bims-conane Biomed News
on Congenital anemias
Issue of 2024–11–03
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Erythropoiesis and Gene Expression Analysis in Erythroid Progenitor Cells Derived from Patients with Hemoglobin H/Constant Spring Disease.
  2. Hemoglobinopathies in the Neonate.
  3. Efficacy and safety of thalidomide in patients with β-thalassemia intermedia and major.
  4. Impact of HbE mutation on the clinical severity of HbH disease: A multicentre study from Thailand.
  5. The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels.
  6. Overview on Hereditary Spherocytosis Diagnosis.
  7. Impact of met-haemoglobin and oxidative stress on endothelial function in patients with transfusion dependent β-thalassemia.
  8. Immunoregulation role of the erythroid cells.
  1. Int J Mol Sci. 2024 Oct 19. pii: 11246. [Epub ahead of print]25(20):
    Erythropoiesis and Gene Expression Analysis in Erythroid Progenitor Cells Derived from Patients with Hemoglobin H/Constant Spring Disease.
    Narawich Wongkhammul, Pinyaphat Khamphikham, Siripong Tongjai, Adisak Tantiworawit, Kanda Fanhchaksai, Somsakul Pop Wongpalee, Alisa Tubsuwan, Supawadee Maneekesorn, Pimlak Charoenkwan.
      Hemoglobin H/Constant Spring (Hb H/CS) disease represents a form of non-deletional Hb H disease characterized by chronic hemolytic anemia that ranges from moderate to severe and may lead to transfusion-dependent thalassemia. To study the underlying mechanisms of this disease, we conducted an analysis of erythropoiesis and gene expression in erythroid progenitor cells derived from CD34+ hematopoietic stem/progenitor cells from patients with Hb H/CS disease and normal controls. Twelve patients with Hb H/CS disease and five normal controls were enrolled. Peripheral blood samples were collected to isolate CD34+ hematopoietic stem/progenitor cells for the analysis of cell proliferation and differentiation. Six samples from patients with Hb H/CS disease and three controls were subsequently studied for gene expression by next generation sequencing analysis. Erythroid progenitor cells derived from patients with Hb H/CS disease exhibited a trend towards increased rates of erythroid proliferation and decreased cell viability compared to those from controls. Moreover, erythroid progenitor cells derived from patients with Hb H/CS disease demonstrated delayed terminal differentiation. Gene expression profiling revealed elevated levels of genes encoding molecular chaperones, including the heat shock protein genes (HSPs) and the chaperonin containing TCP-1 subunit genes (CCTs) in the Hb H/CS disease group. In summary, erythroid progenitor cells derived from patients with Hb H/CS disease exhibit a trend towards heightened erythroid proliferation, diminished cell viability, and delayed terminal differentiation. Additionally, the increased expression of genes encoding molecular chaperones was observed, providing information on potential underlying pathophysiological mechanisms.
    Keywords:  erythropoiesis; gene expression; hemoglobin H/Constant Spring disease; molecular chaperone; α-thalassemia
    DOI:  https://doi.org/10.3390/ijms252011246
  2. Neoreviews. 2024 Nov 01. 25(11): e720-e728
    Hemoglobinopathies in the Neonate.
    Katrina Blankenhorn, Kaitlin Strumph.
      Hemoglobinopathies in neonates constitute a group of disorders influenced by genetic mutations in the human globin genes. They are often broadly categorized into quantitative defects or qualitative defects, though they are not mutually exclusive. In quantitative defects, the mutation causes insufficient production of a normal globin chain, which can range from no production to mild deficiency. These are typically referred to as thalassemias. In qualitative defects, the structure of the hemoglobin is altered. The most common structural hemoglobinopathy is sickle cell disease. During fetal development, distinct globin chains are synthesized, which undergo a progressive switch to adult globin chains perinatally. This affects the timing of the clinical presentation of these disorders and thus, our ability to diagnose them. In this review, we focus on the epidemiology, genetic causes, clinical presentation, and general overview and management of common hemoglobin disorders that may be encountered in the neonatal period.
    DOI:  https://doi.org/10.1542/neo.25-11-e720
  3. Medicine (Baltimore). 2024 Oct 25. 103(43): e40328
    Efficacy and safety of thalidomide in patients with β-thalassemia intermedia and major.
    Wendong Ju, Gaomin Din, Jun Huang, Minmin Zheng, Xiaoyou Wang, Lingling Liu, Li Wang, Suling Xuan, Weiqun Xiao, Ang Chen.
