The role of soluble transferrin receptor in iron overload in children with chronic hemolytic anemia

2013 ◽  
Vol 26 (2) ◽  
pp. 132
Author(s):  
RedaI Rakha ◽  
SamarM.K. El-Din Fathallah ◽  
FathiaM El-Nemr ◽  
FaridaH El-Rashidi ◽  
SehamM Ragab
Keyword(s):  
Iron Overload ◽  
Hemolytic Anemia ◽  
Transferrin Receptor ◽  
Soluble Transferrin Receptor ◽  
Chronic Hemolytic Anemia

Peroxiredoxin-2 (Prx-2) Shows a Dual Role as Antioxidant and Chaperone in Red Cells from a β Thalassemic Mouse Model.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1783-1783 ◽  
Author(s):  
Alessandro Matte’ ◽  
Franco Turrini ◽  
Lucia De Franceschi
Keyword(s):  
Mouse Model ◽  
Oxidative Damage ◽  
Hemolytic Anemia ◽  
Dual Role ◽  
Lower Amount ◽  
Mouse Strains ◽  
Dependent Manner ◽  
Oligomeric State ◽  
Chronic Hemolytic Anemia

Abstract Peroxiredoxins are a ubiquitous family of anti-oxidant enzymes, which have been recently involved in different cellular functions such as cell proliferation or intracellular signaling. In red blood cells (RBCs) Prx-2 is present as scavenger of the reactive oxygen species generated by hemoglobin auto-oxidation as supported also by the evidences in mouse RBCs genetically lacking Prx-2. β thalassemia (thal) is an inherited RBC disorder due to defective β-globin chain synthesis, leading to ineffective erythropoiesis and chronic hemolytic anemia related to severe RBCs membrane oxidative damage. Here, we evaluated Prx-2 expression and localization in RBCs from a mouse model of β thal, which shows biological and clinical features similar to human β thal intermedia. We studied βthal (Hbbth/th) and wild-type mice (WT) at different ages (2- 6 months old), divided into groups of 10 mice each. Since β thal is characterized by high reticulocyte count due to the chronic hemolytic anemia, we divided RBCs into reticulocyte enriched fraction (F1) and dense RBCs fraction (F2), corresponding to the oldest cells. Then, RBCs from F1 and F2 were studied as total RBCs lysate and as RBCs membrane fraction. No significant differences in Prx-2 expression related to animals aging were present within mouse strains. βthal total RBCs lysates showed increase expression of Prx-2 as monomers and dimers in both F1 and F2 fractions compared to WT ones; increase dimerization of Prx-2 in F1 compared to F2, while no differences were present between F1 and F2 in WT RBCs, suggesting an upregulation of Prx-2 synthesis in β thal reticulocytes, since it is already present, and a Prx-2 hyperoxidation in circulating β thal RBCs. Since a chaperone activity for Prx-2 has been recently shown in yeasts and bacteria and being the assistance to denaturated proteins one of the major activity of chaperones, we evaluated Prx-2 membrane localization in β thal RBCs, characterized by severe membrane oxidative damage. Prx-2, as monomers and dimers, was recruited to the membrane in both mouse strains, suggesting a possible dual role of Prx-2 as antioxidant and chaperone. We also observed that the amount of Prx-2 bound to the RBCs membrane was higher in WT than in β thal mice, most likely related to either removal of the more severely damaged β thal RBCs from circulation or to perturbation of Prx-2 function in β thal RBCs. In order to evaluate Prx-2 functions we exposed WT RBCs to either Phenylhydrazine (PHZ 10–20 μM), mimicking β thal RBCs membrane damage or H2O2 at low concentration (5 μM). PHZ treatment significantly reduced the amount of Prx-2 monomers and dimers bound to the membrane in a dose dependent manner, whereas H2O2 did not significantly modify them, indicating that PHZ and H2O2 differently affect Prx-2 membrane recruitment. Since Prx-2 functions seem to be related to phosphorylation events, we analysed Prx-2 localization in RBCs lacking protein tyrosin phosphatase- ε (PTP-ε). In the absence of PTP-ε we observed a lower amount of Prx-2 bound to the membrane as monomers, with undetectable Prx-2 dimers compared to WT ones. When PTP-ε RBCs were treated with PHZ, Prx-2 was almost undetectable on RBCs membrane, suggesting a possible role of PTP-ε in changes of Prx-2 oligomeric state. In conclusion, in β thal mouse RBCs Prx-2 expression is up-regulated, is present in both monomeric and dimeric state, and is modulated by oxidative damage and phosphorylation events supporting a dual role of Prx-2 as antioxidant and chaperone.

