004); that is not shown with the serum ferritin (r = 0.23; p = 0.192) or the hepcidin levels (r = 0.22; p = 0.251). There was not a correlation between the C-Reactive Protein, reticulocyte count, and CHr. The 13 patients who did not receive the iron prior to the study showed high FI levels, but not an increased of the serum ferritin or the serum hepcidin levels. CONCLUSIONS: The administration of a small quantity of iron at the end of every HD session keeps the EA and the FI levels and allows reducing the iron overload administered and/or decreasing the iron stores markers in some patients.

Pathogenetic Evaluation of Dysfunction in the Erythron System of Experimental Animals during Modeling of Iron Deficiency Anemia in the Gestation Period.

We studied the dynamics of erythropoiesis in CBA mice during gestation against the background of treatment with iron-binding drug. The mechanisms of suppression of the bone marrow erythroid stem were evaluated. Administration of deferoxamine in a dose of 1 g/kg induced hypoplasia of the erythroid hemopoietic lineage. Suppression of bone marrow erythropoiesis manifested in a decrease of hemoglobin concentration and counts of reticulocytes, erythrocytes, and erythrokaryocytes. These changes were accompanied by a decrease in functional activity of erythropoietic precursors and secretion of erythropoietically active humoral factors by bone marrow myelokaryocytes. These data indicate that deferoxamine can be used for modeling of iron defi ciency anemia in pregnancy.

Mechanisms of Erythropoietin-Stimulating Action of Anti-Erythropoietin Release-Active Antibodies in Complex Treatment of Experimental Anemia during Gestation.

We studied the mechanisms of erythropoiesis stimulation and effectiveness of Poetam, a preparation containing release-active anti-erythropoietin antibodies as a supplement treatment for experimental iron deficiency anemia during gestation. The results confirmed potency of combined therapy to stimulate erythropoiesis, which was more efficacious in comparison with monotherapy as assessed by the count of erythrokaryocytes and erythroid progenitors in the hematopoietic tissue as well as by the content of erythrocytes and hemoglobin in the peripheral blood. Activation of erythropoiesis is related to the modulatory effect of Poetam on proliferative activity and differentiation of erythroid precursors, which in most aspects results from stimulatory action of Poetam on secretion of the hematopoietically active factors by adherent elements of the hematopoietic microenvironment.

Role of PI3K, MAPK/ERK 1/2, and p38 in Production of Erythropoietic Activity by Bone Marrow Cells after Blood Loss.

The leading role in the regulation of erythropoietic activity of adherent bone marrow cells under conditions of post-hemorrhagic anemia is played by classical MAP kinase pathway (ERK pathway). Erythropoietin is not the decisive factor in the formation of erythropoietic activity of adherent cells. PI3K, MAPK/ERK 1/2, and p38-signaling proteins are not the main regulators of local production of erythropoietin after 30% loss of circulating blood volume.

Role of PI3K, ERK, and p38 Signaling Pathways in the Production of Humoral Erythropoiesis Regulators under Normal Conditions.

PI3- and MAP-kinase signaling pathways duplicate and interchange each other in production of agents that determine total erythropoietic activity under conditions of balanced erythropoiesis. The alternative p38-dependent MAP-kinase pathway is the major regulator of erythropoietic activity of adherent bone marrow cells. Blockade of PI3K and p38 signaling pathways stimulated production of erythropoietin by cells that do not produce it constitutively.

Placental ferroportin protein abundance is associated with neonatal erythropoietic activity and iron status in newborns at high risk for iron deficiency and anemia.

BACKGROUND: Murine data suggest that the placenta downregulates ferroportin (FPN) when iron is limited to prioritize iron for its own needs. Human data on the impact of maternal and neonatal iron status on placental FPN expression are conflicting. OBJECTIVES: This study aimed to identify determinants of placental FPN protein abundance and to assess the utility of the placental iron deficiency index (PIDI) as a measure of maternal/fetal iron status in newborns at high risk for anemia. METHODS: Placental FPN protein abundance was measured by western blots in placentae collected from 133 neonates born to adolescents (17.4 ± 1.1 y) carrying singletons (delivery gestational age [GA]: 39.9 ± 1.3 wk) and from 130 neonates born to 65 females (30.4 ± 5.2 y) carrying multiples (delivery GA: 35.0 ± 2.8 wk). Placental FPN and the PIDI (FPN:transferrin receptor 1) were evaluated in relation to neonatal and maternal iron-related markers (hemoglobin [Hb], serum ferritin [SF], soluble transferrin receptor [sTfR], total body iron [TBI], hepcidin, erythropoietin [EPO], erythroferrone). RESULTS: FPN protein was detected in all placentae delivered between 25 and 42 wk GA. Placental FPN protein abundance was associated with neonatal iron and erythropoietic markers (EPO: ß: 0.10; 95% confidence interval [CI]: 0.06, 0.35; sTfR: ß: 0.20; 95% CI: 0.03, 0.18; hepcidin: ß: -0.06; 95% CI: -0.13, -0.0003; all P < 0.05). Maternal sTfR was only indirectly associated with placental FPN, with neonatal sTfR as the mediator (ß-indirect: 0.06; 95% CI; 0.03, 0.11; P = 0.003). The PIDI was associated with neonatal Hb (ß: -0.02; 95% CI: -0.03, -0.003), EPO (ß: 0.07; 95% CI: 0.01, 0.14), and sTfR (ß: 0.13; 95% CI: 0.004, 0.3) and with maternal SF (ß: 0.08, 95% CI: 0.02, 0.14), TBI (ß: 0.02; 95% CI: 0.009, 0.04), EPO (ß: -0.10; 95% CI: -0.19, -0.01), sTfR (ß: -0.16: 95% CI: -0.27, -0.06), and hepcidin (ß: 0.05; 95% CI: 0.002, 0.11) at delivery (all P < 0.05). CONCLUSIONS: Placental FPN abundance was positively associated with neonatal indicators of increased erythropoietic activity and poor iron status. The PIDI was associated with maternal and neonatal iron-related markers but in opposite directions. More data are needed from a lower-risk normative group of females to assess the generalizability of findings. These trials were registered at clinicaltrials.gov as NCT01019902 and NCT01582802.

