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Biosensors Aug 2018In red blood cell (RBC) disorders, such as sickle cell disease, hereditary spherocytosis, and diabetes, alterations to the size and shape of RBCs due to either mutations... (Review)
Review
In red blood cell (RBC) disorders, such as sickle cell disease, hereditary spherocytosis, and diabetes, alterations to the size and shape of RBCs due to either mutations of RBC proteins or changes to the extracellular environment, lead to compromised cell deformability, impaired cell stability, and increased propensity to aggregate. Numerous laboratory approaches have been implemented to elucidate the pathogenesis of RBC disorders. Concurrently, computational RBC models have been developed to simulate the dynamics of RBCs under physiological and pathological conditions. In this work, we review recent laboratory and computational studies of disordered RBCs. Distinguished from previous reviews, we emphasize how experimental techniques and computational modeling can be synergically integrated to improve the understanding of the pathophysiology of hematological disorders.
Topics: Anemia, Sickle Cell; Biomechanical Phenomena; Computer Simulation; Diabetes Mellitus; Elastic Modulus; Erythrocytes; Humans; Spherocytosis, Hereditary
PubMed: 30103419
DOI: 10.3390/bios8030076 -
British Journal of Haematology Aug 2004Hereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in... (Review)
Review
Hereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in Caucasian populations; most affected individuals have mild or only moderate haemolysis. There is usually a family history, and a typical clinical and laboratory picture so that the diagnosis is often easily made without additional laboratory tests. Atypical cases may require measurement of erythrocyte membrane proteins to clarify the nature of the membrane disorder and in the absence of a family history, occasionally molecular genetic analysis will help to determine whether inheritance is recessive or non-dominant. It is particularly important to rule out stomatocytosis where splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 years and with appropriate counselling about the infection risk. In all cases careful dialogue between doctor, patient and the family is essential. Laparoscopic surgery, when performed by experienced surgeons, can result in a shorter hospital stay and less pain.
Topics: Folic Acid; Humans; Mass Screening; Spherocytosis, Hereditary; Splenectomy
PubMed: 15287938
DOI: 10.1111/j.1365-2141.2004.05052.x -
Acta Medica Portuguesa 1985
Review
Topics: Arteriosclerosis; Blood; Blood Flow Velocity; Blood Sedimentation; Blood Viscosity; Erythrocyte Aggregation; Erythrocyte Deformability; Erythrocyte Membrane; Hematologic Diseases; Humans; Rheology; Risk; Spectrophotometry; Spherocytosis, Hereditary; Thalassemia
PubMed: 3914190
DOI: No ID Found -
Cellular Physiology and Biochemistry :... Mar 2021Hereditary Spherocytosis (HS) is the most common erythrocyte membrane disorder causing hemolytic anemia. The wide heterogeneity of both clinical and laboratory... (Clinical Trial)
Clinical Trial
BACKGROUND/AIMS
Hereditary Spherocytosis (HS) is the most common erythrocyte membrane disorder causing hemolytic anemia. The wide heterogeneity of both clinical and laboratory manifestations of HS contributes to difficulties associated with the diagnosis of this disorder. Although massive data previously reported worldwide, there is yet no data on HS among the Tunisian population. Here we aim to characterize HS in Tunisian patients at biochemical and cellular levels, identify the membrane protein deficiency, and compare the accuracy of the diagnostic tests to identify the most appropriate assay for HS diagnosis.
METHODS
We investigated 81 patients with hemolytic anemia and 167 normal controls. The exploration of HS based on clinical and family history, physical examination, and the results of laboratory tests: blood smear, osmotic fragility test (OFT), cryohemolysis test (CT), pink test (PT), eosine-5'-maleimide (EMA) test, and erythrocyte membrane protein electrophoresis.
RESULTS
We identified 21 patients with HS, classified as severe (6/21;28.5%), moderate (10/21;47.6%), and mild (5/21;23.8%). The most prevalent protein deficiency was the band 3 protein detected in ten Tunisian HS patients. The EMA test showed a high specificity (97.5%) and sensitivity (94.7%) for HS diagnosis compared to the other screening tests. Interestingly, fourteen among sixteen patients presenting with homozygous sickle cells HbSS showed an increase of EMA fluorescence intensity compared to other anemic patients.
CONCLUSION
Our study highlights the efficiency of the EMA dye for the detection of HS whatever the nature of the involved protein deficiency. We report for the first time, the most prevalent protein deficiency among Tunisians with HS. Moreover, we found that the combination of the EMA-binding test with PT or incubated OFT improves the diagnosis sensitivity while maintaining a good specificity.
