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Genetic mutations in the b-globin gene lead to a decrease or removal of the bglobin chain, causing the build-up of unstable alpha-hemoglobin. This condition is referred to as beta-thalassemia (BT). The present treatment strategies primarily target the correction of defective erythropoiesis, with a particular emphasis on gene therapy and hematopoietic stem cell transplantation. However, the presence of inefficient erythropoiesis in BT bone marrow (BM) is likely to disturb the previously functioning BM microenvironment. This includes accumulation of various macromolecules, damage to hematopoietic function, destruction of bone cell production and damage to osteoblast(OBs), and so on. In addition, the changes of BT BM microenvironment may have a certain correlation with the occurrence of hematological malignancies. Correction of the microenvironment can be achieved through treatments such as iron chelation, antioxidants, hypoglycemia, and biologics. Hence, This review describes damage in the BT BM microenvironment and some potential remedies. [ABSTRACT FROM AUTHOR]

Hereditary dyserythropoietic anemias, or congenital dyserythropoietic anemias (CDAs), are rare disorders disrupting normal erythroid lineage development, resulting in ineffective erythropoiesis and monolinear cytopenia. CDAs include three main types (I, II, III), transcription‐factor‐related forms, and syndromic forms. The widespread use of next‐generation sequencing in the last decade has unveiled novel causative genes and unexpected genotype–phenotype correlations. The discovery of the genetic defects underlying the CDAs not only facilitates accurate diagnosis but also enhances understanding of CDA pathophysiology. Notable advancements include identifying a hepatic‐specific role of the SEC23B loss‐of‐function in iron metabolism dysregulation in CDA II, deepening CDIN1 dysfunction during erythroid differentiation, and uncovering a recessive CDA III form associated with RACGAP1 variants. Current treatments primarily rely on supportive measures tailored to disease severity and clinical features. Comparative studies with pyruvate kinase deficiency have illuminated new therapeutic avenues by elucidating iron dyshomeostasis and dyserythropoiesis mechanisms. We herein discuss recent progress in diagnostic methodologies, novel gene discoveries, and enhanced comprehension of CDA pathogenesis and molecular genetics. [ABSTRACT FROM AUTHOR]

The β-thalassemias are inherited genetic disorders affecting the hematopoietic system. In β-thalassemias, more than 350 mutations of the adult β-globin gene cause the low or absent production of adult hemoglobin (HbA). A clinical parameter affecting the physiology of erythroid cells is the excess of free α-globin. Possible experimental strategies for a reduction in excess free α-globin chains in β-thalassemia are CRISPR-Cas9-based genome editing of the β-globin gene, forcing "de novo" HbA production and fetal hemoglobin (HbF) induction. In addition, a reduction in excess free α-globin chains in β-thalassemia can be achieved by induction of the autophagic process. This process is regulated by the Unc-51-like kinase 1 (Ulk1) gene. The interplay with the PI3K/Akt/TOR pathway, with the activity of the α-globin stabilizing protein (AHSP) and the involvement of microRNAs in autophagy and Ulk1 gene expression, is presented and discussed in the context of identifying novel biomarkers and potential therapeutic targets for β-thalassemia. [ABSTRACT FROM AUTHOR]

Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2−/− mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2−/− mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2−/− mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2−/− mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2−/− mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2−/− mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging. [ABSTRACT FROM AUTHOR]

TMPRSS6 is a serine protease highly expressed in the liver. Its role in iron regulation was first reported in 2008 when mutations in TMPRSS6 were shown to be the cause of iron-refractory iron deficiency anemia (IRIDA) in humans and in mouse models. TMPRSS6 functions as a negative regulator of the expression of the systemic iron-regulatory hormone hepcidin. Over the last decade and a half, growing understanding of TMPRSS6 biology and mechanism of action has enabled development of new therapeutic approaches for patients with diseases of erythropoiesis and iron homeostasis.ClinicalTrials.gov identifier NCT03165864.

Congenital dyserythropoietic anemia (CDA) is characterized by anemia—mild to severe, hemolysis, ineffective erythropoiesis, and in some cases, iron overload. There are three major types of CDA (I, II, and III), and the other types are rarer. The rarity of this disease, as well as signs and symptoms that overlap with other hematological diseases, can make the diagnosis difficult and delayed over several years. Evaluation includes basic laboratory testing, magnetic resonance imaging of organs for assessment of iron overload, bone marrow assessment, and genetic testing. Laboratory tests to evaluate for ineffective erythropoiesis include indirect bilirubin level, which can be normal or increased, reticulocyte production index < 2 signifying hyperproliferation of erythrocytes, and complete iron panel (serum iron, ferritin, and iron saturation), which may suggest iron overload. Genetic testing is crucial for CDA diagnosis and includes next-generation sequencing. A multidisciplinary team of providers including a hematologist, hepatologist, hematopathologist, and genetic counselor are important and sometimes necessary for the evaluation, diagnosis, and management of these patients. Management depends on the clinical phenotype, and some severe cases may require blood transfusion, iron chelation therapy, splenectomy, and in extreme cases, hematopoietic stem cell transplant may be necessary. This mini-review illustrates the challenges involved in the diagnosis and management of the most common CDA, which is type II. It will highlight clinical signs and symptoms in patients that should prompt providers to test for CDA. It will also increase awareness of this disease, discuss possible barriers to testing, and provide guidance on how to manage the disease.