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits.

BACKGROUND AND AIMS: Erythropoiesis is closely related to iron metabolism in a balanced homeostasis. Analyses of diverse erythroid and iron metabolism disorders have shown that disrupted erythropoiesis negatively affects iron homeostasis and vice versa. The aim of this study was to characterize the relationship between erythropoietic activity and iron homeostasis in pediatric patients with erythrocyte membrane defects and thalassemia traits. METHODS: Selected markers of erythropoietic activity (erythropoietin, soluble transferrin receptor - sTfR and growth differentiation factor 15) and iron status parameters (serum iron, ferritin and hepcidin) were evaluated in pediatric patients with erythrocyte membrane defects and thalassemia traits. RESULTS: The patients with erythrocyte membrane defects and thalassemia traits had altered iron homeostasis due to disturbed erythropoiesis. In comparison with healthy controls, they had a normal to low hepcidin/ferritin ratio and concomitantly elevated sTfR. CONCLUSION: The findings suggest that pediatric patients with erythrocyte membrane defects and thalassemia traits are more susceptible to iron overload than the general population and that the (hepcidin/ferritin)/sTfR ratio can be used to monitor any worsening of the disease.

Subpopulações dos reticulócitos e fração de reticulócitos imaturos como indicadores de aumento da eritropoese em doentes com anemia por deficiência de ferro / Reticulocyte subpopulations and immature reticulocyte fractions as indicators of increased erythropoiesi in patients with iron deficiency anaemia

O objetivo deste trabalho é o de estudar as subpopulações dos reticulócitos e a fração de reticulócitos imaturos (IFR) enquanto indicadores de atividade eritropoética em pacientes com anemia por deficiência de ferro e determinar o seu grau de correlação com os marcadores tradicionais de deficiência de ferro. Estudamos um total de 96 indivíduos, com idades compreendidas entre os 20 e os 86 anos, divididos em dois grupos: indivíduos controle (n=30) e indivíduos com anemia por deficiência de ferro (n=66). A todos eles foi efetuado hemograma completo, incluindo contagem de reticulócitos e os seus índices de maturação, ferro, transferrina, ferritina e capacidade total de fixação do ferro. Os indivíduos com anemia por deficiência de ferro mostraram um aumento da proporção de IFR quando comparados com o grupo controle (15.02 ± 9.70 por cento vs 6.43 ± 3.98 por cento, p<0.01, respectivamente). Em relação às subpopulações dos reticulócitos, no grupo de pacientes encontramos um aumento na proporção de reticulócitos com valores médios de fluorescência (12.69 ± 6.69 por cento vs 5.88 ± 3.59 por cento, p<0.01) e na proporção de reticulócitos com alta fluorescência (1.45 [0.38-3.10] vs 0.40 [0.00-0.90], p<0.05) e diminuição na proporção de reticulócitos com baixa fluorescência (84.83 ± 9.65 por cento vs 93.57 ± 3.98 por cento, p<0.01). Foi encontrada correlação, positiva ou negativa, entre os parâmetros de maturação dos reticulócitos entre si, e destes com o RDW (red cell distribution width). Não foi encontrada correlação com os outros indicadores laboratoriais de deficiência de ferro. Em conclusão, a anemia por deficiência de ferro está associada com aumento da proporção de IFR, refletindo aumento da atividade eritropoética destes pacientes.

The aim of this work is to investigate reticulocyte subpopulations and immature reticulocyte fractions as indicators of bone marrow erythropoietic activity in patients with iron-deficiency anemia and their correlations with traditional hematological and biochemical markers of iron deficiency. A total of 96 individuals, aged 20 to 86 years old, were included in this study. These individuals were divided into two groups: healthy controls (n=30) and iron-deficiency anemia (n=66). Complete blood counts including reticulocytes and their subpopulations, iron, ferritin and transferrin and total binding capacity were determined in all individuals. Patients with iron-deficiency anemia had an increased proportion of immature reticulocyte fractions when compared with controls (15.02 ± 9.70 percent vs. 6.43 ± 3.98 percent, p<0.01, respectively). Comparing patients with healthy controls, the investigation of the subpopulations revealed higher medium-fluorescent reticulocyte (12.69 ± 6.69 percent vs. 5.88 ± 3.59 percent, respectively p<0.01) and high-fluorescent reticulocyte (1.45 [0.38-3.10] vs. 0.40 [0.00-0.90], p<0.05) regions and a smaller low-fluorescent reticulocyte region (84.83 ± 9.65 percent vs. 93.57 ±3.98 percent, p<0.01). Positive or negative correlations were found between reticulocyte subpopulations and red cell distribution width. No correlation was found with the other iron deficiency markers. In conclusion, iron deficiency anemia is associated with an increased proportion of immature reticulocyte fractions, reflecting an increase in erythropoietic activity in these patientss.