scholarly journals Implications of Low Zinc and Copper Levels As Well As Altered Iron Trafficking Proteins on Oxidant Stress in Patients with Transfusion Dependant Thalassemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1289-1289
Author(s):  
Patrick B Walter ◽  
Michael Minkley ◽  
Caitlin Curtis ◽  
Hodge Maeve ◽  
Razavi Morty ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Transferrin Receptor ◽  
Oxidative Stress Markers ◽  
Soluble Transferrin Receptor ◽  
Secondary Complications ◽  
Plasma Iron ◽  
Stress Markers ◽  
Iron Trafficking ◽  
Redox Active

Abstract Introduction:Patients with transfusion dependent thalassemia (TDT) have a genetic anemia that causes incomplete erythropoiesis and iron overload. Plasma zinc deficiency is also seen in roughly 25% of patients with TDT. Iron overload is thought to be related to a number of secondary complications in TDT including cardiomyopathy and diabetes. However, in TDT the effects of altered Zn status are not as well characterized and the effects of low copper (Cu) are even less well known. One possible cause of these complications is oxidative damage to tissues. This oxidative stress can be caused by labile plasma iron (LPI), a component of the non-transferrin bound iron pool, which is often seen in individuals suffering from iron overload. LPI is both redox-active and chelatable and is the likely culprit distributing iron to extra-hepatic tissues. Through reactive Fenton chemistry, LPI, can also cause lipid peroxidation releasing malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), which are damage-associated molecular patterns and markers of oxidative tissue damage that activate the immune system to induce inflammation. Incomplete erythropoiesis as well as transfusional iron overload are responsible for an increase in the amount of poorly handled, redox active LPI in TDT. Thus, we hypothesized that changes in the levels of key iron trafficking proteins (such as soluble transferrin receptor (sTfR) or hemopexin) would affect oxidative stress levels in TDT. We also hypothesized that metal dyshomeostasis, such as a functional Zn or Cu deficiency would affect oxidative stress. Aims: The purpose of this pilot project is to 1) Determine the state of circulating levels of oxidative stress markers and iron trafficking proteins in TDT patients and 2) Explore the relationship between the markers and proteins measured in (1)and the Zn and Cu status of TDT patients. Methods:39 subjects with informed consent were enrolled (29 patients with TDT and 10 controls). Liver iron concentration (LIC) was measured by a superconducting quantum interference device (SQUID™). LPI was measured using dihydrorhodamine 123. Both MDA and MDA + 4-HNE were measured using N-methyl-2-phenylindole. The iron trafficking proteins sTfR, transferrin, haptoglobin and hemopexin were measured by immunoassay isolation followed by multiplex multiple reaction monitoring mass spectrometry. Zn and Cu were assessed by inductively coupled plasma atomic emission spectroscopy. Fructosamine was measured by quantitative spectrophotometry. Results: Patients with TDT had elevated LIC levels of 2681 ± 2424 ug iron/g wet weight. Plasma levels of the iron trafficking proteins, transferrin, hemopexin and haptoglobin were all decreased in TDT patients (P<0.001) with a corresponding increase in soluble transferrin receptor (StfR) and the LPI (P<0.001). Serum Zn was significantly reduced in TDT patients (p = 0.028) and urinary Zn was significantly elevated (p =0.024). Serum Cu was also significantly reduced in TDT patients (p =0.026). Reduced Zn levels in TDT patients correlated with elevated MDA levels (p = 0.0195, R = -0.382) as were serum Cu levels (p = 0.0158, R = -0.394). Reduced levels of plasma iron trafficking proteins (haptoglobin, hemopexin, and transferrin) were correlated with elevated levels of MDA and LPI (all p-values < 0.05). Plasma MDA was also correlated with fructosamine levels (p < 0.001, R= 0.57). Conclusion: Metal dyshomeostasis involving Zn and Cu may be important contributors to oxidative stress and iron injury in TDT. We confirm previous findings in TDT of elevated levels of LPI as well as the oxidative stress markers MDA and 4-HNE. We expand previous findings of reduced transferrin levels in TDT to show a similar reduction in both haptoglobin and hemopexin. StfR levels were elevated in TDT patients, possibly due to a strong erythropoietic drive. Both reduced haptoglobin and hemopexin as well as decreased Zn and Cu levels and increased Zn excretion appear to be present in TDT. These preliminary findings suggest that low levels of Zn, Cu, haptoglobin and hemopexin may be related to increased oxidative stress and LPI in TDT, which could be important contributors to secondary complications of TDT. Disclosures Walter: Apopharma: Research Funding.