In Guangxi, Hainan, and Fujian Province in southern China, β-thalassemia is a frequent monogenic hereditary disorder that is primarily defined by hemolytic anemia brought on by inefficient erythropoiesis. It has been found that ineffective erythropoiesis in β-thalassemia is closely associated with a high accumulation of Reactive oxygen species, a product of oxidative stress, in erythroid cells. During recent years, ferroptosis is an iron-dependent lipid peroxidation that involves abnormalities in lipid and iron metabolism as well as reactive oxygen species homeostasis. It is a recently identified kind of programmed cell death. β-thalassemia patients experience increased iron release from reticuloendothelial cells and intestinal absorption of iron, ultimately resulting in iron overload. Additionally, the secretion of Hepcidin is inhibited in these patients. What counts is both ineffective erythropoiesis and ferroptosis in β-thalassemia are intricately linked to the iron metabolism and Reactive oxygen species homeostasis. Consequently, to shed further light on the pathophysiology of β-thalassemia and propose fresh ideas for its therapy, this paper reviews ferroptosis, ineffective erythropoiesis, and the way they interact. [ABSTRACT FROM AUTHOR]

The β-thalassemias are inherited genetic disorders affecting the hematopoietic system. In β-thalassemias, more than 350 mutations of the adult β-globin gene cause the low or absent production of adult hemoglobin (HbA). A clinical parameter affecting the physiology of erythroid cells is the excess of free α-globin. Possible experimental strategies for a reduction in excess free α-globin chains in β-thalassemia are CRISPR-Cas9-based genome editing of the β-globin gene, forcing “de novo” HbA production and fetal hemoglobin (HbF) induction. In addition, a reduction in excess free α-globin chains in β-thalassemia can be achieved by induction of the autophagic process. This process is regulated by the Unc-51-like kinase 1 (Ulk1) gene. The interplay with the PI3K/Akt/TOR pathway, with the activity of the α-globin stabilizing protein (AHSP) and the involvement of microRNAs in autophagy and Ulk1 gene expression, is presented and discussed in the context of identifying novel biomarkers and potential therapeutic targets for β-thalassemia.

Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.

Khaled M Musallam,1 Ali T Taher,2 Antonis Kattamis,3 Kevin HM Kuo,4 Sujit Sheth,5 Maria Domenica Cappellini6 1Thalassemia Center, Burjeel Medical City, Abu Dhabi, United Arab Emirates; 2Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 3First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece; 4Division of Hematology, University of Toronto, Toronto, ON, Canada; 5Division of Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; 6Department of Clinical Sciences and Community, University of Milan, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, ItalyCorrespondence: Maria Domenica Cappellini, Department of Clinical Sciences and Community, University of Milan, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, 20122, Italy, Tel + 39 02 5503 3752, Email maria.cappellini@unimit.itAbstract: Over the past decade, evidence has been mounting on the detrimental clinical sequelae of untreated anemia in patients with non-transfusion-dependent β-thalassemia (NTDT). There are no pharmacologic agents that are specifically approved for the management of anemia in NTDT, and available options such as splenectomy, transfusion therapy, and hydroxyurea each come with their own shortcomings, especially for long-term use. Luspatercept is an erythroid maturation agent that has been evaluated in a Phase 2, randomized trial and showed a significant benefit in raising hemoglobin level by at least 1 g/dL in adults with NTDT and a baseline hemoglobin level ≤ 10 g/dL. These data led to luspatercept’s approval by the European Commission for the treatment of anemia in adults with NTDT and presents the first evidence-based approach for a novel agent that is able to ameliorate anemia in this patient population.Keywords: anemia, ineffective erythropoiesis, iron, management, thalassemia, transfusion

Myelodysplastic syndrome (MDS) is a heterogeneous group of bone marrow stem cell disorders characterized by ineffective hematopoiesis and cytopenias, most commonly anemia. Red cell transfusion therapy for anemia in MDS results in iron overload, correlating with reduced overall survival. Whether the treatment of iron overload benefits MDS patients remains controversial. We evaluate underlying iron-related pathophysiology and the effect of iron chelation using deferiprone on erythropoiesis in NUP98-HOXD13 transgenic mice, a highly penetrant well-established MDS mouse model. Our results characterize an iron overload phenotype with aberrant erythropoiesis in these mice which was reversed by deferiprone-treatment. Serum erythropoietin levels decreased while erythroblast erythropoietin receptor expression increased in deferiprone-treated MDS mice. We demonstrate, for the first time, normalized expression of the iron chaperones Pcbp1 and Ncoa4 and increased ferritin stores in late-stage erythroblasts from deferiprone-treated MDS mice, evidence of aberrant iron trafficking in MDS erythroblasts. Importantly, erythroblast ferritin is increased in response to deferiprone, correlating with decreased erythroblast ROS. Finally, we confirmed increased expression of genes involved in iron uptake, sensing, and trafficking in stem and progenitor cells from MDS patients. Taken together, our findings provide evidence that erythroblast-specific iron metabolism is a novel potential therapeutic target to reverse ineffective erythropoiesis in MDS.