      To investigate the short-term and long-term efficacy and safety of thalidomide in the treatment of intermediate and severe β-thalassemia. We analyzed patients with intermediate and severe β-thalassemia treated at our hospital from February 2019 to February 2024. Patients who received treatment for more than 3 months were included. The efficacy of thalidomide was assessed by comparing changes in hemoglobin (Hb), ferritin, bilirubin, and Hb electrophoresis before and after treatment. Adverse drug reactions during treatment were also recorded. A total of 42 β-thalassemia patients were included, with thalidomide dosages ranging from 75 to 150 mg/d. The response rates at 1, 3, and 6 months of treatment were 73.8% (31/42), 75.0% (24/32), and 94.7% (18/19), respectively. The increase in Hb levels was primarily attributed to fetal hemoglobin (HbF). After 1 month of treatment, the HbF percentage increased from a baseline of 34.04 ± 27.58% to 56.25 ± 28.40% (P < .001). At 3 and 6 months, HbF further increased to 67.21 ± 27.12% (P < .001) and 73.93 ± 22.96% (P < .001), respectively. The average duration of thalidomide treatment was 25.3 ± 9.2 months (range: 4-60 months), with 6 patients treated for over 60 months and 18 patients for over 48 months. Two homozygous patients who failed thalidomide treatment achieved Hb levels above 100 g/L and discontinued transfusion therapy after 3 months of hydroxyurea treatment. The most common adverse reaction was somnolence, which was mild and tolerable. Thalidomide demonstrates significant and sustained therapeutic effects in β-thalassemia patients. The adverse reactions are mild and tolerable, allowing patients to continue treatment.
    DOI:  https://doi.org/10.1097/MD.0000000000040328
  4. Br J Haematol. 2024 Oct 30.
    Impact of HbE mutation on the clinical severity of HbH disease: A multicentre study from Thailand.
    Red Blood Cell Disorders Study Group
      Haemoglobin (Hb) H disease and HbH disease with co-inherited HbE mutation are the most prevalent forms of α-thalassaemia in Southeast Asia. Data were limited when comparing clinical phenotypes between these two patient groups. We conducted a Thai multicentre study and enrolled 588 patients [median (IQR) age 13.0 (6.7-20.3) years], including those with deletional HbH disease with (n = 47) and without (n = 187) co-inherited HbE mutation and non-deletional HbH disease with (n = 101) and without (n = 253) co-inherited HbE mutation. Patients with HbH disease with co-inherited HbE mutation suffered more severe manifestations than those without. This observation was more pronounced in patients with non-deletional HbH disease. A greater proportion of patients with non-deletional HbH disease with co-inherited HbE mutation (43.6%) eventually required regular transfusions compared to those without (30.4%, p = 0.019). Among those with non-deletional HbH disease who did not require regular transfusions, Hb levels were lower in patients with co-inherited HbE mutation [8.1 (7.2-8.6) vs. 8.8 (8.2-9.5) g/dL, p < 0.001]. Among patients requiring regular transfusions who underwent splenectomy, 11/12 patients with non-deletional HbH disease stopped transfusion compared with 1/3 in non-deletional HbH disease with co-inherited HbE mutation group (p = 0.024). These findings provide insights for the clinical monitoring and management of HbH disease in the region.
    Keywords:  HbH; HbH disease; HbH disease with co‐inherited HbE; alpha‐thalassaemia; haemoglobin H disease
    DOI:  https://doi.org/10.1111/bjh.19869
  5. Annu Rev Physiol. 2024 Oct 30.
    The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels.
    Virgilio L Lew.
      Calcium ions mediate the volume homeostasis of human red blood cells (RBCs) in the circulation. The mechanism by which calcium ions affect RBC hydration states always follows the same sequence. Deformation of RBCs traversing capillaries briefly activates mechanosensitive PIEZO1 channels, allowing Ca2+ influx down its steep inward gradient transiently overcoming the calcium pump and elevating [Ca2+]i. Elevated [Ca2+]i activates the Ca2+-sensitive Gardos channels, inducing KCl loss and cell dehydration, a sequence operated with infinite variations in vivo and under experimental conditions. The selected health and disease themes for this review focus on landmark experimental results that led to the development of highly constrained models of the circulatory changes in RBCs homeostasis. Based on model predictions, a new perspective emerged, pointing to PIEZO1 dysfunction as the main trigger in the formation of the profoundly dehydrated irreversible sickle cells, the main pathogenic participants in vaso-occlusion, the root cause of sickle cell disease.
    DOI:  https://doi.org/10.1146/annurev-physiol-022724-105119
  6. Int J Lab Hematol. 2024 Oct 28.
    Overview on Hereditary Spherocytosis Diagnosis.
    A Polizzi, L P Dicembre, C Failla, T Di Matola, M Moretti, S Chiatamone Ranieri, F Papa, A M Cenci, M Buttarello.
       INTRODUCTION: Hereditary spherocytosis (HS) is a congenital haemolytic disorder, resulting from plasma membrane protein deficiency of red blood cells (RBCs). Typical pathological signs are anemia, jaundice, and splenomegaly; in newborns, jaundice is the main symptom.
    MATERIAL AND METHODS: This study focused on the state of art about the HS diagnosis, from traditional to innovative methods, including diagnostic algorithms that can be applied for pediatric and adult patients, for different laboratory diagnostic levels.
