bims-conane Biomed News
on Congenital anemias
Issue of 2024–07–21
fiveteen papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Association between fetal hemoglobin, lactate dehydrogenase, and disease severity in patients with sickle cell disease at Bugando Medical Centre, Mwanza, Tanzania.
  2. A Budget Impact Analysis of Gene Therapy for Sickle Cell Disease: An Updated Analysis.
  3. Transcriptional Repressor BCL11A in Erythroid Cells.
  4. Priorities for sickle cell disease global research and implementation.
  5. Ferroptosis as an emerging target in sickle cell disease.
  6. Safety and efficacy of L-Glutamine in reducing the frequency of acute complications among patients with sickle cell disease: A randomized controlled study.
  7. Concomitant sickle cell disease and systemic lupus erythematosus: A single-center case series.
  8. Measurement of left atrial size as a predictor of severity of illness in sickle cell disease.
  9. Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease and Thalassemia Major: A National Database Study.
  10. Chronic automated red cell exchange therapy for sickle cell disease.
  11. Impact of Hydroxyurea on follicle density in patients with sickle cell disease.
  12. α-Globin mutations and Genetic Variants in γ-globin Promoters are Associated with Unelevated Hemoglobin F Expression of Atypical β0-thalassemia/HbE.
  13. Erythroid Krüppel-Like Factor (KLF1): A Surprisingly Versatile Regulator of Erythroid Differentiation.
  14. Mimicry of inherited red cell disorders: the result of somatic mutations in a clonal myeloid disease.
  15. Successful Hematopoietic Stem Cell Transplantation in a Child with Thalassemia major and Moderate Haemophilia A.
  1. PLoS One. 2024 ;19(7): e0286891
    Association between fetal hemoglobin, lactate dehydrogenase, and disease severity in patients with sickle cell disease at Bugando Medical Centre, Mwanza, Tanzania.
    Samwel Edward Kahema, Cosmas H Mbulwa, Charles Nkubi Bagenda, Nixon Niyonzima, Enoch Muwanguzi, Tunzo L Mcharo.
       INTRODUCTION: There is a wide range of clinical manifestations in sickle cell disease (SCD). Despite having the same condition, each person's response to disease complications differs greatly. Individuals can be categorized according to the severity of their diseases to determine which group they fall into and receive the appropriate care based on their needs. The relationship between fetal hemoglobin (HbF), lactate dehydrogenase (LDH), and disease severity in Tanzania is little understood. This investigation sought to ascertain the relationship between HbF, LDH, and disease severity in SCD patients at the Bugando Medical Center.
    METHOD: This cross-sectional study was carried out on SCD patients aged 6 months and older at the Bugando Medical Center in Mwanza, Tanzania. A total of 130 SCD patients were enrolled. The clinical history and laboratory test results for SCD patients were recorded on a specially constructed patient report form.
    RESULTS: The majority of participants (56.9%) were men. For the population under study, more than half (60.8%) of participants had a moderate clinical phenotype (MCP), followed by 31.5% of asymptomatic participants and 7.7% of people with severe clinical phenotypes (SCP). Participants with SCP had substantially higher levels of LDH, with a mean level of 810.97IU/L (95% CI: 559.31-1062.64) and a p-value of 0.005. The severe clinical phenotype exhibited a significantly higher mean HbF score value of 10.09% (95% CI: 7.44-13.74%) with a p-value of 0.024 when compared to the asymptomatic and moderate clinical phenotypes.
    CONCLUSION: In SCD patients with SCP compared to ACP and MCP, the HbF levels were higher, but did not show a protective effects, and LDH can be used to predict the severity of SCD.
    DOI:  https://doi.org/10.1371/journal.pone.0286891
  2. Blood Adv. 2024 Jul 18. pii: bloodadvances.2024013093. [Epub ahead of print]
    A Budget Impact Analysis of Gene Therapy for Sickle Cell Disease: An Updated Analysis.
