Transfusion avoidance in myelodysplastic neoplasms.

PURPOSE OF REVIEW: Myelodysplastic neoplasms (MDS) are diseases of stem cell aging associated with complications from inadequate hematopoiesis (red cells, neutrophils and platelets) and variable risk for transformation to acute myeloid leukemia. Those with low-risk disease also suffer and die from MDS-related complications. Among the most challenging is development of anemia and transfusion dependence, which impacts quality of life and is associated with reduced survival. Appreciating and measuring the quality-of-life impact, preventing (if possible), treating, and managing the complications from anemia in MDS are of critical importance. RECENT FINDINGS: Recent developments in basic science highlight the potential deleterious impact of iron overload within the developing red cell niche. Iron overload can compromise red cell maturation from healthy as well as malignant clones and produces an environment favoring expansion of mutant clonal cells, potentially driving disease progression. Observational studies in nontransfusion dependent MDS highlight that iron overload occurs even in the nontransfusion dependent. The newly approved (and established) therapies for management of MDS-related anemia work best when begun before patients become heavily transfusion-dependent. SUMMARY: Iron overload is detrimental to hematopoiesis. Understanding the benefit afforded by transfusion is critical to optimal application and patient reported outcomes can inform this. Recently developed therapies are active and optimized application may improve response.

Calcium channel blockers for preventing cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.

BACKGROUND: Beta-thalassaemia is an inherited blood disorder that reduces the production of haemoglobin. The most severe form requires recurrent blood transfusions, which can lead to iron overload. Cardiovascular dysfunction caused by iron overload is the leading cause of morbidity and mortality in people with transfusion-dependent beta-thalassaemia. Iron chelation therapy has reduced the severity of systemic iron overload, but removal of iron from the myocardium requires a very proactive preventive strategy. There is evidence that calcium channel blockers may reduce myocardial iron deposition. This is an update of a Cochrane Review first published in 2018. OBJECTIVES: To assess the effects of calcium channel blockers plus standard iron chelation therapy, compared with standard iron chelation therapy (alone or with a placebo), on cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia. SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books, to 13 January 2022. We also searched ongoing trials databases and the reference lists of relevant articles and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of calcium channel blockers combined with standard chelation therapy versus standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included six RCTs (five parallel-group trials and one cross-over trial) with 253 participants; there were 126 participants in the amlodipine arms and 127 in the control arms. The certainty of the evidence was low for most outcomes at 12 months; the evidence for liver iron concentration was of moderate certainty, and the evidence for adverse events was of very low certainty. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may have little or no effect on cardiac T2* values at 12 months (mean difference (MD) 1.30 ms, 95% confidence interval (CI) -0.53 to 3.14; 4 trials, 191 participants; low-certainty evidence) and left ventricular ejection fraction (LVEF) at 12 months (MD 0.81%, 95% CI -0.92% to 2.54%; 3 trials, 136 participants; low-certainty evidence). Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may reduce myocardial iron concentration (MIC) after 12 months (MD -0.27 mg/g, 95% CI -0.46 to -0.08; 3 trials, 138 participants; low-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on heart T2*, MIC, or LVEF after six months, but the evidence is very uncertain. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may increase liver T2* values after 12 months (MD 1.48 ms, 95% CI 0.27 to 2.69; 3 trials, 127 participants; low-certainty evidence), but may have little or no effect on serum ferritin at 12 months (MD 0.07 µg/mL, 95% CI -0.20 to 0.35; 4 trials, 187 participants; low-certainty evidence), and probably has little or no effect on liver iron concentration (LIC) after 12 months (MD -0.86 mg/g, 95% CI -4.39 to 2.66; 2 trials, 123 participants; moderate-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on serum ferritin, liver T2* values, or LIC after six months, but the evidence is very uncertain. The included trials did not report any serious adverse events at six or 12 months of intervention. The studies did report mild adverse effects such as oedema, dizziness, mild cutaneous allergy, joint swelling, and mild gastrointestinal symptoms. Amlodipine may be associated with a higher risk of oedema (risk ratio (RR) 5.54, 95% CI 1.24 to 24.76; 4 trials, 167 participants; very low-certainty evidence). We found no difference between the groups in the occurrence of other adverse events, but the evidence was very uncertain. No trials reported mortality, cardiac function assessments other than echocardiographic estimation of LVEF, electrocardiographic abnormalities, quality of life, compliance with treatment, or cost of interventions. AUTHORS' CONCLUSIONS: The available evidence suggests that calcium channel blockers may reduce MIC and may increase liver T2* values in people with transfusion-dependent beta thalassaemia. Longer-term multicentre RCTs are needed to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should also investigate the role of baseline MIC in the response to calcium channel blockers, and include a cost-effectiveness analysis.