Luspatercept has been shown to act as a ligand trap, selectively suppressing the deleterious effects of GDF11 that blocks terminal erythroid maturation, restoring normal erythroid differentiation and improving anemia in animal models of β-thalassemia. Effective doses of luspatercept achieved hemoglobin increase within 7 days of the first dose, and plasma half-life supports subcutaneously administration every 21 days in adults with β-thalassemia. A Phase 3, placebo-controlled 1-year study with starting dose of 1.0 up to 1.25 mg/kg every 21 days achieved ≥33% reduction in red cell transfusion volume in 21.4% of adult transfusion-dependent β-, HbE/β-thalassemia patients on luspatercept vs. 4.5% on placebo over a fixed 12-week period, and 41.1% of patients in luspatercept vs. 2.7% placebo in any 24-week period. Luspatercept allowed ≥1.0 and ≥1.5 g/dL increase in hemoglobin from baseline in 77% and 52.1% of adult non-transfusion-dependent β-, HbE/β-thalassemia patients vs. 0% placebo over a 12-week interval. Although not significant, a greater improvement in patient-reported outcomes was observed with luspatercept. Luspatercept had a manageable safety profile with notable adverse effects of venous thromboembolism in 3.6% of transfusion-dependent β-thalassemia vs. 0.9% of placebo and extramedullary hematopoiesis in 6% of non-transfusion-dependent β-thalassemia vs. 2% of placebo. The pediatric study started patients’ enrollment.

Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II. [ABSTRACT FROM AUTHOR]

Summary: Beta‐thalassaemia is an inherited haemoglobin disorder characterised by ineffective erythropoiesis (IE). The detailed pathogenesis of IE remains unclear. In this study, we used single‐cell RNA sequencing (scRNA‐seq) to examine IE in Th3/+ β‐thalassaemic mice. The results showed that the erythroid group was remarkably expanded, and genes involved in biological processes such as iron metabolism, haeme synthesis, protein folding, and response to heat were significantly upregulated from erythroid progenitors to reticulocytes in β‐thalassaemic mice. In particular, we identified a unique cell population close to reticulocytes, named ThReticulocytes, characterised by a high level of heat shock protein 70 (Hsp70) expression and dysregulation of iron metabolism and haeme synthesis signalling. Treatment of β‐thalassaemic mice with the haeme oxygenase inhibitor tin‐mesoporphyrin effectively improved the iron disorder and IE, and the ThReticulocyte population and Hsp70 expression were significantly suppressed. This study revealed in detail the progression of IE at the single‐cell level and possibly provided clues to find therapeutic targets in thalassaemia. [ABSTRACT FROM AUTHOR]

Luspatercept has recently been approved for the treatment of beta-thalassemia and its use in clinical practice has been increasing. As it is the first erythroid maturation drug available for this diagnosis, the expertise about its use is still limited. To address this point, and to promote awareness and guide the clinical use of luspatercept in beta-thalassemia, this paper was developed as a consensus by experts from the Italian Society of Thalassemia and Hemoglobinopathies (SITE). After a brief presentation of the core features of luspatercept, a comprehensive set of questions is addressed, covering relevant aspects for the practical management of this new therapeutic option. [ABSTRACT FROM AUTHOR]

Luspatercept has been shown to act as a ligand trap, selectively suppressing the deleterious effects of GDF11 that blocks terminal erythroid maturation, restoring normal erythroid differentiation and improving anemia in animal models of β-thalassemia. Effective doses of luspatercept achieved hemoglobin increase within 7 days of the first dose, and plasma half-life supports subcutaneously administration every 21 days in adults with β-thalassemia. A Phase 3, placebo-controlled 1-year study with starting dose of 1.0 up to 1.25 mg/kg every 21 days achieved ≥33% reduction in red cell transfusion volume in 21.4% of adult transfusion-dependent β-, HbE/β-thalassemia patients on luspatercept vs. 4.5% on placebo over a fixed 12-week period, and 41.1% of patients in luspatercept vs. 2.7% placebo in any 24-week period. Luspatercept allowed ≥1.0 and ≥1.5 g/dL increase in hemoglobin from baseline in 77% and 52.1% of adult non-transfusion-dependent β-, HbE/β-thalassemia patients vs. 0% placebo over a 12-week interval. Although not significant, a greater improvement in patient-reported outcomes was observed with luspatercept. Luspatercept had a manageable safety profile with notable adverse effects of venous thromboembolism in 3.6% of transfusion-dependent β-thalassemia vs. 0.9% of placebo and extramedullary hematopoiesis in 6% of non-transfusion-dependent β-thalassemia vs. 2% of placebo. The pediatric study started patients’ enrollment. [ABSTRACT FROM AUTHOR]

Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta‐thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT‐associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often‐serious disease‐associated complications. However, appropriate follow‐up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept‐associated erythroid expansion. [ABSTRACT FROM AUTHOR]

Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders. [ABSTRACT FROM AUTHOR]

One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia, abnormal erythropoiesis has been observed in malaria patients and may contribute significantly to anemia. The interaction between inadequate erythropoiesis and Plasmodium parasite infection, which partly occurs in the bone marrow, has been poorly investigated to date. However, recent findings may provide new insights. This review outlines clinical and experimental studies describing different aspects of ineffective erythropoiesis and dyserythropoiesis observed in malaria patients and in animal or in vitro models. We also highlight the various human and parasite factors leading to erythropoiesis disorders and discuss the impact that Plasmodium parasites may have on the suppression of erythropoiesis. [ABSTRACT FROM AUTHOR]