    Patrick C DeMartino, Meredith B Haag, Aaron B Caughey, Joshua A Roth.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013093
  3. Adv Exp Med Biol. 2024 ;1459 199-215
    Transcriptional Repressor BCL11A in Erythroid Cells.
    Ge Zheng, Stuart H Orkin.
      BCL11A, a zinc finger repressor, is a stage-specific transcription factor that controls the switch from fetal (HbF, α2γ2) to adult (HbA, α2β2) hemoglobin in erythroid cells. While BCL11A was known as a factor critical for B-lymphoid cell development, its relationship to erythroid cells and HbF arose through genome-wide association studies (GWAS). Subsequent work validated its role as a silencer of γ-globin gene expression in cultured cells and mice. Erythroid-specific loss of BCL11A rescues the phenotype of engineered sickle cell disease (SCD) mice, thereby suggesting that downregulation of BCL11A expression might be beneficial in patients with SCD and β-thalassemia. Common genetic variation in GWAS resides in an erythroid-specific enhancer within the BCL11A gene that is required for its own expression. CRISPR/Cas9 gene editing of the enhancer revealed a GATA-binding site that confers a large portion of its regulatory function. Disruption of the GATA site leads to robust HbF reactivation. Advancement of a guide RNA targeting the GATA-binding site in clinical trials has recently led to approval of first-in-man use of ex vivo CRISPR editing of hematopoietic stem/progenitor cells (HSPCs) as therapy of SCD and β-thalassemia. Future challenges include expanding access and infrastructure for delivery of genetic therapy to eligible patients, reducing potential toxicity and costs, exploring prospects for in vivo targeting of hematopoietic stem cells (HSCs), and developing small molecule drugs that impair function of BCL11A protein as an alternative option.
    Keywords:  Gene editing; Globin regulation; Hemoglobin switch; Sickle cell disease; β-thalassemia; γ-globin
    DOI:  https://doi.org/10.1007/978-3-031-62731-6_9
  4. Lancet. 2024 Jul 10. pii: S0140-6736(24)01400-4. [Epub ahead of print]
    Priorities for sickle cell disease global research and implementation.
    Ambroise Wonkam, Nchangwi Syntia Munung, Aldiouma Guindo, Obiageli Nnodu.
      
    DOI:  https://doi.org/10.1016/S0140-6736(24)01400-4
  5. Curr Res Toxicol. 2024 ;7 100181
    Ferroptosis as an emerging target in sickle cell disease.
    Vitor Fortuna, Jaqueline Lima, Gabriel F Oliveira, Yasmin S Oliveira, Bruk Getachew, Sergei Nekhai, Michael Aschner, Yousef Tizabi.
      Sickle cell disease (SCD) is an inherited hemoglobin disorder marked by red blood cell sickling, resulting in severe anemia, painful episodes, extensive organ damage, and shortened life expectancy. In SCD, increased iron levels can trigger ferroptosis, a specific type of cell death characterized by reactive oxygen species (ROS) and lipid peroxide accumulation, leading to damage and organ impairments. The intricate interplay between iron, ferroptosis, inflammation, and oxidative stress in SCD underscores the necessity of thoroughly understanding these processes for the development of innovative therapeutic strategies. This review highlights the importance of balancing the complex interactions among various factors and exploitation of the knowledge in developing novel therapeutics for this devastating disease.
    Keywords:  Ferroptosis; Iron toxicity; Lipid peroxidation; Novel targets; Oxidative stress; Sickle cell disease
    DOI:  https://doi.org/10.1016/j.crtox.2024.100181
  6. Ann Hematol. 2024 Jul 19.
    Safety and efficacy of L-Glutamine in reducing the frequency of acute complications among patients with sickle cell disease: A randomized controlled study.
    Fatma Soliman Elsayed Ebeid, Nihal Hussien Aly, Naglaa Mohammed Shaheen, Samah Mohammed Ahmed Abdellatif, Ahmed Ashraf Mahmoud Okba, Nada Ayman Gad, Sara Mostafa Makkeyah.
