Translate this page into:
Erythroid activity modulates iron regulation in pathological erythropoiesis: A cross-sectional case-control study
For correspondence: Prof Eunice Sindhuvi, Department of Haematology, Christian Medical College, Vellore 632 517, Tamil Nadu, India e-mail: eunice@cmcvellore.ac.in
-
Received: ,
Accepted: ,
Abstract
Background & objectives
Genetic defects and altered synthesis of RBCs characterise β-thalassemia and polycythaemia vera (PV), respectively. In both diseases, stress erythropoiesis leads to accelerated erythroid expansion, although iron regulation has not been well studied. Here, we analysed iron parameters and iron regulatory gene expression in individuals affected with β-thalassemia and PV.
Methods
Biochemical iron parameters and gene expression analysis were carried out in 20 individuals with transfusion-dependent thalassemia (TDT), 20 individuals with non-transfusion-dependent thalassemia (NTDT), 25 individuals affected with PV, and 50 healthy controls.
Results
Increased soluble transferring receptor (sTfR) levels in both diseases are evidence of increased erythropoietic activity. Compared to the β-thalassemia intermedia group, affected individuals with β-thalassemia major showed significantly elevated serum ferritin levels, whereas subnormal ferritin levels were observed in the PV group. In TDT, hepcidin levels were relatively low compared to ferritin levels, whereas in PV, the increase in erythropoiesis resulted in reduced hepcidin production. In both thalassemia cohorts, diminished TFRC expression in reticulocytes suggested impaired iron uptake, whereas in PV, increased TFRC and FPN1B expression implied increased iron acquisition in reticulocytes despite reduced iron reserves.
Interpretation & conclusions
Thus, increased erythropoietic activity has a crucial role in determining the quantity of iron transported to the marrow. This is achieved through the modulation of iron regulation within erythroid cells, ultimately affecting systemic iron levels.
Keywords
Beta thalassemia
iron regulators
polycythaemia vera
Increased erythropoiesis is commonly observed in pathological conditions such as β-thalassemia and polycythaemia vera (PV). β-thalassemia is characterised by ineffective erythropoiesis, enlargement of the spleen, expansion of extramedullary haematopoietic sites, premature death of erythroid precursors, and shortened survival of mature erythrocytes1. It manifests in three forms based on severity and genotype: β-thalassemia trait, thalassemia intermedia, and thalassemia major. β-globin mutation results in the accumulation of excess α-globin chains, leading to haemolysis1. Often, the chronic state of anaemia is treated with RBC transfusions, which in turn result in iron overload. Several studies have reported the crosstalk between iron and erythropoiesis in β-thalassemia, with a focus on hepcidin as a therapeutic target for β-thalassemia2. Patients with β-thalassemia major have higher hepcidin levels than β-thalassemia intermedia patients3. Further investigations are warranted to understand how iron regulation and erythroid activity influence ineffective erythropoiesis.
PV is a chronic myeloproliferative disorder marked by unlimited proliferation of erythrocytes, megakaryocytes, and granulocytes. WHO defined PV as Hb >18.5g/dl for males and >16.5g/dl for females. It was also defined as the occurrence of Janus kinase 2 (JAK2) mutation, mostly related to the V617F allele4. Clinical trials such as the PV study group and European Collaboration on Low-dose Aspirin in PV (ECLAP) trial have recommended hydroxyurea as the drug of choice for PV treatment5. An in vitro erythroid expansion system using peripheral blood mononuclear cells from patients with PV demonstrated hyperproliferation of erythroid precursors and accelerated maturation between days 9 and 14, accompanied by aberrant expression of EPO receptors6. The JAK2 mutation is evident in more than 90 per cent of PV patients, which results in increased EPO signalling. Hepcidin and GDF15 levels were measured; higher GDF15 levels were observed in individuals with JAK2V617F mutant. No significant changes in hepcidin levels were observed despite high erythroid activity7. Therefore, it is crucial to investigate the molecular mechanisms by which iron regulates erythropoiesis in PV.
Both β-thalassemia and PV exhibit dysregulated iron metabolism. However, studies investigating iron regulation and how stress affects erythropoietic activity and manages iron supply under these conditions are lacking. Here, we investigated alterations in iron regulation in response to stress erythropoiesis and compared them in β-thalassemia and PV.