Background: Neonatal hemochromatosis causes acute liver failure during the neonatal period, mostly due to gestational alloimmune liver disease (GALD). Thalassemia causes hemolytic anemia and ineffective erythropoiesis due to mutations in the globin gene. Although neonatal hemochromatosis and thalassemia have completely different causes, the coexistence of these diseases can synergistically exacerbate iron overload. We report that a newborn with εγδβ-thalassemia developed neonatal hemochromatosis, which did not respond to iron chelators and rapidly worsened, requiring living-donor liver transplantation.Case Presentation: A 1-day-old Japanese boy with hemolytic anemia and targeted red blood cells was diagnosed with εγδβ-thalassemia by genetic testing, and required frequent red blood cell transfusions. At 2 months after birth, exacerbation of jaundice, grayish-white stool, and high serum ferritin levels were observed, and liver biopsy showed iron deposition in hepatocytes and Kupffer cells. Magnetic resonance imaging scans showed findings suggestive of iron deposits in the liver, spleen, pancreas, and bone marrow. The total amount of red blood cell transfusions administered did not meet the criteria for post-transfusion iron overload. Administration of an iron-chelating agent was initiated, but iron overload rapidly progressed to liver failure without improvement in jaundice and liver damage. He underwent living-donor liver transplantation from his mother, after which iron overload disappeared, and no recurrence of iron overload was observed. Immunohistochemical staining for C5b-9 in the liver was positive. Serum hepcidin levels were low and serum growth differentiation factor-15 levels were high prior to living-donor liver transplantation.Conclusions: We reported that an infant with εγδβ-thalassemia developed NH due to GALD, and that coexistence of ineffective erythropoiesis in addition to erythrocyte transfusions may have exacerbated iron overload. Low serum hepcidin levels, in this case, might have been caused by decreased hepcidin production arising from fetal liver damage due to neonatal hemochromatosis and increased hepcidin-inhibiting hematopoietic mediators due to the ineffective hematopoiesis observed in thalassemia. [ABSTRACT FROM AUTHOR]

Non-transfusion-dependent thalassemia (NTDT) has been considered less severe than its transfusion-dependent variants. The most common forms of NTDT include β-thalassemia intermedia, hemoglobin E/beta thalassemia, and hemoglobin H disease. Patients with NTDT develop several clinical complications, despite their regular transfusion independence. Ineffective erythropoiesis, iron overload, and hypercoagulability are pathophysiological factors that lead to morbidities in these patients. Therefore, an early and accurate diagnosis of NTDT is essential to ascertaining early interventions. Currently, several conventional management options are available, with guidelines suggested by the Thalassemia International Federation, and novel therapies are being developed in light of the advancement of the understanding of this disease. This review aimed to increase clinicians' awareness of NTDT, from its basic medical definition and genetics to its pathophysiology. Specific complications to NTDT were reviewed, along with the risk factors for its development. The indications of different therapeutic options were outlined, and recent advancements were reviewed. [ABSTRACT FROM AUTHOR]

• Ineffective erythropoiesis (IE) plays a significant role in the pathophysiology of β-thalassemia; however, its precise molecular mechanisms are not well understood. • BNIP3 can induce cell death through an autophagy-dependent pathway under hypoxic conditions. • Inhibiting the expression of BNIP3 may present a new therapeutic strategy for targeting IE in patients with b-thalassemia. Ineffective erythropoiesis (IE) and the premature destruction of erythroblasts play important roles in the pathophysiology of β-thalassemia. Accumulating evidence suggests that the pathology of IE is associated with multiple factors, including apoptosis and reactive oxygen species (ROS) generation. A previous study also indicated that dysregulation of mitochondrial homeostasis and autophagy contributes to IE in the bone marrow of β-thalassemia patients. However, the precise molecular mechanism underlying mitochondria-mediated IE remains poorly understood. Here, we propose that the increased activity of adenovirus E1B 19-kDa-interacting protein 3 (BNIP3) promotes mitochondrial fragmentation, autophagy, and apoptosis of erythroid progenitors in β-thalassemia. The present hypothesis is based on the published literature showing that 1) BNIP3 is involved in mitochondrial dysfunction and autophagy, 2) BNIP3 expression is regulated by p53 and hypoxia-inducible factor-1α, and 3) BNIP3 expression can be attenuated by a number of approaches. Our hypothesis can be verified through both in vitro and in vivo experiments. BNIP3 could be a promising therapeutic target for minimizing the pathophysiology of IE and reducing ROS generation associated with mitochondrial dysfunction in patients with β-thalassemia. [ABSTRACT FROM AUTHOR]

Abstract Background Although precursor‐targeted immune‐mediated anemia (PIMA) is thought to be caused by immune targeting of erythroid precursors (nucleated RBCs, nRBCs), its pathogenesis is unknown. Immunoglobulin G (IgG) or phosphatidylserine (PS) may promote nRBC destruction in PIMA. Hypothesis Dogs with PIMA have increased nRBC IgG and PS, and dogs with immune‐mediated hemolytic anemia (IMHA) have increased RBC PS compared to healthy dogs. Animals Blood from 20 healthy dogs and from dogs with IMHA (11) or other (non‐IMHA) conditions (9), and marrow aspirates with or without blood from 10 healthy dogs and from dogs with PIMA (17) or other (non‐IMHA, non‐PIMA) conditions (7). Methods Marrow nRBC stages were separated by density gradient. Flow cytometry was used to assess the percentage of RBCs or nRBCs with increased IgG or PS. Results Red blood cell (RBC) IgG positivity was increased in 9/11 IMHA dogs and 0/9 non‐IMHA dogs. Red blood cell PS positivity was increased in 10/11 IMHA dogs and 2/9 non‐IMHA dogs. Five of 17 PIMA dogs had increased nRBC IgG positivity in mid‐ or late‐stage fractions, whereas all 7 non‐PIMA dogs were negative. Mid‐ and late‐stage erythroid precursor PS was significantly higher in PIMA dogs compared to healthy dogs. Five of 14 PIMA dogs had increased RBC IgG positivity. Conclusions Immunoglobulin G and PS may promote destruction of nRBCs in PIMA dogs; PS may promote destruction of RBCs in IMHA dogs.