Betibeglogene Autotemcel Gene Therapy for Non-ß0/ß0 Genotype ß-Thalassemia.

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent ß-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the ß-globin (ßA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent ß-thalassemia and a non-ß0/ß0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-ß0/ß0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.).

In silico and in vivo protective effect of Morus nigra leaves on oxidative damage induced by iron overload.

Morus nigra L. is a plant popularly known as 'amoreira preta', very used in folk medicine. Iron overload (hemochromatosis) is a clinical condition that causes damage to various tissues due to oxidative stress. Therapy to control iron overload is still unsatisfactory. The protective effect on oxidative stress induced by iron overload was verified. Phytochemical characterization was evaluated by UHPLC-MS/MS. The in silico toxicity predictions of the main phytochemicals were performed via computer simulation. To induce iron overload, the animals received iron dextran (50 mg/kg/day). The test groups received doses of 500 and 1000 mg/kg of M. nigra extract for six weeks. Body weight, organosomatic index, serum iron, hepatic markers, cytokines, interfering factors in iron metabolism, enzymatic and histopathological evaluations were analyzed. Vanillic acid, caffeic acid, 6-hydroxycoumarin, p-coumaric acid, ferulic acid, rutin, quercitrin, resveratrol, apigenin and kaempferol were identified in the extract. In addition, in silico toxic predictions showed that the main compounds presented a low probability of toxic risk. The extract of M. nigra showed to control the mediators of inflammation and to reduce iron overload in several tissues. Our findings illustrate a novel therapeutic action of M. nigra leaves on hemochromatosis caused by iron overload.

Klotho ameliorated cognitive deficits in a temporal lobe epilepsy rat model by inhibiting ferroptosis.

Cognitive deficits are among the most common comorbidities of temporal lobe epilepsy (TLE). Ferroptosis associated with the accumulation of iron overload-dependent lipid peroxidation produces significant cognitive deficits in TLE. The anti-aging protein, klotho, has been shown to exert neuroprotective effects while enhancing cognition in neurodegenerative disorders. However, the role of klotho in TLE progression has not been established. In this study, we evaluated the effects and underlying mechanisms of klotho in a rat model of TLE induced by lithium-chloride and pilocarpine (LiCl-Pilo). The expression of klotho was found to be inhibited in the hippocampus following LiCl-Pilo induced TLE in rats. An adeno-virus (AAV), which mediated klotho overexpression (AAV-KL) was injected into the bilateral hippocampus of the rat models. After 3 weeks, rats were treated through intraperitoneal injections of LiCl-Pilo. After 9 weeks, AAV-KL was found to have significantly induced klotho overexpression in the hippocampus, effectively ameliorated cognitive deficits and exerted neuroprotective effects in LiCl-Pilo induced TLE rat models. Klotho significantly prevented ferroptosis and iron overload. Meanwhile, klotho regulated the expressions of divalent metal transporter 1 (DMT 1) and ferroportin (FPN) that were associated with iron accumulation in the hippocampus. Furthermore, klotho significantly elevated glutathione peroxidase-4 (GPX-4) and glutathione (GSH) levels while suppressed reactive oxygen species (ROS) levels. In conclusion, klotho ameliorated cognitive deficits and exerted neuroprotective effects by inhibiting ferroptosis in LiCl-Pilo induced TLE rat models.

Ilex paraguariensis (A. St.-Hil.) leaf infusion decreases iron absorption in patients with hereditary hemochromatosis: a randomized controlled crossover study.

This study proposed to investigate the effect of Ilex paraguariensis infusion on the absorption of non-heme iron in hereditary hemochromatosis (HH) patients with the HFE genotype. A two-way randomized, controlled, crossover trial was conducted on patients, aged 29-69 years, undergoing maintenance therapy. Fourteen HFE-HH patients ingested a meal containing 11.4 mg iron and 200 mL either of water (control) or of Ilex paraguariensis leaf infusion. The beverages were offered in random order, at intervals separated by a washout period of 7 days. Active surveillance showed no adverse effects. Blood samples were drawn shortly before and 1, 2, 3, and 4 h after the meal for serum iron measurement. A significant reduction in the postprandial serum iron was observed for HH patients after intake of the Ilex paraguariensis infusion (area under the curve (AUC) expressed as mean ± SEM: 173.3 ± 44.7 µmol h-1 L-1) compared to water (1449.4 ± 241.5 µmol h-1 L-1) (p < 0.001). In summary, intake of Ilex paraguariensis leaf infusion significantly inhibited the absorption of iron in patients with HH and, therefore, should be considered as a potential adjuvant for iron overload control.