    RESULTS: The first erythrocyte parameters used for HS diagnosis were the mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), and red blood cell distribution width (RDW); nowadays new parameters are used in blood cell counter. Advia analyzers (Siemens Medical Solutions) supply the hyper-dense cell percentage (% Hyper), which reflects the red blood cells hyperchromia. Sysmex instruments (i.e. XT-4000i, XE-5000, XN-Series) provide the MicroR, that is the percentage of erythrocytes smaller than 60 fL, Hypo-He, which is the percentage of erythrocytes with a content of hemoglobin less than 17 pg and % Hyper-He, which represents the percentage of RBC with cellular hemoglobin content higher than 49 pg. CELL-DYN Sapphire (Abbott Diagnostics) introduced the HPR parameter (% HPR), which represents the erythrocytes with hemoglobin > 410 g/L. Beckman Coulter instruments supply the mean sphered corpuscular volume (MSCV), which is the average volume of all erythrocytes, including mature erythrocytes and reticulocytes. Other reference tests for screening and diagnosis of HS are the acidified glycerol lysis test (AGLT), the eosin-5-maleimide (EMA) binding test and genetic testing by next-generation sequencing.
    CONCLUSIONS: The diagnostic workup of hereditary spherocytosis could be improved thanks to all the available tests, including new molecular tools. However, it requires synergy between clinicians and laboratory staff, evaluating clinical manifestations, all available data related to the disease and the prognosis to fill the diagnostic gaps in the near future.
    Keywords:  RBC; RBC membrane; hemolytic anemia; morphology; reticulocytes
    DOI:  https://doi.org/10.1111/ijlh.14376
  7. Sci Rep. 2024 10 25. 14(1): 25328
    Impact of met-haemoglobin and oxidative stress on endothelial function in patients with transfusion dependent β-thalassemia.
    Maha Abubakr Feissal Rabie, Sanaa A El Benhawy, Inas M Masoud, Amal R R Arab, Sally A M Saleh.
      Transfusion dependent β-thalassemia is a genetic blood disorder characterized by chronic anaemia. Blood transfusion is lifesaving but comes at a cost. Iron overload emerges as a prime culprit as a free radicals damage endothelial cells. Chronic anaemia further disrupts oxygen delivery, exacerbating the oxidative stress. Increased levels of met-haemoglobin and malondialdehyde compromise endothelial function. This research sheds light on the impact of met-haemoglobin and oxidative stress on endothelial function in 50 patients with transfusion dependent β-thalassemia major compared to 50 healthy individuals as control. Blood samples were collected & subjected to CBC, biochemical analysis including creatinine, ferritin, CRP, LDH, and HCV antibodies. Oxidative stress was assessed using met-haemoglobin & malondialdehyde. Endothelial dysfunction was evaluated by endothelial activation and stress index (EASIX). EASIX, met-haemoglobin and malondialdehyde were significantly increased in patients (1.44 ± 0.75, 2.07 ± 0.2, 4.8 ± 0.63; respectively) compared to the control (0.52 ± 0.24,0.88 ± 0.34,0.8 ± 0.34; respectively). Significant strong positive correlation was found between EASIX and met-haemoglobin, malondialdehyde, serum ferritin and CRP (P = 0.00, r = 0.904, P = 0.00, r = 0.948, P = 0.00, r = 0.772, P = 0.00, r = 0.971; respectively. Met-haemoglobin as well as EASIX should be routinely estimated to assess endothelial function especially before the decision of splenectomy. Antioxidant drugs should be supplemented.
    Keywords:  EASIX; Malondialdehyde; Met-Hb; Oxidative stress; Transfusion depended β-thalassemia
    DOI:  https://doi.org/10.1038/s41598-024-74930-3
  8. Front Immunol. 2024 ;15 1466669
    Immunoregulation role of the erythroid cells.
    Chunxiao Niu, Jiyan Zhang.
      Erythroid cells are the most abundant cells in the human body. In addition to their established function in gas-transportation, erythroid cells at various stages of differentiation have recently been shown to have immunomodulatory roles. Red blood cells may serve as modulators of innate and adaptive immunity, while their immature counterparts, CD71+ erythroid cells (CECs) have important immunomodulatory functions in various contexts. CECs are abundant in human cord blood and placenta, where they contribute to fetomaternal tolerance. CECs also accumulate in patients with infections, tumors, and anemia, and effectively suppress T cells by producing high levels of arginase, reactive oxygen species, programmed death-ligand 1, transforming growth factor β, and/or interleukin-10. Here, we systematically summarize the immunomodulatory functions of erythroid cells and propose some potential therapeutic applications based on their characteristics.
    Keywords:  CD71 + erythroid cells; PD-L1; ROS; TGF-β; erythropoiesis; immunoregulation
    DOI:  https://doi.org/10.3389/fimmu.2024.1466669
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