bims-conane Biomed News
on Congenital anemias
Issue of 2024–08–25
twelve papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo



  1. Transfus Apher Sci. 2024 Aug 08. pii: S1473-0502(24)00159-9. [Epub ahead of print]63(5): 103988
      In France, sickle cell disease (SCD) is the most common rare disease and represents the most prevalent genetic disorder, with 19,800 to 32,400 patients diagnosed in 2016 and 1:714 newborns affected in 2019. SCD is caused by a single mutation in the β-globin gene, resulting in the production of abnormal hemoglobin (called HbS), chronic hemolytic anemia, and impaired red blood cell rheology. SCD patients face several severe acute and chronic complications, including stroke, acute chest syndrome (ACS), painful vaso-occlusive crisis (VOC), organ failure, and a high risk of infections. As patients' care pathway remains unclear in France, a roundtable advisory board meeting was organized in the country to provide insights into the management of SCD in alignment with clinical guidelines. The meeting brought together a panel of esteemed key opinion leaders (KOLs) in SCD management, encompassing both clinical practice and research. During the meeting, the KOLs discussed clinical practices and their alignment with French guidelines, identifying areas of concordance and discrepancy. They also addressed disparities in SCD clinical practices across regions and medical centers. The KOLs discussed the prophylactic and therapeutic options currently available for SCD patients in France, with a focus on transfusion therapies, especially automated red blood cell exchange (aRBCX). The results of this advisory board meeting provide a valuable platform for gathering expert perspectives on SCD management, clinical practices, guideline alignment, and the potential for contributions to guideline updates.
    Keywords:  Automated RBC exchange; Clinical guidelines; Clinical practice; French guidelines; Healthcare disparities; Patient-centered care; Sickle cell disease; Transfusion
    DOI:  https://doi.org/10.1016/j.transci.2024.103988
  2. Blood. 2024 Aug 23. pii: blood.2024024608. [Epub ahead of print]
      Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability leading to microvascular obstruction and inflammation. While the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, where endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations of varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs leads to aberrant margination of the less-deformable RBC subpopulations towards the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (i.e., direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.
    DOI:  https://doi.org/10.1182/blood.2024024608
  3. Hemoglobin. 2024 Aug 23. 1-5
      We report the molecular and hematological identifications of two novel δ-globin gene mutations found in Guangxi Zhuang Autonomous Region, China. Capillary electrophoresis of the proband showed 1.3% Hb A2, accompanied by a minor unknown peak (0.7%) within the Z1 zone. High-performance liquid chromatography also revealed the presence of 1.5% Hb A2 and a 0.6% unknown peak. Routine genetic testing (Gap-PCR and reverse dot-blot hybridization) for common α-thalassemia was performed, and no mutations were observed. Sanger sequencing identified a heterozygous mutation for GAC > AAC at codon 79 (HBD:c.238G > A) and G > A at polyA + 70 (HBD:c.*200G > A) of the δ-globin gene. This variant was named Hb A2-Guangxi [δ79 (EF3) Asp→Asn, HBD:c.238G > A] after the geographic origin of the proband.
    Keywords:  HBD gene; Hb A2-Guangxi; poly A + 70; variant; δ-globin
    DOI:  https://doi.org/10.1080/03630269.2024.2390934
  4. Blood Cells Mol Dis. 2024 Aug 08. pii: S1079-9796(24)00061-5. [Epub ahead of print]109 102883
      Despite several existing laboratory-based studies of hemoglobin (Hb) E (HBB:c.79 G > A)/ β (nucleotide (NT) -28 A > G) (HBB:c.-78 A > G) -thalassemia, no reports have ever provided clinical severity information as well as dependency of blood transfusion. Previously, a comparative study of community- and hospital-recruited Hb E/β-thalassemia subjects was conducted in the lower northern Thailand between June 2020 and December 2021. A mobile medical team visited each community hospital on-site, collecting clinical severity parameters, and conducting Hb and DNA analyses. The control included Hb E/β-thalassemia patients undergoing transfusions. Subgroup study of adult Hb E/β (NT -28 A > G) -thalassemia subjects was subsequently conducted. Additional pediatric individuals were recruited from prenatal diagnosis databases. Twenty adult and nine pediatric subjects were enrolled; all were classified as having mild disease severity. Twenty-two individuals (75.9 %) were asymptomatic. Six adults (20.7 %) required blood transfusion. The mean Hb level of subjects without transfusion (23 [79.3 %]) was 10.77 ± 1.10 g/dL. Hb analysis revealed a distinct EFA pattern with low Hb F fraction. The positive impact of genetic modifiers could not be statistically demonstrated except rs7482144-XmnI. These findings could provide essential information for parents carrying fetuses with Hb E/β (NT -28 A > G) -thalassemia.