Materials & Methods
This cross-sectional study was conducted by the department of Haematology, Christian Medical College (CMC), Vellore, Tamil Nadu, India, after obtaining the ethical approval from the Institutional Review Board.
Study population
Individuals who visited the department of Haematology, CMC, with β-thalassemia and PV between 2019 and 2022 were included in this study. The β-thalassemia cohort consisted of affected individuals with transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT)8,9.TDT included β-thalassemia major affected individuals aged ≤10 yr with ≤50 transfusions; NTDT included with HbE-β thalassemia affected individuals aged ≤10 yr who were recruited in the study. Nine study participants received occasional transfusions, while the others did not have a transfusion history. Newly diagnosed affected individuals with PV were recruited based on World Health Organization criteria: Hb >16.5 g/dl in men, >16.0 g/dl in women, or Hct >49 per cent in men, >48 per cent in women, and with the presence of JAK2V617F mutation in exon 144. This study did not include individuals who had undergone hydroxyurea treatment. Male voluntary blood donors (n=50) with normal haematological parameters and adequate iron stores were included in the control group. The sample size was determined according to the Gpower (version 3.1) power analysis, with an effect size of 0.5, alpha error of 0.05, and power of 0.80.
Reticulocyte isolation
Reticulocytes were isolated from peripheral blood following the protocol described by Bresnick et al10. Initially, the plasma and buffy coat were removed by centrifugation. The resulting reticulocyte-rich fraction was resuspended in phosphate-buffered saline (PBS) and layered onto a cellulose column (Sigma) composed of two parts cellulose and one-part microcrystalline cellulose. The column was then gently centrifuged at 1500 rpm for 5 min to enrich reticulocytes. The leuco-depleted elute was washed with PBS and stored in TRIzol at -80°C until RNA extraction.
Haematological and biochemical assessment
Peripheral blood samples were collected from study participants, and serum was stored at -80°C for further analysis. Complete blood counts (CBC) were analysed using an automated haematology analyser (Sysmex KX21, Kobe, Japan). Serum ferritin and soluble transferrin receptor (sTfR) levels were analysed by chemiluminescence immunoassay using the Advia Centaur Siemens XPI (Immulite 2000 siemens Xpi, Germany). Interleukin-6 (IL-6) levels were analysed using a chemiluminescent immunoassay. To assess the relative hepcidin levels in relation to body iron stores, the hepcidin-ferritin ratio was calculated by dividing the serum hepcidin level (ng/ml) by the corresponding serum ferritin level (ng/ml). The ratio provides a normalised index of hepcidin relative to iron status.
Measurement of Serum Hepcidin-25
Serum hepcidin-25 levels were quantified using an Enzyme Immunoassay following the manufacturer’s protocol (DRG, GmbH, Germany). The assay is a solid-phase competitive enzyme-linked immunosorbent assay (ELISA). The colour intensity developed during the assay was inversely related to the hepcidin level in the sample. Each sample was analysed in duplicate, and quality controls with both high and low concentrations were included in every run. The results were determined using a 4-parameter logistic (4PL) curve fit, and measurements were taken using a Spectramax M4 plate reader (CA, USA).
Screening of Jak2 mutation in PV
DNA was extracted from whole blood samples using a GentraPuregene Blood DNA Kit (Qiagen, Hilden, Germany). DNA quality and concentration were assessed using a Nanodrop 2000 spectrophotometer (Thermo Scientific, USA). Detection of the JAK2V617F mutation was performed using an allele-specific polymerase chain reaction (PCR) assay with a sensitivity of 1 per cent, following protocols outlined in previous studies11.
Real-time PCR
Total RNA was isolated from reticulocytes using TRIzol reagent (Invitrogen, CA, USA) following the standard protocol and further stored at -80°C. cDNA synthesis and genomic DNA elimination were performed using the RT2 First Strand Kit (QIAGEN, Hilden, Germany). Real-time PCR was conducted on a 7500 QPCR System (Applied Biosystems, USA) with SYBR green detection (TaKaRa, Japan). To control for plate-to-plate variation, gene expression was normalised to that of β-actin using the 2ΔΔCt method12.