SLN124, a GalNac-siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron-overload in a mouse model of ß-thalassaemia.

Beta-thalassaemia is an inherited blood disorder characterised by ineffective erythropoiesis and anaemia. Consequently, hepcidin expression is reduced resulting in increased iron absorption and primary iron overload. Hepcidin is under the negative control of transmembrane serine protease 6 (TMPRSS6) via cleavage of haemojuvelin (HJV), a co-receptor for the bone morphogenetic protein (BMP)-mothers against decapentaplegic homologue (SMAD) signalling pathway. Considering the central role of the TMPRSS6/HJV/hepcidin axis in iron homeostasis, the inhibition of TMPRSS6 expression represents a promising therapeutic strategy to increase hepcidin production and ameliorate anaemia and iron overload in ß-thalassaemia. In the present study, we investigated a small interfering RNA (siRNA) conjugate optimised for hepatic targeting of Tmprss6 (SLN124) in ß-thalassaemia mice (Hbbth3/+ ). Two subcutaneous injections of SLN124 (3 mg/kg) were sufficient to normalise hepcidin expression and reduce anaemia. We also observed a significant improvement in erythroid maturation, which was associated with a significant reduction in splenomegaly. Treatment with the iron chelator, deferiprone (DFP), did not impact any of the erythroid parameters. However, the combination of SLN124 with DFP was more effective in reducing hepatic iron overload than either treatment alone. Collectively, we show that the combination therapy can ameliorate several disease symptoms associated with chronic anaemia and iron overload, and therefore represents a promising pharmacological modality for the treatment of ß-thalassaemia and related disorders.

Astragaloside IV protects against retinal iron overload toxicity through iron regulation and the inhibition of MAPKs and NF-κB activation.

Iron overload toxicity has been implicated in retinal pigment epithelial cell injury in age-related macular degeneration. This study investigates the effects of astragaloside IV (AS-IV), a potential retinal protective agent, on the toxicity process of retinal iron overload in vivo and in vitro. AS-IV partially restored the retinal expression of rhodopsin and retinal pigment epithelium-specific 65 kDa protein, suppressed oxidative stress and inflammatory markers, and alleviated iron deposition and retinal pathological changes in vivo. Also, AS-IV inhibited the phosphorylation of p38 and ERK mitogen-activated protein kinases (MAPKs), as well as the nuclear translocation of nuclear factor-kappa B (NF-κB). Furthermore, AS-IV prevented cell death by decreasing the ratio of Bax/Bcl-2, caspase-3, and cleaved caspase-3 expression in vitro. Although there are no chelation effects between AS-IV and iron, AS-IV can reduce intracellular iron by regulating iron-handling proteins in ARPE-19 cells (Cav1.2, divalent metal transporter-1, transferrin receptor 1, and heavy-chain ferritin). In conclusion, the results show that AS-IV has significant protective effects against retinal iron overload toxicity and suggest that iron regulation and the inhibition of MAPKs and NF-κB activation might be mechanisms underlying the effects of AS-IV.

Reduction of cardiac iron overload by optimising iron chelation therapy in transfusion dependent thalassaemia using cardiac T2* MRI: a quality improvement project from Pakistan.

OBJECTIVES: Cardiac T2* MRI (T2*CMR), for accurate estimation of myocardial siderosis, was introduced as part of a QI collaborative to optimise chelation therapy in order to improve cardiac morbidity in transfusion dependent thalassaemia (TDT) patients. We report the impact of this QI initiative from two thalassaemia centres from this collaborative. DESIGN AND SETTING: A key driver based quality initiative was implemented to improve chelation in TDT patients registered at these two centres in Karachi, Pakistan. Protocol optimisation and compliance to treatment through training, communication and feedback were used as the drivers for QI intervention. Preintervention variables (demographics, chelation history, T2*CMR, echocardiography and holters) were collected from January 2015 to December 2016) and compared with variables in the post implementation phase (January to December 2019). A standardised adverse event severity for chelators and its management was devised for safe drug therapy as well as ensuring compliance to the regimen. Preintervention and postintervention variables were compared using non-parametric test. P value<0.05 was statistically significant. RESULTS: 100 patients with TDT, median age 17 (9-34) years, were included. An increase or stabilisation of T2*CMR was documented in 82% patients in the postintervention phase especially in patients with severe myocardial iron overload (5.5 vs 5.3 ms, p <0.01). Significantly fewer patients had abnormal echocardiographic findings (3.5% vs 26%, p <0.05) in the postintervention versus preintervention period. CONCLUSION: This QI initiative improved the chelation therapy leading to improved cardiac status in TDT patients at the participating centres.