      To evaluate the safety and efficacy of L-glutamine in reducing vaso-occlusive crisis (VOC) and improving cerebral arterial blood flow in children with sickle cell disease (SCD). This is an interventional randomized controlled trial that recruited sixty SCD patients, aged 9.2 ± 3.7 years, who had at least two VOCs during the last 12 months and on a stable dose of hydroxyurea. They were randomly assigned in a 1:1 ratio to receive glutamine (0.3 gm/kg/dose/12h) orally for 24 weeks or the standard of care (SOC). All patients had VOCs in the last year > 3, those on glutamine had a higher number of VOCs and hospitalization for VOC in the last year. There was a decreasing trend in the number, severity, and hospitalization of VOC and a significantly lower cumulative number of VOCs and hospitalizations in the glutamine group than in SOC (p = 0.008, p < 0.001 respectively). Time-averaged mean maximum velocity for the glutamine group had a marginal increase in both middle cerebral arteries, all values remained normal within a normal range, and in both internal carotid arteries, values increased from abnormally low to normal ranges at week 24. Glutamine reduced the number of VOCs and severity and may have a potentially favorable impact on the cerebral arterial flow velocities.
    Keywords:  Children; Egypt; L-Glutamine; Sickle Cell Disease; Vaso-occlusive crisis
    DOI:  https://doi.org/10.1007/s00277-024-05877-8
  7. Pediatr Blood Cancer. 2024 Jul 14. e31194
    Concomitant sickle cell disease and systemic lupus erythematosus: A single-center case series.
    Ajibike Lapite, Luisana M Sánchez, Ana Luiza Altaffer, Meredith Rae, Andrea Ann Ramirez, Eyal Muscal, Cagri Yildirim-Toruner, Venée N Tubman.
      Sickle cell disease (SCD) and systemic lupus erythematosus (SLE) are two uncommon disorders each characterized by multisystemic manifestations. Individuals with SCD exhibit abnormalities in the complement pathway, which may predispose patients to develop autoimmune disorders such as SLE. As many manifestations of SLE mimic those of SCD, diagnosis and therapeutic management of SLE in a patient with known SCD may be delayed. In this study, we describe our institutional experience of diagnosing and managing concomitant SCD and SLE. We offer insights into the complex interplay between these conditions to enhance early recognition and effective management of concurrent SCD and SLE.
    Keywords:  complement system; sickle cell disease; systemic lupus erythematosus
    DOI:  https://doi.org/10.1002/pbc.31194
  8. Am J Emerg Med. 2024 Jul 04. pii: S0735-6757(24)00317-6. [Epub ahead of print]83 126-128
    Measurement of left atrial size as a predictor of severity of illness in sickle cell disease.
    Farrah Shahrzad Nasrollahi, Dino J Gutierrez, Judith Nocek, Jennifer Folami, Sahrish Ekram, Wesley Eilbert, Joseph S Colla.
       BACKGROUND: Sickle cell disease (SCD) is characterized by microvascular occlusion which leads to multiorgan damage, including left ventricular diastolic dysfunction. Left ventricular diastolic dysfunction has been shown to be an independent risk factor for death in SCD patients. Left atrial dilation (LAD) has been used as a surrogate marker for identification of left ventricular diastolic dysfunction.
    OBJECTIVE: Investigate the association of LAD, as determined by echocardiography, with increased disease burden in SCD as reflected by increased emergency department (ED) utilization, increased hemolysis markers, and worsening anemia.
    METHODS: A retrospective cohort study of patients from a single university hospital were selected from a national registry. Age, sickle cell phenotype, echocardiogram findings, ED utilization, baseline hemoglobin, and lab values needed for calculation of hemolytic index were recorded for each patient. Patients were then stratified into two distinct groups based on the presence or absence of LAD to compare ED utilization, baseline hemoglobin and hemolytic index between the two groups.