Statistical analysis
Statistical analysis was performed using SPSS software (version 21, USA). Prevalence data were analysed using frequencies. To ensure accuracy, appropriate statistical tests, such as the t-test for continuous variables, analysis of variance (ANOVA) for group comparison, and Mann-Whitney and Kruskal-Wallis tests for non-parametric data, were utilised. We assessed significant differences in hepcidin, ferritin, IL-6, and sTfR levels, as well as the hepcidin-to-ferritin ratio, among the groups using the Kruskal-Wallis test. For post-hoc analysis, we applied Bonferroni correction to adjust for multiple comparisons. Pearson’s or Spearman’s correlation coefficient was used to assess the relationship between variables. Statistical significance was set at P< 0.05.
Results
In this prospective study, we included 20 individuals diagnosed with TDT, all of whom had received fewer than 50 transfusions, and 20 with NTDT. Among them, 22.5 per cent were female (N=9) and 77.5 per cent were male (N=31). The mean age (minimum-maximum) of the study participants TDT, NTDT, and control groups was 4 (1-10), 8 (4-17), and 29 (19-52) yr, respectively. TDT and NTDT affected individuals had mean (±standard deviation) Hb levels of 9.4±8 g/dl and 8.6±2.8 g/dl, respectively. TDT patients who had received >25 transfusions exhibited higher ferritin levels, with a median concentration of 2033 (minimum-maximum: 602-3284) ng/ml (P=0.032, TDT >25 vs. TDT<25 transfusions).
Twenty-five affected individuals with PV with the JAK2V617F mutation and without hydroxyurea treatment were investigated. Patients with PV who underwent venesections had a mean age of 53 (29-57) yr and a mean haemoglobin concentration of 15.8± 1 g/dl. Sixteen percent of affected individuals with PV (N=4) had iron deficiency (Ferritin<15ng/ml). The demographic and laboratory parameters have been tabulated in table.
| Parameters |
TDT N=20 |
NTDT N=20 | PV N=25 | Control N=50 | P value (vs Control) |
|---|---|---|---|---|---|
| Age (yr) | 4 (1-10) | 8 (4-17) | 53 (29-57) | 29 (19-52) | — |
| Hb (g/dl) | 9.4±1.8* | 8.6±2.8* | 15.8±1* | 14.7±1.1* | — |
| HCT (%) | 28.3±5.1 | 26.7±8.6 | 50.1±4.3 | 44.6±3.4 | — |
| MCV (fl) | 80±8 | 66.8±9 | 79±8.6 | 89±6.4 | — |
| Ferritin (ng/ml) |
1800 (105-3150) |
612 (130-3284) |
36.1 (9.5-405) |
79.2 (46.7-574) |
TDT: 0.0001 NTDT: 0.0001 PV: 0.024 |
| Hepcidin (ng/ml) |
76.6 (42.9-80) |
42.3 (4.6-53.2) |
8.5 (1-35) |
14.8 (4.6-36.3) |
TDT: 0.014 NTDT: 0.0001 PV: 0.006 |
| H:F ratio |
0.14 (0.01-0.26) |
0.04 (0.01-2.36) |
0.41 (0.02-0.51) |
0.21 (0.01-0.43) |
TDT: 0.002 NTDT: 0.0001 PV: 0.001 |
| sTfR (mg/ml) |
13 (2.78-37) |
26.8 (9.19-45.8) |
16.4 (3-59.2) |
3.2 (1.7-4.65) |
TDT: <0.001 NTDT: <0.001 PV: 0.0001 |
Values are presented as mean ± SD. Ferritin, hepcidin, H:F ratio, hepcidin:ferritin ratio and sTfR-soluble transferrin receptor are presented as median (range). *Transfused individuals with β-thalassemia and PV who underwent venesection after the Hb value. Hb, haemoglobin; HCT, haematocrit; MCV, mean corpuscular volume
Iron regulation in β thalassemia
The median serum ferritin levels were 1800 (105-3150) ng/ml in TDT (P<0.001, TDT vs. Control), 612 (130-3284) ng/ml in affected individuals with NTDT (P<0.001, NTDT vs. control), and 63.4 (46.7-574) ng/ml in controls. Serum hepcidin levels were significantly increased in TDT (median: 76.6;42.9-80 ng/ml, P=0.014, TDT vs. control) as compared to controls [median:14.8 (4.6-36.3) ng/ml]. However, the median hepcidin concentration in NTDT did not exhibit a significant alteration [median: 42.3 (4.6-53.2) ng/ml, P=0.111, NTDT vs. control]. Both TDT and NTDT affected individuals exhibited a significantly lower hepcidin to ferritin ratio than controls (P=0.002 and P=0.0001, respectively). The median IL-6 levels were 4.3 (1.5-27.5) pg/ml for TDT and 5.6 (1.5-33.2) pg/ml for NTDT. Six study participants with TDT and five with NTDT had higher IL-6 levels (>7 pg/ml). Both cohorts showed an increase in sTfR levels, with a median of 13 (2.78-37) mg/l in TDT (P<0.001, TDT vs. control) and 26.8 (9.19-45.8) mg/l in NTDT (P<0.001, NTDT vs. control) compared to the control group [median: 3.2 (1.7-4.65) mg/l]. These results indicate an increase in erythropoietic activity (Fig. 1).
