Confounding factors in the diagnosis and clinical course of rare congenital hemolytic anemias.
TL;DR: Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis as discussed by the authors.
Abstract: Congenital hemolytic anemias (CHAs) comprise defects of the erythrocyte membrane proteins and of red blood cell enzymes metabolism, along with alterations of erythropoiesis. These rare and heterogeneous conditions may generate several difficulties from the diagnostic point of view. Membrane defects include hereditary spherocytosis and elliptocytosis, and the group of hereditary stomatocytosis; glucose-6-phosphate dehydrogenase and pyruvate kinase, are the most common enzyme deficiencies. Among ultra-rare forms, it is worth reminding other enzyme defects (glucosephosphate isomerase, phosphofructokinase, adenylate kinase, triosephosphate isomerase, phosphoglycerate kinase, hexokinase, and pyrimidine 5′-nucleotidase), and congenital dyserythropoietic anemias. Family history, clinical findings (anemia, hemolysis, splenomegaly, gallstones, and iron overload), red cells morphology, and biochemical tests are well recognized diagnostic tools. Molecular findings are increasingly used, particularly in recessive and de novo cases, and may be fundamental in unraveling the diagnosis. Notably, several confounders may further challenge the diagnostic workup, including concomitant blood loss, nutrients deficiency, alterations of hemolytic markers due to other causes (alloimmunization, infectious agents, rare metabolic disorders), coexistence of other hemolytic disorders (autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, etc.). Additional factors to be considered are the possible association with bone marrow, renal or hepatic diseases, other causes of iron overload (hereditary hemochromatosis, hemoglobinopathies, metabolic diseases), and the presence of extra-hematological signs/symptoms. In this review we provide some instructive clinical vignettes that highlight the difficulties and confounders encountered in the diagnosis and clinical management of CHAs.
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TL;DR: In this paper , the authors provide an insight in the current challenges of PKD diagnosis and management and discuss the future application of novel drugs and gene therapy, including a focus on quality of life.
Abstract: Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disease marked by chronic hemolytic anemia of various severity and frequent complications including gallstones, splenomegaly, iron overload, and others. Disease phenotype is highly heterogeneous and changes over time with children, adolescents and adult patients displaying different transfusion requirement and rates of complications. The diagnosis relies on the initial clinical suspicion in a patient with chronic hemolysis and exclusion of other more common congenital forms of hemolytic anemias; it is supported by the demonstration of reduced PK enzyme activity, and further confirmed by the detection of (homozygous or compound heterozygous) mutations of PKLR gene. Therapy is mainly supportive, with vitamin supplementation and transfusions (based on symptoms and patient growth rather than on fixed Hb thresholds). Splenectomy is widely performed, although it is less effective than in membrane defects and carries thrombotic and infectious risk. In the last decade, the allosteric PK enzyme activator mitapivat showed dramatic clinical benefit in clinical trials and gene therapy is also being studied to substitute the defective enzyme. In this review, we provide an insight in the current challenges of PKD diagnosis and management and discuss the future application of novel drugs and gene therapy, including a focus on quality of life.
5 citations
TL;DR: It can be inferred that the chronic hemolytic anemia may be attributable to the SPTB mutation only, without influence of the concomitant PKLR, according to the recommendations for pathogenicity of the American College of Medical Genetics and the Association for Molecular Pathology.
Abstract: Background: Hereditary spherocytosis (HS) and pyruvate kinase deficiency (PKD) are the most common causes of hereditary chronic hemolytic anemia. Here, we describe clinical and genetic characteristics of a Spanish family with concomitant β-spectrin (SPTB) c.647G>A variant and pyruvate kinase (PKLR) c.1706G>A variant. Methods: A family of 11 members was studied. Hematological investigation, hemolysis tests, and specific red cell studies were performed in all family members, according to conventional procedures. An ektacytometric study was performed using the osmoscan module of the Lorca ektacytometer (MaxSis. RR Mechatronics). The presence of the SPTB and PKLR variants was confirmed by t-NGS. Results: The t-NGS genetic characterization of the 11 family members showed the presence of a heterozygous mutation for the β-spectrin (SPTB; c.647G>A) in seven members with HS, three of them co-inherited the PKLR variant c.1706G>A. In the remaining four members, no gene mutation was found. Ektacytometry allowed a clear diagnostic orientation of HS, independently from the PKLR variant. Conclusions: This family study allows concluding that the SPTB mutation, (c.647G>A) previously described as likely pathogenic (LP), should be classified as pathogenic (P), according to the recommendations for pathogenicity of the American College of Medical Genetics and the Association for Molecular Pathology. In addition, after 6 years of clinical follow-up of the patients with HS, it can be inferred that the chronic hemolytic anemia may be attributable to the SPTB mutation only, without influence of the concomitant PKLR. Moreover, only the family members with the SPTB mutation exhibited an ektacytometric profile characteristic of HS.
2 citations
TL;DR: Ana Paula Marte Chacra,1 Anita L. R. Saldanha,2 Tania Leme da Rocha Martinez as mentioned in this paper ,1,2 Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo InCor-FMUSP,1,SP -Brasil Departamento de Nefrologia Beneficência Portuguesa de Sao Paulo.