    RESULTS: 129 patients met the criteria for inclusion with 88 having normal left atrial volume and 41 with LAD. There was a higher percentage of high ED utilizers in the LAD group compared to the normal left atrial volume group [34% vs. 17%, p = 0.03]. Average hemoglobin was lower in the LAD group compared with the normal left atrial volume group [mean 8.57 g/dL vs. 9.47 g/dL, p = 0.011]. The mean hemolytic index was higher in the LAD group when compared with the normal left atrial volume group [0.44 vs. -0.21, p < 0.001].
    CONCLUSIONS: LAD was associated with higher ED utilization, lower hemoglobin level, and more hemolysis in patients with SCD.
    Keywords:  Atrial; Cell; Disease; Hematology; Illness; Left; Severity; Sickle; Size; Ultrasound
    DOI:  https://doi.org/10.1016/j.ajem.2024.07.001
  9. Pediatr Hematol Oncol. 2024 Jul 15. 1-15
    Hematopoietic Stem Cell Transplantation in Children with Sickle Cell Disease and Thalassemia Major: A National Database Study.
    Camila De Avila, Paul A Martinez, Prithvi Sendi, Jorge R Galvez Silva, Ossama M Maher, Balagangadhar R Totapally.
      In patients with sickle cell disease (SCD) and beta-thalassemia major (TM), allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment option with a good survival rate. However, with the recent approval of gene therapies, more information is needed to understand the benefits and risks of these interventions. We performed a retrospective analysis of the Kids Inpatient Database to describe demographic features, short-term complications, and hospital charges of patients with SCD and TM treated with HSCT during 2006-2019 in the United States. The database was filtered using the International Classification of Diseases, 9th and 10th edition codes to identify children under 20 years of age with SCD or TM who underwent HSCT. A total of 513 children with SCD or TM who received HSCT were analyzed. The prevalence of HSCT per 1000,000 U.S. population increased from 0.31 in 2006 to 1.99 in 2019 (p < 0.001). The median age of children with SCD who underwent HSCT was 10 (6-15) years, and that for TM was 6 (3-11.5) years (p < 0.001). The combined mortality rate was 4% (2.4%-6.6%) but higher in the TM group. The length-of-stay and total charges were higher in the TM population (p < 0.01). This study provides national data on HSCT among hospitalized children with SCD and TM in the United States, demonstrating an increasing use of HSCT between 2006 and 2019. Although hospital mortality of HSCT in these conditions is low, it still represents a challenge, especially in TM patients.
    Keywords:  Beta thalassemia; gene therapy; sickle cell disease; transplantation
    DOI:  https://doi.org/10.1080/08880018.2024.2378282
  10. Transfusion. 2024 Jul 14.
    Chronic automated red cell exchange therapy for sickle cell disease.
    Abdulhafiz Zakieh, Nicolas Mercure-Corriveau, Sophie Lanzkron, Xinyi Feng, Sonja Vozniak, Elizabeth P Crowe, Herleen Rai, Courtney Lawrence, Denise Bekkouri, Ruchika Goel, Aaron A R Tobian, Evan M Bloch.
       BACKGROUND: The data to support chronic automated red cell exchange (RCE) in sickle cell disease (SCD) outside of stroke prevention, is limited, especially in adults.
    STUDY DESIGN AND METHODS: A retrospective analysis was conducted of patients with SCD who were referred for chronic RCE at our institution over a 10-year period. Data that were evaluated included patient demographics, referral indications, and procedural details (e.g., vascular access, adverse events, etc.). In a subanalysis, the number of annual acute care encounters during 3 years of chronic RCE was compared with that in the year preceding the first RCE.