β-Thalassemia is one of the most common genetically inherited disorders worldwide, and it is characterized by defective β-globin chain synthesis leading to reduced or absent β-globin chains. The excess α-globin chains are the key factor leading to the death of differentiating erythroblasts in a process termed ineffective erythropoiesis, leading to anemia and associated complications in patients. The mechanism of ineffective erythropoiesis in β-thalassemia is complex and not fully understood. Autophagy is primarily known as a cell recycling mechanism in which old or dysfunctional proteins and organelles are digested to allow recycling of constituent elements. In late stage, erythropoiesis autophagy is involved in the removal of mitochondria as part of terminal differentiation. Several studies have shown that autophagy is increased in earlier erythropoiesis in β-thalassemia erythroblasts, as compared to normal erythroblasts. This review summarizes what is known about the role of autophagy in β-thalassemia erythropoiesis and shows that modulation of autophagy and its interplay with apoptosis may provide a new therapeutic route in the treatment of β-thalassemia. Literature was searched and relevant articles were collected from databases, including PubMed, Scopus, Prospero, Clinicaltrials.gov, Google Scholar, and the Google search engine. Search terms included: β-thalassemia, ineffective erythropoiesis, autophagy, novel treatment, and drugs during the initial search. Relevant titles and abstracts were screened to choose relevant articles. Further, selected full-text articles were retrieved, and then, relevant cross-references were scanned to collect further information for the present review. [ABSTRACT FROM AUTHOR]

Beta‐thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have migrated there owing to demographic migration, β‐thalassaemia can now be detected in areas other than malaria‐endemic areas. Every year, an estimated 300 000–500 000 infants, the vast majority of whom are from developing countries, are born with a severe haemoglobin anomaly. Currently, some basic techniques, which include iron chelation therapy, hydroxyurea, blood transfusion, splenectomy and haematopoietic stem cell transplantation, are being used to manage thalassaemia patients. Despite being the backbone of treatment, traditional techniques have several drawbacks and limitations. Ineffective erythropoiesis, correction of globin chain imbalance and adjustment of iron metabolism are some of the innovative treatment methods that have been developed in the care of thalassaemia patients in recent years. Moreover, regulating the expression of B‐cell lymphoma/leukaemia 11A and sex‐determining region Y‐box through the enhanced expression of micro RNAs can also be considered putative targets for managing haemoglobinopathies. This review focuses on the biological basis of β‐globin gene production, the pathophysiology of β‐thalassaemia and the treatment options that have recently been introduced. [ABSTRACT FROM AUTHOR]

Genetic mutations in the β-globin gene lead to a decrease or removal of the β-globin chain, causing the build-up of unstable alpha-hemoglobin. This condition is referred to as beta-thalassemia (BT). The present treatment strategies primarily target the correction of defective erythropoiesis, with a particular emphasis on gene therapy and hematopoietic stem cell transplantation. However, the presence of inefficient erythropoiesis in BT bone marrow (BM) is likely to disturb the previously functioning BM microenvironment. This includes accumulation of various macromolecules, damage to hematopoietic function, destruction of bone cell production and damage to osteoblast(OBs), and so on. In addition, the changes of BT BM microenvironment may have a certain correlation with the occurrence of hematological malignancies. Correction of the microenvironment can be achieved through treatments such as iron chelation, antioxidants, hypoglycemia, and biologics. Hence, This review describes damage in the BT BM microenvironment and some potential remedies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Yao, Zhang, Yang, Ni and Wang.)

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.

Congenital dyserythropoietic anemia type II (CDA II) is an inherited autosomal recessive blood disorder which belongs to the wide group of ineffective erythropoiesis conditions. It is characterized by mild to severe normocytic anemia, jaundice, and splenomegaly owing to the hemolytic component. This often leads to liver iron overload and gallstones. CDA II is caused by biallelic mutations in the SEC23B gene. In this study, we report 9 new CDA II cases and identify 16 pathogenic variants, 6 of which are novel. The newly reported variants in SEC23B include three missenses (p.Thr445Arg, p.Tyr579Cys, and p.Arg701His), one frameshift (p.Asp693GlyfsTer2), and two splicing variants (c.1512-2A>G, and the complex intronic variant c.1512-3delinsTT linked to c.1512-16_1512-7delACTCTGGAAT in the same allele). Computational analyses of the missense variants indicated a loss of key residue interactions within the beta sheet and the helical and gelsolin domains, respectively. Analysis of SEC23B protein levels done in patient-derived lymphoblastoid cell lines (LCLs) showed a significant decrease in SEC23B protein expression, in the absence of SEC23A compensation. Reduced SEC23B mRNA expression was only detected in two probands carrying nonsense and frameshift variants; the remaining patients showed either higher gene expression levels or no expression changes at all. The skipping of exons 13 and 14 in the newly reported complex variant c.1512-3delinsTT/c.1512-16_1512-7delACTCTGGAAT results in a shorter protein isoform, as assessed by RT-PCR followed by Sanger sequencing. In this work, we summarize a comprehensive spectrum of SEC23B variants, describe nine new CDA II cases accounting for six previously unreported variants, and discuss innovative therapeutic approaches for CDA II.