Effectiveness of Deferasirox in Pediatric Thalassemia Patients: Experience from a Tertiary Care Hospital of Odisha.

BACKGROUND AND OBJECTIVES: Patients with beta-thalassemia require lifelong blood transfusions, leading to chronic iron overload, which can lead to growth retardation, as well as hinder sexual development during the adolescent period and dysfunction of organs such as heart, pancreas, and endocrine glands. These patients are in need of lifelong transfusion therapy and hence lifelong iron chelation therapy as well. Hence, this study was aimed to assess the effectiveness of deferasirox for iron chelation in pediatric thalassemia cases in a tertiary care hospital of Eastern India. SUBJECTS AND METHODS: This prospective, observational, hospital-based study was conducted from June 2015 to December 2016. Two hundred and fifty patients were assessed for eligibility, of which 174 were included. Effectiveness of deferasirox was observed by measuring serum ferritin levels which were monitored at the end of every 3 months till 1 year. We also evaluated the compliance with deferasirox therapy in the same study cohort. RESULTS: The serum ferritin level reduced significantly at the end of 12 months in comparison to baseline (P = 0.04). There was a mean absolute decrease in serum ferritin only in the dose range of 21-30 mg/kg/day. Approximately 90% of the patients had 100% compliance with deferasirox therapy. CONCLUSIONS: Deferasirox is an effective iron chelator when started at an optimum time and with optimum dose. At least 1 year of deferasirox therapy is needed for a significant lowering of serum ferritin levels of pediatric thalassemia patients on multiple blood transfusions.

Iron homeostasis disorder in piglet intestine.

Iron plays an essential role in preventing iron deficiency anemia and ensuring the healthy growth of animals. The special physiological condition of piglets is the main cause of iron deficiency. Iron metabolism in the intestine is the basis for understanding the effects of iron on the health of piglets. In order to scientifically evaluate dietary iron supplementation doses, it is necessary to recognize the effects of iron deficiency and iron overload on piglet intestinal health. Besides, iron as a cofactor is essential for the growth of microorganisms, and microorganisms compete with the host to absorb iron. Under the stress of iron deficiency and iron overload, various control schemes (such as precise nutrition, element balance, elimination of oxidation, etc.) are effective measures to eliminate adverse effects. In this review, we comprehensively review recent findings on the effects of iron deficiency and iron overload on intestinal health. This review will provide a rational design strategy to achieve a reasonable iron supplement, which will guide the use of iron in animal husbandry.

Correcting ß-thalassemia by combined therapies that restrict iron and modulate erythropoietin activity.

ß-Thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly, and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (ie, using hepcidin activators like Tmprss6-antisense oligonucleotides [ASOs]) or increase erythropoiesis (by erythropoietin [EPO] administration or modulating the ability of transferrin receptor 2 [Tfr2] to control red blood cell [RBC] synthesis). Targeting Tmprss6 messenger RNA by Tmprss6-ASO was proven to be effective in improving IE and splenomegaly by inducing iron restriction. However, we postulated that combinatorial strategies might be superior to single therapies. Here, we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by ß-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single-allele deletion alone, respectively, exacerbated or did not improve splenomegaly in ß-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, the combination of Tmprss6-ASO + EPO or Tmprss6-ASO + Tfr2 single-allele deletion produced significantly higher hemoglobin levels and reduced splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating IE and anemia in ß-thalassemia and could provide guidance to translate some of these approaches into viable therapies.

American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support.