- Iron parameters (A) ferritin; (B) hepicidin; (C) sTfR; and (D) hepicidin:ferritin in study participants with TDT, NTDT, and healthy controls. Ferritin, hepcidin, sTfR levels and H:F ratio was compared between TDT (n=20), NTDT (n=20), and healthy controls (n=50). The data are presented as Mean±SEM. P values are denoted as NS, not significant, P*=0.05;**=0.001;***=0.0001 and ****=0.00001.
Analysis of reticulocyte iron and erythroid regulators in β thalassemia
Iron and erythroid genes, including FPN1A, FPN1B, IRP1, IRP2, TFRC, KLF1, GATA1, and GATA2, were assessed in the reticulocytes of the TDT, NTDT, and control groups. Non-IRE FPN1B, TFRC, GATA1, and KLF1 mRNA were expressed in the reticulocytes of TDT and NTDT (Fig. 2 and Supplementary Fig. 1). The mRNA expression of TFRC was significantly reduced in the TDT (P=0.045) and NTDT (P=0.038) groups compared to that in the control group.
- Iron gene expression (A) TFRC; and (B) FPN1B in reticulocytes of study participants with TDT, NTDT, and healthy controls quantified using real-time PCR. The expression level was normalized to β-actin. FPN1B (N=14,15,15) and TFRC (N=14,15,15) (number of study participants with TDT, NTDT samples, controls, respectively) are shown.
Iron regulation in PV
Study participants with PV exhibited elevated levels of haemoglobin and haematocrit, with ferritin levels falling within the mid-to-normal range. The median levels of ferritin and hepcidin in PV were 36.1 (9.5-405) ng/ml and 8.5 (1-35) ng/ml, respectively. Serum ferritin and hepcidin levels were significantly lower in individuals with PV compared to controls (P=0.024 and P=0.006, respectively). sTfR levels were significantly increased in the PV group with a median of 16.4 (3-59.2) mg/l (P=0.001, PV vs. control), indicating an increased rate of erythropoiesis. The hepcidin to ferritin ratio was significantly increased in the PV group (P=0.001, PV vs. control). There was no indication of inflammation in affected individuals with PV, as reflected by the normal IL-6 levels with a median of 1.71(1.5-7.93) pg/ml (Fig. 3). The median sTfR index (sTfR: log ferritin) was 10.77 (1.18-35.3) in PV and control [1.76 (0.76-4.2)]. The significantly elevated sTfR index (P<0.001, PV vs. control) confirmed functional iron deficiency in PV.
- Iron and erythroid parameters in study participants with PV and healthy controls. (A) Haemoglobin (Hb), (B) haematocrit (HCT), (C) ferritin, (D) hepcidin, and (E) sTfR levels were compared between study participants with PV (n=25) and healthy controls (n=50). (F) Interleukin-6 (IL-6) levels were represented for each individual with PV (n=24). The data are presented as Mean±SEM. P values are denoted as NS, not significant. P*=0.05, **=0.001, ***=0.0001 and ****=0.00001.