    RESULTS: A total of 164 patients were referred for chronic RCE: median age was 28 years (interquartile range [IQR] = 22-36) at referral and 60% were female. Seventy (42.6%) were naïve to chronic transfusion (simple or RCE) prior to referral. The leading indications for referral were refractory pain (73/164, 44.5%) and iron overload (57/164, 34.7%). A total of 5090 procedures occurred during the study period (median = 19, IQR = 5-45). Of the 138 patients who had central vascular access, 8 (6%) and 16 (12%) had ≥1 central-line-related thrombosis and/or infection, respectively. Of those who were not RBC alloimmunized at initiation of RCE, 12/105 (11.4%) developed new antibodies during chronic RCE. In those 30 patients who were adherent to therapy for 3 years, there was no significant difference in acute care encounters following initiation of RCE.
    CONCLUSION: Prospective clinical trials are needed to determine which patients are most likely to benefit from chronic RCE and refine selection accordingly.
    Keywords:  apheresis; blood transfusion; exchange transfusion; hemoglobinopathies; sickle cell anemia
    DOI:  https://doi.org/10.1111/trf.17924
  11. Blood Adv. 2024 Jul 18. pii: bloodadvances.2023011536. [Epub ahead of print]
    Impact of Hydroxyurea on follicle density in patients with sickle cell disease.
    Tamara Diesch-Furlanetto, Carlos Sanchez, Andrew Atkinson, Corinne Pondarre, Nathalie Dhedin, Bénédicte Neven, Cécile Arnaud, Annie Kamdem, France Pirenne, Gilles Lenaour, Isabelle Brocheriou, Benoit Terris, Françoise Bernaudin, Jean-Hugues Dalle, Catherine Poirot.
      The impact of hydroxyurea (HU) on the ovarian reserve of female patients with sickle cell disease (SCD) remains poorly elucidated. Only direct histological analysis of ovarian follicle density can effectively evaluate HU's effect on ovarian reserve. By analyzing digitized slides of ovarian tissue from girls and young women with SCD who underwent ovarian tissue cryopreservation (OTC) before hematological stem cell transplantation (HSCT), we meticulously counted follicles and categorized them based on their growth stage. We then calculated the densities of different follicle types and assessed their correlation with patient characteristics, clinical manifestations, and treatments extracted from medical records. Seventy-six SCD patients participated in the study, with a median age at OTC of 10.2 years (interquartile range [IQR] 7.5, 14.6), and 50 (65.8%) were prepubertal. Of these, 35 patients (46.1%) had received HU, with a median daily dosage of 23.0 mg/kg (IQR 20.0, 25.0) and median exposure time of 44 months (IQR 24.0, 54.0). Primordial follicle density was comparable between the HU and non-HU groups (5.8 follicles/mm2 [IQR 1.0, 13.3] versus 4.2 follicles/mm2 [IQR 1.1, 14.4], respectively; P = .95). However, in the HU group, after adjusting for age, the density of growing follicles was marginally lower compared to the non-HU group (P = .09). Notably, other parameters such as vaso-occlusive crisis did not affect follicular density. In conclusion, exposure to hydroxyurea did not demonstrate a reduction in ovarian reserve in girls/women with SCD. Therefore, fertility preservation measures before initiating HU treatment do not seem necessary.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011536
  12. Arch Med Res. 2024 Jul 18. pii: S0188-4409(24)00107-3. [Epub ahead of print]55(6): 103055
    α-Globin mutations and Genetic Variants in γ-globin Promoters are Associated with Unelevated Hemoglobin F Expression of Atypical β0-thalassemia/HbE.
    Surada Satthakarn, Sitthichai Panyasai.
       BACKGROUND: Excessive expression of hemoglobin F (HbF) is a characteristic feature and important diagnostic marker of β0-thalassemia/HbE disease. However, some patients may exhibit low-HbF levels, leading to misdiagnosis and precluding genetic counseling. The genetic factors influencing these differences in HbF expression in this atypical disease are not completely understood.
    AIMS: To investigate determinants contributing to the non-elevation of HbF expression in β0-thalassemia/HbE disease.