Background: The presence of Plasmodium vivax malaria parasites in the human bone marrow (BM) is still controversial. However, recent data from a clinical case and experimental infections in splenectomized nonhuman primates unequivocally demonstrated the presence of parasites in this tissue.Methods: In the current study, we analyzed BM aspirates of 7 patients during the acute attack and 42 days after drug treatment. RNA extracted from CD71+ cell suspensions was used for sequencing and transcriptomic analysis.Results: We demonstrated the presence of parasites in all patients during acute infections. To provide further insights, we purified CD71+ BM cells and demonstrated dyserythropoiesis and inefficient erythropoiesis in all patients. In addition, RNA sequencing from 3 patients showed that genes related to erythroid maturation were down-regulated during acute infections, whereas immune response genes were up-regulated.Conclusions: This study thus shows that during P. vivax infections, parasites are always present in the BM and that such infections induced dyserythropoiesis and ineffective erythropoiesis. Moreover, infections induce transcriptional changes associated with such altered erythropoietic response, thus highlighting the importance of this hidden niche during natural infections. [ABSTRACT FROM AUTHOR]

Rationale and Objectives: Molecular studies have shown the changes in bone marrow fat in relation to altered hematopoiesis. This study aims to investigate the changes in the bone marrow fat in patients affected by β-thalassemia by using chemical shift-encoded (CSE)-MRI.Materials and Methods: Twenty-three subjects, comprising of six healthy (17-31 years old) and 17 β-thalassemia subjects (19-39 years old), were scanned using a multiecho fast low angle shot sequence (0.94 × 0.94 × 3.00 mm3) and a stimulated echo acquisition mode sequence using 3T MRI. Bone marrow proton density fat fraction (PDFF) was quantified in the left femur of each subject. Regression and Bland-Altman analysis were used to analyze agreement between CSE-MRI and 1H-MRS. PDFF distribution was analyzed using Hartigan's dip test and the computed Wasserstein distances. Jonckheere-Terpstra trend analysis was performed to evaluate the effect of disease severity on PDFF distribution.Results: An excellent agreement was found between PDFF measured using CSE-MRI with 1H-MRS (R2 = 0.91; bias =-1.41%). Healthy subjects showed left-skewed or bimodal PDFF distribution while β-thalassemia subjects showed bimodal, normal or right-skewed distribution. Jonckheere-Terpstra test shows that PDFF distribution was increasingly different from the norm as disease severity increased (TJT = 166.0, z = 3.806, p < 0.05). Increase in variability of PDFF distribution within each subject group was also seen with increasing disease severity (TJT = 169.0, z = 3.971, p < 0.05).Conclusion: CSE-MRI is a promising tool to demonstrate spatial changes and variability in marrow fat distribution, resulting from ineffective erythropoiesis. [ABSTRACT FROM AUTHOR]

Luspatercept has recently been approved for the treatment of beta-thalassemia and its use in clinical practice has been increasing. As it is the first erythroid maturation drug available for this diagnosis, the expertise about its use is still limited. To address this point, and to promote awareness and guide the clinical use of luspatercept in beta-thalassemia, this paper was developed as a consensus by experts from the Italian Society of Thalassemia and Hemoglobinopathies (SITE). After a brief presentation of the core features of luspatercept, a comprehensive set of questions is addressed, covering relevant aspects for the practical management of this new therapeutic option.

Background: Although precursor‐targeted immune‐mediated anemia (PIMA) is thought to be caused by immune targeting of erythroid precursors (nucleated RBCs, nRBCs), its pathogenesis is unknown. Immunoglobulin G (IgG) or phosphatidylserine (PS) may promote nRBC destruction in PIMA. Hypothesis: Dogs with PIMA have increased nRBC IgG and PS, and dogs with immune‐mediated hemolytic anemia (IMHA) have increased RBC PS compared to healthy dogs. Animals Blood from 20 healthy dogs and from dogs with IMHA (11) or other (non‐IMHA) conditions (9), and marrow aspirates with or without blood from 10 healthy dogs and from dogs with PIMA (17) or other (non‐IMHA, non‐PIMA) conditions (7). Methods: Marrow nRBC stages were separated by density gradient. Flow cytometry was used to assess the percentage of RBCs or nRBCs with increased IgG or PS. Results: Red blood cell (RBC) IgG positivity was increased in 9/11 IMHA dogs and 0/9 non‐IMHA dogs. Red blood cell PS positivity was increased in 10/11 IMHA dogs and 2/9 non‐IMHA dogs. Five of 17 PIMA dogs had increased nRBC IgG positivity in mid‐ or late‐stage fractions, whereas all 7 non‐PIMA dogs were negative. Mid‐ and late‐stage erythroid precursor PS was significantly higher in PIMA dogs compared to healthy dogs. Five of 14 PIMA dogs had increased RBC IgG positivity. Conclusions: Immunoglobulin G and PS may promote destruction of nRBCs in PIMA dogs; PS may promote destruction of RBCs in IMHA dogs. [ABSTRACT FROM AUTHOR]

Introduction: β-Thalassemia/hemoglobin E represents one-half of all the clinically severe β-thalassemias worldwide. Despite similar genetic backgrounds, patients show clinical heterogeneity ranging from nearly asymptomatic to transfusion-dependent thalassemia. The underlying disease modifying factors remain largely obscure. Methods: To elucidate the correlation between ineffective erythropoiesis and β0-thalassemia/hemoglobin E (HbE) disease severity, in vitro culture of erythroid cells derived from patients with different clinical symptoms was established. Cell proliferation, viability, and differentiation were investigated. To identify potential molecular mechanisms leading to the arrested erythroid maturation, the expression levels of erythropoiesis modifying factors were measured. Results: The β0-thalassemia/HbE cells exhibited enhanced proliferation, limited differentiation, and impaired erythroid terminal maturation but did not show accelerated erythroblast differentiation and increased cell death. Erythroblasts derived from mild patients showed the highest proliferation rate with a faster cell division time, while erythroblasts derived from severe patients displayed extremely delayed erythroid maturation. Downregulation of growth differentiation factor 11 and FOXO3a was observed in mild β0-thalassemia/HbE erythroblasts, while upregulation of heat shock protein 70 and activin receptor 2A was revealed in severe erythroblasts. Discussion/Conclusion: The degree of erythroid expansion and maturation arrest contributes to the severity of β0-thalassemia/HbE patients, accounting for the disease heterogeneity. The findings suggest a restoration of erythroid maturation as a promising targeted therapy for severe patients. [ABSTRACT FROM AUTHOR]

Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders.