BACKGROUND: Red cell transfusions remain a mainstay of therapy for patients with sickle cell disease (SCD), but pose significant clinical challenges. Guidance for specific indications and administration of transfusion, as well as screening, prevention, and management of alloimmunization, delayed hemolytic transfusion reactions (DHTRs), and iron overload may improve outcomes. OBJECTIVE: Our objective was to develop evidence-based guidelines to support patients, clinicians, and other healthcare professionals in their decisions about transfusion support for SCD and the management of transfusion-related complications. METHODS: The American Society of Hematology formed a multidisciplinary panel that was balanced to minimize bias from conflicts of interest and that included a patient representative. The panel prioritized clinical questions and outcomes. The Mayo Clinic Evidence-Based Practice Research Program supported the guideline development process. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to form recommendations, which were subject to public comment. RESULTS: The panel developed 10 recommendations focused on red cell antigen typing and matching, indications, and mode of administration (simple vs red cell exchange), as well as screening, prevention, and management of alloimmunization, DHTRs, and iron overload. CONCLUSIONS: The majority of panel recommendations were conditional due to the paucity of direct, high-certainty evidence for outcomes of interest. Research priorities were identified, including prospective studies to understand the role of serologic vs genotypic red cell matching, the mechanism of HTRs resulting from specific alloantigens to inform therapy, the role and timing of regular transfusions during pregnancy for women, and the optimal treatment of transfusional iron overload in SCD.

Alleviation Effect of Grape Seed Proanthocyanidins on Neuronal Apoptosis in Rats with Iron Overload.

We aimed to evaluate the effect of grape seed proanthocyanidins (GSPCs) on neuronal apoptosis, particularly through their roles in maintaining divalent mineral element balance and resisting oxidation in rats with iron overload. A total of 40 Sprague-Dawley rats were randomly divided into control, iron overload, GSPCs, and iron overload + GSPCs groups. The iron, calcium, zinc, magnesium, and copper contents in the brain tissue of the rats were measured using inductively coupled plasma mass spectrometry. Their oxidative stress state was determined using the relevant kit. The number of apoptotic neurons was evaluated using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and synaptosome numbers were determined using the immunohistochemical approach. Fas, Bax, and Bcl-2 gene expressions in the cortex and hippocampus were detected using quantitative real-time polymerase chain reaction. After 7 weeks, compared with the control group, the zinc and magnesium contents; superoxide dismutase, glutathione peroxidase, and catalase activities; and synaptophysin and Bcl-2 gene expressions in the iron overload group were significantly decreased, whereas the iron, calcium contents, and malondialdehyde contents; TUNEL-positive cell numbers; and Fas and Bax gene expressions were significantly increased. There were no significant changes in the copper content. Conversely, the rats exhibited better recovery when GSPCs were used instead of iron alone. In summary, GSPCs protected against iron overload induced neuronal apoptosis in rats by maintaining the divalent mineral element balance, reducing oxidative stress, and regulating apoptotic genes expressions.

Diagnosis of iron deficiency in hemodialysis patients: Usefulness of measuring reticulocyte hemoglobin equivalent.

The evaluation of iron status in dialysis patients provides information essential to the planning of adequate recombinant human erythropoietin treatment. To diagnose iron deficiency in patients undergoing hemodialysis (HD), reticulocyte hemoglobin content and percentage of hypochromic red cells are incorporated into the European best practice guidelines on anemia management in chronic kidney disease (CKD), the mean reticulocyte hemoglobin content (Ret-HE) was proposed as alternatives to standard biochemical tests. Reticulocyte hemoglobin content and percentage of hypochromic red cells are incorporated into the European best practice guidelines on anemia management in CKD. Our aim was to assess the value of Ret-HE parameter, in terms of the sensitivity and specificity for detecting iron deficiency, in HD patients. We studied 50 patients undergoing HD three times weekly , to clarify the accuracy of Ret-HE in diagnosing iron deficiency in dialysis patients, we initially compared Ret-HE with such iron parameters as serum ferritin levels, transferrin saturation, and hypochromic red blood cell (Hypo%) which has been established as indicators of functional iron deficiency. Ret-HE mean value in anemic patients was (25.84 ± 4.23 pg) and had good correlation (P <0.001) between Ret-HE, serum iron, ferritin, transferrin, and transferin saturation in dialysis patients. Receiver operating characteristic curve analysis revealed, values of the area was 0.887, and at a cutoff value of 27.0 pg, a sensitivity of 90.4% and a specificity of 80.8% were achieved. The newly proposed Ret-HE can provide clinicians with information equivalent to iron deficiency anemia markers. Ret-HE is a new parameter that is easily measurable is suggested as reliable parameters for the study of erythropoiesis status in HD patients.

Indications for RBC Exchange Transfusion in Patients with Sickle Cell Disease: Revisited.