Abstract: Ana Paula Marte Chacra,1 Anita L. R. Saldanha,2 Tania Leme da Rocha Martinez1,2 Instituto do Coração da Faculdade de Medicina da Universidade de São Paulo InCor-FMUSP,1 São Paulo, SP – Brasil Departamento de Nefrologia Beneficência Portuguesa de São Paulo,2 São Paulo, SP – Brasil Minieditorial referente ao artigo: Prevalência das Complicações Cardiovasculares nos Indivíduos com Anemia Falciforme e Outras Hemoglobinopatias: Uma Revisão Sistemática
TL;DR: For rare congenital (hemoglobinopathies, membrane and enzyme defects, congenital dyserythropoietic anemia) and acquired anemias [warm autoimmune hemolytic anemia, cold agglutinin disease CAD, paroxysmal nocturnal hemoglobinuria (PNH), and aplastic anemia (AA)] are rapidly expanding as mentioned in this paper .
Abstract: Therapeutic options for rare congenital (hemoglobinopathies, membrane and enzyme defects, congenital dyserythropoietic anemia) and acquired anemias [warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease CAD, paroxysmal nocturnal hemoglobinuria (PNH), and aplastic anemia (AA)] are rapidly expanding. The use of luspatercept, mitapivat and etavopivat in beta-thalassemia and pyruvate kinase deficiency (PKD) improves transfusion dependence, alleviating iron overload and long-term complications. Voxelotor, mitapivat, and etavopivat reduce vaso-occlusive crises in sickle cell disease (SCD). Gene therapy represents a fascinating approach, although patient selection, the toxicity of the conditioning regimens, and the possible long-term safety are still open issues. For acquired forms, wAIHA and CAD will soon benefit from targeted therapies beyond rituximab, including B-cell/plasma cell targeting agents (parsaclisib, rilzabrutinib, and isatuximab for wAIHA), complement inhibitors (pegcetacoplan and sutimlimab for CAD, ANX005 for wAIHA with complement activation), and inhibitors of extravascular hemolysis in the reticuloendothelial system (fostamatinib and FcRn inhibitors in wAIHA). PNH treatment is moving from the intravenous anti-C5 eculizumab to its long-term analog ravulizumab, and to subcutaneous and oral proximal inhibitors (anti-C3 pegcetacoplan, factor D and factor B inhibitors danicopan and iptacopan). These drugs have the potential to improve patient convenience and ameliorate residual anemia, although patient compliance becomes pivotal, and long-term safety requires further investigation. Finally, the addition of eltrombopag significantly ameliorated AA outcomes, and data regarding the alternative agent romiplostim are emerging. The accelerated evolution of treatment strategies will need further effort to identify the best candidate for each treatment in the precision medicine era.
TL;DR: In this paper , the prevalence of cardiovascular complications in individuals with Sickle Cell Anemia and Other Hemoglobinopathies was found to be significantly higher than the general population.
Abstract: Short Editorial related to the article: Prevalence of Cardiovascular Complications in Individuals with Sickle Cell Anemia and Other Hemoglobinopathies: A Systematic Review
References
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TL;DR: The current concept of the red cell membrane envisions it as a composite structure in which a membrane envelope composed of cholesterol and phospholipids is secured to an elastic network of skeletal proteins via transmembrane proteins.
895 citations
TL;DR: A family with X-linked dyserythropoietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1 is described and the importance of FOG-1, Gata-1 associations in both megakaryocyte and erythroid development, is underscored.
Abstract: Haematopoietic development is regulated by nuclear protein complexes that coordinate lineage-specific patterns of gene expression. Targeted mutagenesis in embryonic stem cells and mice has revealed roles for the X-linked gene Gata1 in erythrocyte and megakaryocyte differentiation. GATA-1 is the founding member of a family of DNA-binding proteins that recognize the motif WGATAR through a conserved multifunctional domain consisting of two C4-type zinc fingers. Here we describe a family with X-linked dyserythropoietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1. This highly conserved valine is necessary for interaction of the amino-terminal zinc finger of GATA-1 with its essential cofactor, FOG-1 (for friend of GATA-1; refs 9-12). We show that the V205M mutation abrogates the interaction between Gata-1 and Fog-1, inhibiting the ability of Gata-1 to rescue erythroid differentiation in an erythroid cell line deficient for Gata-1 (G1E). Our findings underscore the importance of FOG-1:Gata-1 associations in both megakaryocyte and erythroid development, and suggest that other X-linked anaemias or thrombocytopenias may be caused by defects in GATA1.
503 citations
TL;DR: The incidence of sepsis among post-splenectomy patients is low, however, it carries a high mortality rate especially among children with hematological disorders and among patients with thalassaemia major and sickle-cell anaemia.
434 citations
University of Paris1, University of La Réunion2, Leipzig University3, University of London4, University of Texas System5, Sunnybrook Research Institute6, University of Florence7, University of Bologna8, University of Pavia9, Ankara University10, Cleveland Clinic11, University of Oxford12, University of Leeds13, Johns Hopkins University14, Columbia University15, University of Düsseldorf16, Technische Universität München17, university of lille18, University of Rome Tor Vergata19, Ghent University Hospital20, Stanford University21, Karolinska Institutet22, Yale University23, Albert Einstein College of Medicine24, Vanderbilt University25, Celgene26
TL;DR: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event.
Abstract: Background Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusio...
278 citations
TL;DR: Findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells.
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