    Keywords:  Community-recruited case study; Hemoglobin E/β-thalassemia; Mahidol severity score; Nucleotide -28 β-globin mutation; α-Thalassemia coinheritance
    DOI:  https://doi.org/10.1016/j.bcmd.2024.102883
  5. Front Immunol. 2024 ;15 1403458
      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.
    Keywords:  beta-thalassemia; impaired hematopoiesis; ineffective erythropoiesis; metabolic abnormalities; microenvironment correction; osteoblast
    DOI:  https://doi.org/10.3389/fimmu.2024.1403458
  6. Cureus. 2024 Jul;16(7): e64995
      Objectives The study sought to evaluate and compare the maternal and fetal outcomes of pregnancy in women with sickle cell disease (SCD) versus healthy pregnant women in Bahrain. The objective was to update the available data in order to come up with a strategy to implement a multidisciplinary management program, which will enhance pregnancy outcomes for the SCD patient population. Materials and methods This retrospective case-control study was conducted in the Obstetrics and Gynecology Department at Salmaniya Medical Complex (SMC) in Bahrain. The study group consisted of all pregnant women with homozygous SCD (HbSS) who delivered at SMC between January 1, 2019, and December 31, 2021. The control group comprised pregnant women who delivered at SMC during the same period but did not have SCD or trait. Data for the study were collected from the healthcare system records at SMC, specifically the I-Seha electronic medical record system and the labor room registry book. A thorough review and analysis of the data were conducted, encompassing 217 cases of SCD and 200 controls. The variables examined included nationality, age, gravidity, parity, gestational age, reason for admission, antenatal/postnatal complications (such as urinary tract infection, pneumonia, acute chest syndrome, thromboembolism, premature rupture of membranes, hypertension, pre-eclampsia, and intrauterine growth restriction), type of delivery, birth weight, newborn outcome, and postnatal complications. Results Pregnant women with SCD experienced significantly higher rates of antenatal hospitalization compared to controls - 69.6% were admitted at least twice versus only 16.5%. Vaso-occlusive crises were the primary reason for admission in over half of SCD patients, with 22.6% having one episode, 11.1% having two, and 20.3% having more than two during pregnancy. Low hemoglobin levels also necessitated admission in 11.1% of SCD women, while no controls required hospitalization for this. The burden of maternal morbidity was substantially greater in the SCD group, with only 20.3% free of complications versus 94% in controls. SCD women had elevated rates of blood transfusions, acute chest syndrome, and urinary tract infections. Adverse pregnancy outcomes were also more common, including higher risks of preterm birth, low birth weight, and intrauterine growth restriction. Despite these increased maternal and fetal risks, there was no significant difference in the incidence of hypertensive disorders between groups. Interestingly, our data showed a significantly lower incidence of gestational diabetes in the SCD group compared to controls (8.3% vs. 18%). Tragically, one maternal death occurred in the SCD group, although the overall maternal mortality did not differ significantly. Conclusion SCD poses substantial risks for mother and fetus. Careful monitoring with a multidisciplinary team and patient education are crucial. Early detection can reduce morbidity and mortality. Further research is needed on interventions to improve outcomes.
    Keywords:  bahrain; maternal and fetal outcome; maternal death; maternal morbidity; medical disorders in pregnancy; pregnant; sickle cell disease (scd)
    DOI:  https://doi.org/10.7759/cureus.64995
  7. EJHaem. 2024 Aug;5(4): 885-886
      
    Keywords:  G6PD; red cell enzymopathies; stem cell transplantation
    DOI:  https://doi.org/10.1002/jha2.920
  8. Br J Haematol. 2024 Aug 18.
      The alpha-thalassaemia alleles are very frequent in the world's population. The main molecular mechanism is a large deletion with the loss of one or two alpha genes. Another type of rarer abnormality exists: the gain of alpha genes. The consequence of a gain is an overproduction of alpha-globin chains, which aggravates a beta-thalassaemia trait into an intermedia phenotype (non-transfusion-dependent thalassaemia, NTDT). Here, we report the case of a young girl referred for a beta-NTDT with a combination never described in the literature: a heterozygous beta-thalassaemia mutation associated with a copy number gain of the alpha-globin locus and -alpha 3.7 deletion on the same allele.
    Keywords:  diagnostic haematology; haemoglobinopathies; haemolytic anaemia
    DOI:  https://doi.org/10.1111/bjh.19715