Iron and erythroid gene expression in PV
In the PV, we analysed the expression of iron and erythroid genes in reticulocytes. Among the iron-metabolizing genes, TFRC, FPN1B, and IRP2 mRNA were differentially expressed in PV cells compared to the controls. In the late erythroid stage, mRNA expression of the erythroid transcriptional factor GATA1 was detected in both the PV and control groups (Supplementary Fig. 2). Notably, KLF1 mRNA was differentially expressed in PV cells but was below the detectable limit in the control group (Fig. 4).
- Iron and erythroid gene (A)TFRC; (B) FPN1B; and (C) KLF1 expression in reticulocytes of study participants with PV. Study participants with PV, and control group quantified using real-time PCR. The expression level was normalized to β-actin. TFRC (N=15,15), FPN1B (N=15,15), and KLF1 (N=15,15) (number of study participants with PV samples, controls, respectively) are shown.
Association of iron status indicators in stress erythropoiesis
In our cohort, a significant positive correlation was observed between haemoglobin and ferritin levels in study participants with TDT (r=0.572, P=0.036), reflecting ineffective erythropoiesis and iron overload resulting from chronic transfusions. Both haemoglobin and sTfR levels were correlated with IL-6 levels (Hb: r=-0.538, P=0.032; sTfR: r=0.524, P=0.037), suggesting that inflammation may be involved in suppressing erythropoietic activity. Importantly, the total number of transfusions had a significant negative association with the sTfR-ferritin index (r=-0606, P=0.048), further supporting the suppressive effect of transfusions on erythropoiesis.
In the NTDT group, patients without a transfusion history (N=11) showed a negative association between Hb and sTfR levels (r=-0.695, P=0.038), indicating a compensatory marrow response to anaemia. Study participants with NTDT who received transfusions (N=9) had a negative association between sTfR and ferritin levels (r=-0.717, P=0.030). The total number of transfusions was positively correlated with ferritin levels (r=0.819, P=0.007) and negatively correlated with sTfR levels (r=-0.810, P=0.008), consistent with iron loading and suppression of erythropoiesis due to transfusion therapy.
A similar association between sTfR and ferritin levels was also found in study participants with PV (r=-0.553, P=0.003), which was not observed in the control group (r=-0.224, P=0.114). Non-IRE FPN1B mRNA expression in reticulocytes was positively associated with serum ferritin levels in study participants with NTDT (r=0.627, P=0.039). In PV, TFRC mRNA expression was associated with sTfR levels (r=0.593, P=0.020).
Univariate regression analysis revealed that serum ferritin and sTfR levels influenced FPN1B expression in NTDT reticulocytes (P=0.044 and P=0.050, respectively). In PV, serum ferritin levels were significantly associated with TFRC expression in reticulocytes (P=0.027).
Discussion
Erythropoiesis is an intricately regulated process that originates from multipotent stem cells in the bone marrow and matures into enucleated erythrocytes. Erythropoietin triggers the JAK/STAT5 signalling pathway, subsequently resulting in the proliferation, differentiation, and maturation of erythroid progenitors. In pathologically increased erythropoiesis, alterations in red cell production can arise from direct impairment of medullary erythropoiesis, as observed in β-thalassemia and PV. β-Thalassemia occurs due to a partial or complete deficiency in beta-globin chain synthesis, resulting in ineffective erythropoiesis and iron overload13. In PV, JAK2 mutations lead to the overproduction of red blood cells.
The pathophysiology of both β-thalassemia and PV involves disrupted regulation of iron levels. In β-thalassemia, the increased demand for erythroid iron, along with frequent blood transfusions, contributes to iron overload, whereas in PV, therapeutic phlebotomies play a role in reducing the accumulation of total body iron14. To understand iron dysregulation in pathological erythropoietic conditions, we studied the iron mechanisms in β-thalassemia and PV.