Prognostic Impact of Iron Overload During Follow-up After Allogeneic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 347-347
Author(s):  
Sara C. Meyer ◽  
Andreas S. Buser ◽  
André Tichelli ◽  
Jakob R. Passweg ◽  
Martin Stern
Keyword(s):  
Iron Overload ◽  
Transferrin Receptor ◽  
Transferrin Saturation ◽  
Allogeneic Transplantation ◽  
Soluble Transferrin Receptor ◽  
Post Transplant ◽  
Impact On Survival ◽  
Iron Parameters ◽  
Time Point

Abstract Abstract 347 Introduction: Iron overload is frequent in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) due to multiple red blood cell transfusions in the pre- and post-transplant period. Serum ferritin is a routine marker for iron overload. Along with transferrin saturation and soluble transferrin receptor, it was recently shown to strongly impact on survival after HSCT. Reduction of iron overload – e.g. by chelation - might improve the outcome after allogeneic transplantation. To analyze whether patients might benefit from post-transplant interventions aimed at reducing iron overload, we evaluated the impact of iron parameters on survival in a cohort of patients in which complete iron parameters were assessed before and at multiple time-points after transplantation. Methods: We studied 153 consecutive patients undergoing unmanipulated T-cell replete allogeneic transplantation at our center between 2005 and 2009. Among 90 males and 63 females with a median age of 46.5 years (range 18 – 70 years), underlying diseases were AML/MDS (n=87), ALL (n=25), lymphoma/myeloma (n=25), CML/MPN (n=12) and non-malignant (n=4). Donors were HLA-identical (n=78) or one-antigen mismatched (n=2) siblings, or unrelated volunteer donors (n=73). Patients with lymphoma received conditioning with BEAM, fludarabine and single dose total body irradiation (TBI). All other patients were treated with cyclophosphamide and busulfan, or cyclophosphamide and TBI +/− etoposide. Graft-vs-host disease prophylaxis was with Cylosporin A plus either methotrexate or mycophenolate. Serum iron parameters including ferritin, transferrin saturation, transferrin, iron and soluble transferrin receptor (sTfR) were determined before HSCT as well as 3, 6, 12, 24, 36 and 60 months post-transplant. Patients were categorized into groups with high or low iron parameters according to values above or below median at each time-point. Predictors of transplant outcome were further evaluated in multivariable Cox models using disease and stage as covariates. Results: Of the 153 patients, 83 were alive at last contact with a median follow-up of 3.4 years. Ferritin was strongly elevated before HSCT (median 1344 ng/ml, range 16–6507 ng/ml), peaked 3 months post-transplant (median 2508 ng/ml, range 71–9756 ng/ml) and continuously decreased to reach values within the normal range at 5 years (median 242.5 ng/ml, range 28–984ng/ml). Transferrin saturation and iron analogously peaked in the early post-transplant period and subsequently lowered, while transferrin and sTfR increased after an early post-transplant nadir up to 5 years. The post-transplant course of all iron parameters is shown in Fig 1. As demonstrated previously, survival analysis showed a poor survival of patients with a pre-transplant ferritin value above the median (hazard ratio 2.4, p=0.001). Time-stratified landmark survival analysis showed that iron overload (as assessed by ferritin levels above the median at the respective time-point) had a detrimental effect on survival in all periods analyzed (0–6 months p=0.01; 6–12 months p<0.001; 1–2 years p=0.07; and 2–5 years p=0.02. Figure 2). Interestingly, no patient with a ferritin level below the median died more than six months post-transplant. Excess mortality in patients with high ferritin was due to increased transplant related mortality. After adjustment for disease and stage, elevated ferritin values retained their prognostic significance. Analysis of the other iron parameters showed similar trends, but their prognostic value was lower than that of ferritin. Conclusions: Iron overload before HSCT as well as during the post-transplant follow-up confers an increased risk of death. Iron parameters significantly impact on survival during all post-transplant intervals analyzed. Thus, our data suggest that patients may benefit from interventions to reduce iron overload after HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Altered Erythropoiesis in Mouse Models of Type 3 Hemochromatosis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
R. M. Pellegrino ◽  
F. Riondato ◽  
L. Ferbo ◽  
M. Boero ◽  
A. Palmieri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Mouse Models ◽  
Transferrin Receptor ◽  
The Other ◽  
Iron Availability ◽  
Murine Models ◽  
Type 3 ◽  
Old Mice