    METHODS: We studied 231 patients with β0-thalassemia/HbE confirmed by DNA analysis; classified them into the low-HbF (n = 62) and high-HbF (n = 169) groups; analyzed hematological parameters and hemoglobin levels in both groups; and characterized mutations in β- and α-globin genes and genetic variants in γ-globin promoters.
    RESULTS: Both groups showed similar rates of type β0-thalassemia mutations but significantly different proportions of α-globin mutations: approximately 88.7% (95% confidence interval [CI] = 66.8-115.5) and 39.1% (95% CI = 30.2-49.7) in the low- and high-HbF groups, respectively. The results revealed single-nucleotide polymorphisms (SNPs) at -158 (C>T) in the Gγ-globin promoters and novel SNPs at the 5' untranslated region position 25 (G>A) in Aγ-globin promoters. The distribution of CC genotypes of the Gγ-globin promoter in the low-HbF group was significantly higher than that in the high-HbF group.
    CONCLUSIONS: Cases with HbE predominance with low-HbF levels and undetectable HbA may not be as conclusive as those with homozygous HbE until DNA analysis is performed. Concomitant inheritance of α-thalassemia is an important inherent factor modifying HbF expression in a typical β0-thalassemia/HbE, and SNPs with the CC genotype in the Gγ-globin promoter may indicate unelevated HbF expression in patients with this disease.
    Keywords:  Hemoglobin F; XmnI polymorphism; α-thalassemia; β(0)-thalassemia/HbE disease; γ-globin promoter
    DOI:  https://doi.org/10.1016/j.arcmed.2024.103055
  13. Adv Exp Med Biol. 2024 ;1459 217-242
    Erythroid Krüppel-Like Factor (KLF1): A Surprisingly Versatile Regulator of Erythroid Differentiation.
    James J Bieker, Sjaak Philipsen.
      Erythroid Krüppel-like factor (KLF1), first discovered in 1992, is an erythroid-restricted transcription factor (TF) that is essential for terminal differentiation of erythroid progenitors. At face value, KLF1 is a rather inconspicuous member of the 26-strong SP/KLF TF family. However, 30 years of research have revealed that KLF1 is a jack of all trades in the molecular control of erythropoiesis. Initially described as a one-trick pony required for high-level transcription of the adult HBB gene, we now know that it orchestrates the entire erythroid differentiation program. It does so not only as an activator but also as a repressor. In addition, KLF1 was the first TF shown to be directly involved in enhancer/promoter loop formation. KLF1 variants underlie a wide range of erythroid phenotypes in the human population, varying from very mild conditions such as hereditary persistence of fetal hemoglobin and the In(Lu) blood type in the case of haploinsufficiency, to much more serious non-spherocytic hemolytic anemias in the case of compound heterozygosity, to dominant congenital dyserythropoietic anemia type IV invariably caused by a de novo variant in a highly conserved amino acid in the KLF1 DNA-binding domain. In this chapter, we present an overview of the past and present of KLF1 research and discuss the significance of human KLF1 variants.
    Keywords:  Congenital dyserythropoietic anemia type IV; EKLF; Erythropoiesis; Hemoglobin switching; KLF1; Nonspherocytic hemolytic anemia; Transcription factor
    DOI:  https://doi.org/10.1007/978-3-031-62731-6_10
  14. Haematologica. 2024 Jul 18.
    Mimicry of inherited red cell disorders: the result of somatic mutations in a clonal myeloid disease.
    Marshall A Lichtman, Audrey N Jajosky.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286211
  15. Indian J Hematol Blood Transfus. 2024 Jul;40(3): 543-544
    Successful Hematopoietic Stem Cell Transplantation in a Child with Thalassemia major and Moderate Haemophilia A.
    Debranjani Chattopadhyay, Aby Abraham, Biju George.
      
    DOI:  https://doi.org/10.1007/s12288-024-01751-9
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