Clinically, sickle cell disease (SCD) is characterized by chronic hemolytic anemia, recurrent acute vaso-occlusive crises, and progressive multi-organ failure. The management for SCD varies greatly among patients, and in the same patient longitudinally. Some patients may benefit from minimal therapy and infrequent transfusions, while others are transfusion dependent. Transfusion therapy can consist of simple transfusions, which often lead to iron overload and require iron chelation therapy. Simple transfusion, however, cannot reduce HbS levels rapidly, which may be required in certain critical conditions such as acute chest syndrome (ACS) or stroke. On the other hand, red blood cell exchange transfusion (RBCEX) can prevent iron overload and achieve rapid HbS reduction. In RBCEX, the red blood cells (RBCs) of the patient are replaced with normal RBCs, and the removed plasma is returned to the patient with minimal alteration. Plasma of patients with SCD is known to contain increased levels of several inflammatory mediators in the steady state that increase during crises. This finding explains why some patients with severe complications do not respond to RBCEX, but do much better after using plasma exchange in addition to RBCEX, as previously reported. Based on this, a revision of the indications for RBCEX in patents with SCD is recommended. DISCUSSION: In the 1980s and 1990s we used the Haemonetics Corporation's V-50 machine to perform intermittent whole blood (WB) exchange to treat severe complications of sickle cell disease (SCD.) The results were excellent, as previously described [1].

Investigation of correlation between H63D and C282Y mutations in HFE gene and serum Ferritin level in beta-thalassemia major patients.

INTRODUCTION: Mutations in the HFE gene have been shown to be associated with hemochromatosis which is observed in beta-thalassemia major. In this study, we determined the HFE gene mutations (C282Y and H63D) among b-thalassemia major patients to investigate the effect of these mutations on serum Ferritin levels. MATERIAL AND METHODS: In this cross-sectional study, a total of 105 b-thalassemia subjects with a history of regular blood transfusion were selected. They divided into two distinct groups according cut off 1000ng/ml of serum Ferritin levels. The HFE gene mutant allele detected by RFLP-PCR. RESULTS: Of 105 thalassemia patients, 29 patients (14 male and 15 female) were heterozygote for H63D mutation, and just one male was homozygote, but for C282Y mutation just one heterozygote and one homozygote was detected, and overall 31% had coexistence of b-thal and HFE gene mutations. As expected, Ferritin levels significantly differed between groups (P=0.001). CONCLUSION: The impact of detection of HFE mutations could prognosis the likelihood of iron overload in multi-transfused patients, and allowing early diagnosis and proper management to overcome complications of iron overload in beta-thalassemia patients.

Long-Term Risks of Intravenous Iron in End-Stage Renal Disease Patients.

Patients with end-stage renal disease on dialysis commonly receive intravenous iron to treat anemia along with erythropoiesis-stimulating agents. While studies of intravenous iron have demonstrated efficacy in raising hemoglobin, the quantity of administered intravenous iron has raised concerns about iron overload leading to long-term toxicities. The goal of this review is to understand recent trends in intravenous iron use, potential mechanisms of iron toxicity, and to evaluate the available evidence in the literature for potential long-term cardiovascular and infectious complications. We include findings from the recently published landmark clinical trial of intravenous iron for patients receiving hemodialysis to contextualize treatment recommendations.

Iron chelation by deferasirox confers protection against concanavalin A-induced liver fibrosis: A mechanistic approach.

Hepatic iron overload is one of the causative factors for chronic liver injury and fibrosis. The present study aimed to investigate the potential antifibrotic effect of the iron chelator; deferasirox (DFX) in experimentally-induced liver fibrosis in rats. Male Sprague-Dawley rats were administered concanavalin A (Con A) and/or DFX for 6 consecutive weeks. Con A injection induced significant hepatotoxicity as was evident by the elevated transaminases activity, and decreased albumin level. Also, it disturbed the iron homeostasis through increasing C/EBP homologous protein (CHOP), decreasing phosphorylated cAMP responsive element binding protein(P-CREB) and hepcidin levels leading to significant serum and hepatic iron overload. In addition, it induced an imbalance in the oxidative status of the liver via upregulating NADPH oxidase 4 (NOX4), together with a marked decrease in anti-oxidant enzymes' activities. As a consequence, upregulation of nuclear factor-kappa b (NF-κB) and the downstream inflammatory mediators was observed. Those events all together precipitated in initiation of liver fibrosis as confirmed by the elevation of alpha-smooth muscle actin (α-SMA) and liver collagen content. Co-treatment with DFX protected against experimentally-induced liver fibrosis in rats via its iron chelating, anti-oxidant, and anti-inflammatory properties. These findings imply that DFX can attenuate the progression of liver fibrosis.