Type 3 haemochromatosis (HFE3) is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2) gene that codes for two main isoforms (Tfr2αand Tfr2β). Tfr2αis one of the hepatic regulators of iron inhibitor hepcidin. Tfr2βis an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO). The evaluations were performed in bone marrow and spleen, in 14 days’ and 10 weeks’ old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2αleads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2β(Tfr2 KI mice) causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2αin modulation of erythropoiesis and of Tfr2βin favoring iron availability for erythropoiesis.

Prognostic Impact of Different Iron Parameters In Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 168-168
Author(s):  
Godwin Nosakhare Bazuave ◽  
Andreas S. Buser ◽  
Sabine Gerull ◽  
André Tichelli ◽  
Martin Stern
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Iron Overload ◽  
Cell Transplantation ◽  
Transferrin Receptor ◽  
Transferrin Saturation ◽  
Soluble Transferrin Receptor ◽  
Reactive Protein ◽  
Kaplan Meier ◽  
Iron Parameters

Abstract Abstract 168 Pre-transplant iron overload contributes to increased transplant related mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Serum ferritin is a useful marker to detect iron overload, and is strongly associated with survival rates after allogeneic HSCT. Ferritin is also elevated in patients with inflammatory conditions and may therefore lack specificity as a marker of iron overload. Other iron parameters such as the soluble transferrin receptor (which is not elevated during acute phase reactions), or transferrin saturation (which strongly correlates with non-transferrin bound iron causing tissue damage) might be superior as prognostic parameters. We retrospectively studied pre-transplant serum iron parameters (ferritin, transferrin, transferrin saturation, iron, soluble transferrin receptor [sTfR]) in 230 consecutive patients undergoing myeloablative allogeneic stem cell transplantation at our centre between 2002 and 2009. C-reactive protein (CRP) was measured as a marker for inflammatory diseases. Median age at transplant was 45 (range 17–70), 132 patients were male, 98 female. Diagnoses were ALL (n=43), AML (n=123), lymphoma (2=37), MPN (n=20), and non-malignant disorders (n=7). Conditioning was with Cy/TBI +/− VP 16 (n=109), BEAM/Fludarabine/TBI (n=29), BuCy (n=88), or other (n=4). All patients received pharmacological GvHD prophylaxis with CSA/MTX (n=201) or CSA/MMF (n=29). Median values of iron parameters were: ferritin 1342 ng/ml (range 7-7'260); transferrin 1.9 g/l (range 0.8–3.5); transferrin saturation 36% (range 4–106%); iron 18 μ mol/l (range 3–52); sTfR 3.2 mg/l (range 0.3–73). Interestingly, no significant correlation was found between ferritin and CRP (r=0.09, p=0.16). All iron parameters predicted survival, when patients were categorized into those with levels below or above the median. In Kaplan-Meier analysis, transferrin saturation showed the highest predictive power (5 year survival if below median 64±5%; if above median 32±5%; likelihood ratio [LR] 23.2, p<10e5, Figure 1). Ferritin, in comparison, had lower prognostic significance (survival 61±5% versus 39±5%, LR13.1, p=0.0003). The predictive power of sTfR was between that of ferritin and transferrin saturation (34±5% versus 65±5%, LR 20.2, p<10e5), whereas transferrin and iron fared markedly worse and were not further analyzed. In multivariate Cox models adjusted for diagnosis, disease stage, CRP, stem cell source, donor type, and year of transplant, hazard ratios with borderline significance were found for ferritin (HR 1.51, 95% CI 0.98–2.33, p=0.06) and sTfR (HR 1.50, 95% CI 0.96–2.34, p=0.07). In contrast, transferrin saturation retained clear prognostic significance (HR 1.90, 95% CI 1.23–2.94, p=0.004). Receiver operating characteristic curve analysis confirmed the superiority of transferrin saturation as a predictor of transplant outcome over a wide range of cutoff values (area under the curve for transferrin saturation 0.715, for ferritin 0.657, Figure 2). Iron overload strongly influences outcome of allogeneic stem cell transplantation. In this population of patients with a history of repeated red blood cell transfusions, serum ferritin levels were not significantly influenced by inflammatory states, as assessed by the lack of association with elevated CRP levels. Of the iron parameters studied, serum transferrin saturation had the highest predictive power in both univariate and multivariate models. Figure 1. Kaplan-Meier estimates of survival after allogeneic HSCT in patients stratified according to below- or above-median pre-transplant iron parameters and C-reactive protein Figure 1. Kaplan-Meier estimates of survival after allogeneic HSCT in patients stratified according to below- or above-median pre-transplant iron parameters and C-reactive protein Figure 2. Receiver operating characteristics (ROC) curve for pretransplant ferritin, soluble transferrin receptor, and transferrin saturation levels as predictors for 5-year overall survival Figure 2. Receiver operating characteristics (ROC) curve for pretransplant ferritin, soluble transferrin receptor, and transferrin saturation levels as predictors for 5-year overall survival Disclosures: No relevant conflicts of interest to declare.

Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients

2005 ◽  
Vol 11 (3) ◽  
pp. 272-275 ◽  
Author(s):  
Constantinos Sfagos ◽  
Alexandros C Makis ◽  
Aristeidis Chaidos ◽  
Eleftheria C Hatzimichael ◽  
Androniki Dalamaga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Transferrin Receptor ◽  
Serum Iron ◽  
Soluble Transferrin Receptor ◽  
Normal Limits ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
Active Inflammation ◽  
Active Disease

Over the last few years, increased evidence has supported the role of iron dysregulation in the pathogenesis of multiple sclerosis (MS), as iron is essential for myelin formation and oxidative phosphorylation. We studied indices of iron metabolism, such as serum iron, ferritin, transferrin and soluble transferrin receptor (sTFR) levels in 27 MS patients. Seven patients had chronic progressive active disease (CP-A), six had chronic progressive stable (CP-S), ten had relapsing—remitting active (RR-A) and four had relapsing—remitting stable (RR-S) disease. sTFR levels were found to be significantly higher in CP-A (P=0.021) and RR-A (P= 0.004) patients than in controls. sTFR levels were also elevated in CP-S patients but did not reach significance (P=0.064). sTFR values in RR-S patients were comparable to those found in controls (P=0.31). Ferritin levels were significantly elevated only in CP-A patients (P= 0.002). Patients of the CP group had significantly higher ferritin values than the RR patients (P= 0.004). Haemoglobin values as well as iron and transferrin levels were within normal limits in all patients. In conclusion, the increased serum sTFR and ferritin levels in nonanaemic MS patients with active disease reflect the increased iron turnover. The mild elevation of sTFR levels in CP-S patients may indicate active inflammation with ongoing oxidative damage that is not detectable by history or examination.

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