One of the major pathophysiologies of malaria is the development of anemia. Although hemolysis and splenic clearance are well described as causes of malarial anemia, abnormal erythropoiesis has been observed in malaria patients and may contribute significantly to anemia. The interaction between inadequate erythropoiesis and Plasmodium parasite infection, which partly occurs in the bone marrow, has been poorly investigated to date. However, recent findings may provide new insights. This review outlines clinical and experimental studies describing different aspects of ineffective erythropoiesis and dyserythropoiesis observed in malaria patients and in animal or in vitro models. We also highlight the various human and parasite factors leading to erythropoiesis disorders and discuss the impact that Plasmodium parasites may have on the suppression of erythropoiesis.

β-Thalassemia is one of the most common genetically inherited disorders worldwide, and it is characterized by defective β-globin chain synthesis leading to reduced or absent β-globin chains. The excess α-globin chains are the key factor leading to the death of differentiating erythroblasts in a process termed ineffective erythropoiesis, leading to anemia and associated complications in patients. The mechanism of ineffective erythropoiesis in β-thalassemia is complex and not fully understood. Autophagy is primarily known as a cell recycling mechanism in which old or dysfunctional proteins and organelles are digested to allow recycling of constituent elements. In late stage, erythropoiesis autophagy is involved in the removal of mitochondria as part of terminal differentiation. Several studies have shown that autophagy is increased in earlier erythropoiesis in β-thalassemia erythroblasts, as compared to normal erythroblasts. This review summarizes what is known about the role of autophagy in β-thalassemia erythropoiesis and shows that modulation of autophagy and its interplay with apoptosis may provide a new therapeutic route in the treatment of β-thalassemia. Literature was searched and relevant articles were collected from databases, including PubMed, Scopus, Prospero, Clinicaltrials.gov, Google Scholar, and the Google search engine. Search terms included: β-thalassemia, ineffective erythropoiesis, autophagy, novel treatment, and drugs during the initial search. Relevant titles and abstracts were screened to choose relevant articles. Further, selected full-text articles were retrieved, and then, relevant cross-references were scanned to collect further information for the present review.

Congenital sideroblastic anemia (CSA) is a group of disorders caused by different genetic mutations that result in low iron utilization and ineffective erythropoiesis. Current treatments are limited, and some patients do not respond to vitamin B6 therapy. Luspatercept is a novel erythropoietic maturation agent approved for adult β-thalassemia and Myelodysplastic syndromes with ring sideroblasts (MDS-RS) associated with ineffective erythropoiesis. Here we report 2 patients with CSA due to mutations in ALAS2 and SLC25A38 genes who became unresponsive after a period of treatment with vitamin B6 and iron chelators but achieved transfusion independence and a markedly reduced spleen after combination with luspatercept. [ABSTRACT FROM AUTHOR]

A 12‐year‐old spayed female Shiba Inu dog was referred to our hospital for a suspected mast cell tumor (MCT) of the bone marrow (BM). Laboratory abnormalities included severe nonregenerative anemia (packed cell volume or PCV: 12.5%; reference interval (RI): 37.3‐61.7%; reticulocytes: 35.1 × 103/µL; RI: 10‐110 × 103/µL), and a few mast cells were visualized in the blood smear examination. The BM was hypercellular with hematopoietic cells, a decreased myeloid:erythroid (M:E) ratio (0.77; RI, 0.9‐1.8), and no dysplastic hematopoietic cells. Mast cells accounted for 11.5% of the total nucleated BM cells. Neoplastic mast cells and histiocytes phagocytizing erythroid progenitor cells were occasionally noted. The dog was diagnosed with precursor‐targeted immune‐mediated anemia (PIMA) concurrent and a stage IV MCT infiltrating the BM. Multimodal treatment included toceranib, imatinib, vinblastine, lomustine (CCNU), prednisolone, cyclosporine, mycophenolate mofetil, and a blood transfusion. The dog died due to MCT progression lasting 139 days after the initial BM examination. To the best of our knowledge, this is the first report of a dog presenting with PIMA and a stage IV MCT infiltrating the BM. [ABSTRACT FROM AUTHOR]