In our study, study participants with TDT exhibited systemic iron overload, characterised by relatively elevated hepcidin levels compared to controls. However, the hepcidin ferritin ratio was lower than that in the controls, suggesting a disproportionately reduced hepcidin level relative to the extent of iron overload. Several studies have reported similar findings15,16. In addition, early ferrokinetic studies have demonstrated that β-thalassemia patients exhibit a 10-fold increase in plasma iron turnover, with a reduced release of RBCs and elevated oxidative stress due to excess iron17.
In our study group, individuals with TDT exhibited a direct relationship between the number of transfusions and ferritin levels. In contrast, an inverse relationship was observed between transfusions and the sTfR-ferritin index. This finding suggested that transfusion contributed to iron overload and reduced erythropoiesis.
Our study participants with NTDT who received occasional transfusions showed a negative association between ferritin and sTfR levels, suggesting that transfusion-related iron overload and reduced erythropoietic activity. The inverse relationship between sTfR and ferritin levels in study participants with NTDT, not received transfusions, suggested an active erythropoietic response that could have enhanced intestinal iron absorption.
As per our knowledge, this is the first study to analyse iron regulatory gene expression in reticulocytes of patients with β-thalassemia. We observed lower TFRC expression in reticulocytes from individuals with TDT and NTDT than in controls, indicating reduced iron acquisition by erythroid cells during the maturation stage of differentiation. The expression of KLF1, a transcription factor that promotes erythroid differentiation in the terminal maturation stage, was elevated in reticulocytes of both TDT and NTDT patients, implying ineffective erythropoiesis regulating iron requirements in the bone marrow.
PV is a myeloproliferative disorder characterised by increased erythropoiesis and concurrent iron deficiency. Limited research has shown iron deficiency in PV14. In our study, the JAK2V617F mutation was present in all the study participants with PV. These study participants had reduced hepcidin levels, suggesting that the decrease in hepcidin levels was a result of decreased circulating iron levels induced by chronic erythropoiesis. Sixteen per cent of study participants with PV exhibited iron deficiency, while others had subnormal serum ferritin levels (normal range: 15-300 ng/ml). Hepcidin-to-ferritin ratio was comparable between the PV and control groups. A recent study by Bennett et al18 reported similar observations, except for reduced ferritin levels in their study. The levels of the inflammatory marker IL-6 remained within normal limits in PV. The presence of relatively low serum ferritin levels and normal IL-6 levels in patients with PV suggests that inflammation is unlikely to be a primary factor in disrupted iron metabolism. In the PV group, sTfR levels showed a negative correlation with ferritin levels, a pattern that was not observed in the control group. This finding suggested that increased erythropoiesis resulted in lower ferritin levels. Among the iron and erythroid genes analysed in reticulocytes of PV and control, TFRC, FPN1B, IRP2, and KLF1 showed augmented expression in PV. Gene expression analysis revealed that enhanced iron acquisition and transport occurred during the final stages of erythroid maturation when iron reserves were reduced.
In comparison, β-thalassemia TDT, NTDT, and PV showed increased sTfR levels, indicating an increased rate of erythropoiesis. In TDT, higher ferritin levels were due to multiple transfusions, whereas in NTDT, increased iron absorption and intermittent transfusions increased ferritin levels. In the PV group, ferritin levels were lower than normal. Increased erythropoiesis in PV suppresses hepcidin levels, whereas in TDT, hepcidin levels were lower than ferritin levels.
In reticulocytes, TFRC, FPN1B, KLF1, and GATA1 mRNA were expressed in both the β-thalassemia cohort and PV. TFRC mRNA showed decreased expression in TDT and NTDT, indicating decreased iron uptake despite iron overload in circulation. TFRC and FPN1B mRNA expressions increased in PV, suggesting modulation of iron regulation in reticulocytes (Supplementary Fig. 3).
Based on these results, we conclude that in pathological erythropoiesis, erythropoietic activity determines the amount of iron transferred to the bone marrow by modulating iron regulation in erythroid cells and influencing systemic iron levels. Studies using β-thalassemia mouse models have shown that blood transfusions can suppress ineffective erythropoiesis and restrict iron absorption19. Ginzburg et al14 reported reduced hepcidin levels in the PV, potentially due to increased erythropoiesis and iron deficiency. However, iron trafficking in erythroid cells and its function remain unclear. Additionally, studying the relative distribution of transferrin moieties, the association of transferrin receptors (TFR1 and TFR2), and hepcidin with erythroid regulators would reveal a distinct interplay between iron metabolism and ineffective erythropoiesis. Hence, a comprehensive understanding of the potential mechanisms by which pathological erythropoiesis influences iron absorption and hepcidin and ferroportin regulation is required.
Clinically, our findings suggest that including hepcidin levels, sTfR, and sTfR-ferritin index as biomarkers, along with the conventional marker serum ferritin levels, will assess both iron demand and utilisation in pathological erythropoiesis. The observed suppression of hepcidin in both thalassemia and PV, despite differing iron status, emphasises the potential utility of hepcidin-based therapies, such as hepcidin mimetics or TMPRSS6 inhibitors, to restore iron homeostasis by reducing iron absorption and release from stores in thalassemia20,21. Conversely, cautious consideration of iron supplementation in PV patients with symptomatic functional iron deficiency may help optimise erythropoiesis and quality of life without exacerbating thrombotic risk.
Financial support & sponsorship
This study received the funding support from the department of Science and Technology, Government of India (grant DST no: CRG/2019/005494) awarded to corresponding author (ES).
Conflicts of Interest
None.
Use of Artificial Intelligence (AI)-Assisted Technology for manuscript preparation
The authors confirm that there was no use of AI-assisted technology for assisting in the writing of the manuscript and no images were manipulated using AI.
References
- Mini hepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120:3829-36.
- [Google Scholar]
- Association between serum levels of hepcidin and ferritin in patients with thalassemia major and intermedia, the role of iron chelator. J Hematop. 2019;12:143-7.
- [Google Scholar]
- Impact of World Health Organization (WHO) Revised Criteria-2016 on the diagnosis of polycythemia vera. Indian J Hematol Blood Transfus. 2020;36:477-83.
- [Google Scholar]
- Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis. Haematologica. 2019;104:2391-9.
- [Google Scholar]
- Erythropoiesis in polycythemia vera is hyper-proliferative and has accelerated maturation. Blood Cells Mol Dis. 2009;43:81-7.
- [Google Scholar]
- Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia. Eur J Haematol. 2013;91:228-35.
- [Google Scholar]
- Management of transfusion-dependent β-thalassemia (TDT): Expert insights and practical overview from the Middle East. Blood Rev. 2024;63:101138.
- [Google Scholar]
- Neurokinin-B Transcription in erythroid cells: direct activation by the hematopoietic transcription factor gata-1*. J Biol Chem. 2004;279:31348-56.
- [Google Scholar]
- Mutation profile in BCR-ABL1-negative myeloproliferative neoplasms: a single-center experience from India. Hematol Oncol Stem Cell Ther. 2021;15:13-20.
- [Google Scholar]
- Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C (T)) method. Methods. 2001;25:402-8.
- [Google Scholar]
- Beta Thalassemia. In: StatPearls. StatPearls Publishing: Treasure Island (FL); 2024.
- [Google Scholar]
- Dysregulated iron metabolism in polycythemia vera: etiology and consequences. Leukemia. 2018;32:2105-16.
- [Google Scholar]
- The relation between serum hepcidin, ferritin, hepcidin: ferritin ratio, hydroxyurea and splenectomy in children with β-thalassemia. Open Access Maced J Med Sci. 2019;7:2434-9.
- [Google Scholar]
- Hepcidin-to-ferritin ratio as an early diagnostic index of iron overload in β-thalassemia major patients. Hemoglobin. 2022;46:106-13.
- [Google Scholar]
- Iron metabolism and ineffective erythropoiesis in β-thalassemia mouse models. Ann N Y Acad Sci. 2010;1202:24-30.
- [Google Scholar]
- Iron homeostasis governs erythroid phenotype in polycythemia vera. Blood. 2023;141:3199-214.
- [Google Scholar]
- Hepcidin mimetics in polycythemia vera: resolving the irony of iron deficiency and erythrocytosis. Curr Opin Hematol. 2023;30:45-52.
- [Google Scholar]
- β-Thalassemia and Polycythemia vera: targeting chronic stress erythropoiesis. Int J Biochem Cell Biol. 2014;51:89-92.
- [Google Scholar]