Background: β‐thalassemia is a genetic disease that causes abnormal production of red blood cells (ineffective erythropoiesis, IE). IE is a condition known to change bone marrow composition. Purpose: To evaluate the effect of IE on the marrow fat content and fat unsaturation levels in the proximal femur using 1H‐MRS. Study Type: Prospective. Subjects: Twenty‐three subjects were included in this study, seven control and 16 β‐thalassemia subjects. Field Strength/Sequence: 3.0T; stimulated echo acquisition Mode (STEAM); magnetic resonance spectroscopy (MRS) sequence. Assessment: Multiecho MRS scans were performed in four regions of the proximal left femur of each subject, that is, diaphysis, femoral neck, femoral head, and greater trochanter. The examined regions were grouped into red (diaphysis and femoral neck) and yellow marrow regions (femoral head and greater trochanter). Statistical Tests: The Jonckheere–Terpstra test was used to evaluate the impact of increasing disease severity on bone marrow fat fraction (BMFF), marrow conversion index, and fat unsaturation index (UI). Pairwise comparison analysis was performed when a significant trend (P < 0.05) was found. K‐means clustering analysis was used to examine the clusters observed when BMFF in the red and yellow regions were studied (diaphysis against greater trochanter). Results: BMFF showed a significant decreasing trend with increasing disease severity in both red (TJT = 109.00, z = –4.414, P < 0.05) and yellow marrow regions (TJT = 108.00, z = –4.438, P < 0.05). The opposite trend was observed in UI in both bone marrow regions (red marrow: TJT = 180.5, z = 3.515, P < 0.05; yellow marrow: TJT = 155.0, z = 2.282, P = 0.05). Three distinct forms of marrow adipogenesis were found when plotting BMFF diaphysis against BMFF greater trochanter: 1) normal (centroid: 80.4%, 66.6%), 2) partial disruption (centroid: 51.1%, 16.6%), and 3) total disruption (centroid: 2.6%, 1.6%). Data Conclusion: β‐thalassemia is associated with decreased marrow fat, and increased marrow fat unsaturation level. Level of Evidence: 2 Technical Efficacy Stage: 3 [ABSTRACT FROM AUTHOR]

In Guangxi, Hainan, and Fujian Province in southern China, β-thalassemia is a frequent monogenic hereditary disorder that is primarily defined by hemolytic anemia brought on by inefficient erythropoiesis. It has been found that ineffective erythropoiesis in β-thalassemia is closely associated with a high accumulation of Reactive oxygen species, a product of oxidative stress, in erythroid cells. During recent years, ferroptosis is an iron-dependent lipid peroxidation that involves abnormalities in lipid and iron metabolism as well as reactive oxygen species homeostasis. It is a recently identified kind of programmed cell death. β-thalassemia patients experience increased iron release from reticuloendothelial cells and intestinal absorption of iron, ultimately resulting in iron overload. Additionally, the secretion of Hepcidin is inhibited in these patients. What counts is both ineffective erythropoiesis and ferroptosis in β-thalassemia are intricately linked to the iron metabolism and Reactive oxygen species homeostasis. Consequently, to shed further light on the pathophysiology of β-thalassemia and propose fresh ideas for its therapy, this paper reviews ferroptosis, ineffective erythropoiesis, and the way they interact., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Zheng, Chen, Xu and Huang.)

Iron overload comprises one of the main complications of congenital dyserythropoietic anemia type I (CDA-I). When analyzing magnetic resonance imaging T2* (MRI T2*) results in CDA patients, two previous studies reported discordant results regarding iron load in these patients. To further understand iron loading pattern in this group of patients, we analyzed MRI T2* findings in 46 CDA-I patients. Mild to moderate hepatic iron overload was detected in 28/46 (60.8%) patients. A significant correlation was found between serum ferritin and liver iron concentration (LIC). A significant correlation (p value = 0.02) was also found between the patient's age and LIC, reflecting increased iron loading over time, even in the absence of transfusion therapy. Notably, no cardiac iron overload was detected in any patient. Transfusion-naive patients had better LIC and better cardiac T2* values. These results demonstrate that a high percentage of CDA-I patients have liver iron concentration above the normal values, risking them with significant morbidity and mortality, and emphasize the importance of periodic MRI T2* studies for direct assessment of tissue iron concentration in these patients, taking age and transfusional burden into consideration. [ABSTRACT FROM AUTHOR]

For the medical practice, our manuscript acts as a signal, despite only presenting three cases which feature the association between hepatocytolysis, haemolysis and hypermagnesaemia. This clinical–biologic triad was highlighted with the workers who through the nature of their profession were exposing themselves periodically to vapours which contained copper sulphate neutralised with calcium hydroxide, a fungicide used for fruit trees. We are exclusively assessing the haematological perturbation. In this aetiological context, the generating mechanism for haemolysis is very probable biochemical, where hypercupraemia interferes with cellular antioxidant defence mechanisms. Hypothetically, the role of the redox homeostasis disorder in the intravascular destruction of erythrocytes is sustained, and particularly the coexistence of cell cytolysis in the medullary erythroid compartment, which can be assimilated with a possible ineffective erythropoiesis.

Testosterone stimulates iron-dependent erythropoiesis and suppresses hepcidin. To clarify the role of iron in mediating testosterone's effects on erythropoiesis, we induced iron deficiency in mice by feeding low iron diet. Iron-replete and iron-deficient mice were treated weekly with testosterone propionate or vehicle for 3 weeks. Testosterone treatment increased red cell count in iron-replete mice, but, surprisingly, testosterone reduced red cell count in iron-deficient mice. Splenic stress erythropoiesis was stimulated in iron-deficient mice relative to iron-replete mice, and further increased by testosterone treatment, as indicated by the increase in red pulp area, the number of nucleated erythroblasts, and expression levels of TfR1, GATA1, and other erythroid genes. Testosterone treatment of iron-deficient mice increased the ratio of early-to-late erythroblasts in the spleen and bone marrow, and serum LDH level, consistent with ineffective erythropoiesis. In iron-deficient mice, erythropoietin levels were higher but erythropoietin-regulated genes were generally downregulated relative to iron-replete mice, suggesting erythropoietin resistance. Conclusion: Testosterone treatment stimulates splenic stress erythropoiesis in iron-replete as well as iron-deficient mice. However, testosterone worsens anemia in iron-deficient mice because of ineffective erythropoiesis possibly due to erythropoietin resistance associated with iron deficiency. Iron plays an important role in mediating testosterone's effects on erythropoiesis. [ABSTRACT FROM AUTHOR]