Topics: Adolescent; Adult; Child; Child, Preschool; Eosine Yellowish-(YS); Erythrocyte Membrane; Female; Flow Cytometry; Humans; Infant; Male; Membrane Proteins; Osmotic Fragility; Proteomics; Spherocytosis, Hereditary; Tunisia
PubMed: 33667330
DOI: 10.33594/000000333 -
Archivos Argentinos de Pediatria Apr 2015Hereditary spherocytosis must always be suspected in children with anemia, hyperbilirubinemia, splenomegaly or cholelithiasis, in the asymptomatic individual with an... (Review)
Review
Hereditary spherocytosis must always be suspected in children with anemia, hyperbilirubinemia, splenomegaly or cholelithiasis, in the asymptomatic individual with an affected relative, and in the neonate with hyperbilirubinemia with no blood group incompatibility; its early detection is key to avoid kernicterus. Follow-up of these patients is based on periodical control and supply of information on the adequate management of hemolytic or aplastic crisis, and early detection of cholelithiasis. The decision to perform splenectomy is usually associated with quality of life rather than life-threatening risk, and it should result from a consensus between patient, parents and physicians. The postsplenectomy follow-up is based on control of compliance with the prophylactic antibiotic therapy and the early diagnosis of infectious disorders.
Topics: Adolescent; Child; Child, Preschool; Humans; Spherocytosis, Hereditary; Splenectomy; Treatment Outcome
PubMed: 25727830
DOI: 10.5546/aap.2015.168 -
Experimental Physiology Jan 2006Plasmalemmal Cl- -HCO3- exchangers regulate intracellular pH and [Cl-] and cell volume. In polarized epithelial cells, they contribute also to transepithelial secretion... (Comparative Study)
Comparative Study Review
Plasmalemmal Cl- -HCO3- exchangers regulate intracellular pH and [Cl-] and cell volume. In polarized epithelial cells, they contribute also to transepithelial secretion and reabsorption of acid-base equivalents and of Cl-. Members of both the SLC4 and SLC26 mammalian gene families encode Na+-independent Cl- -HCO3- exchangers. Human SLC4A1/AE1 mutations cause either the erythroid disorders spherocytic haemolytic anaemia or ovalocytosis, or distal renal tubular acidosis. SLC4A2/AE2 knockout mice die at weaning. Human SLC4A3/AE3 polymorphisms have been associated with seizure disorder. Although mammalian SLC4/AE polypeptides mediate only electroneutral Cl- -anion exchange, trout erythroid AE1 also promotes osmolyte transport and increased anion conductance. Mouse AE1 is required for DIDS-sensitive erythroid Cl- conductance, but definitive evidence for mediation of Cl- conductance is lacking. However, a single missense mutation allows AE1 to mediate both electrogenic SO4(2-) -Cl- exchange or electroneutral, H+-independent SO4(2)- -SO4(2-) exchange. In the Xenopus oocyte, the AE1 C-terminal cytoplasmic tail residues reported to bind carbonic anhydrase II are dispensable for Cl- -Cl- exchange, but required for Cl- -HCO3- exchange. AE2 is acutely and independently inhibited by intracellular and extracellular H+, and this regulation requires integrity of the most highly conserved sequence of the AE2 N-terminal cytoplasmic domain. Individual missense mutations within this and adjacent regions identify additional residues which acid-shift pHo sensitivity. These regions together are modelled to form contiguous surface patches on the AE2 cytoplasmic domain. In contrast, the N-terminal variant AE2c polypeptide exhibits an alkaline-shifted pHo sensitivity, as do certain transmembrane domain His mutants. AE2-mediated anion exchange is also stimulated by ammonium and by hypertonicity by a mechanism sensitive to inhibition by chelation of intracellular Ca2+ and by calmidazolium. This growing body of structure-function data, together with increased structural information, will advance mechanistic understanding of SLC4 anion exchangers.
Topics: Acidosis, Renal Tubular; Amino Acid Sequence; Animals; Anion Exchange Protein 1, Erythrocyte; Anion Transport Proteins; Antiporters; Carbonic Anhydrases; Chloride-Bicarbonate Antiporters; Elliptocytosis, Hereditary; Humans; Hydrogen-Ion Concentration; Molecular Sequence Data; Multigene Family; Mutation; Polymorphism, Genetic; Protein Conformation; SLC4A Proteins; Spherocytosis, Hereditary; Structure-Activity Relationship
PubMed: 16239253
DOI: 10.1113/expphysiol.2005.031765 -
JCI Insight Oct 2023Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function...
Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS lead to perturbation of the RBC metabolome, with altered glycolysis. In mice genetically lacking protein 4.2 (4.2-/-; Epb42), a murine model of HS, we showed increased expression of pyruvate kinase (PK) isoforms in whole and fractioned RBCs in conjunction with abnormalities in the glycolytic pathway and in the glutathione (GSH) system. Mitapivat, a PK activator, metabolically reprogrammed 4.2-/- mouse RBCs with amelioration of glycolysis and the GSH cycle. This resulted in improved osmotic fragility, reduced phosphatidylserine positivity, amelioration of RBC cation content, reduction of Na/K/Cl cotransport and Na/H-exchange overactivation, and decrease in erythroid vesicles release in vitro. Mitapivat treatment significantly decreased erythrophagocytosis and beneficially affected iron homeostasis. In mild-to-moderate HS, the beneficial effect of splenectomy is still controversial. Here, we showed that splenectomy improves anemia in 4.2-/- mice and that mitapivat is noninferior to splenectomy. An additional benefit of mitapivat treatment was lower expression of markers of inflammatory vasculopathy in 4.2-/- mice with or without splenectomy, indicating a multisystemic action of mitapivat. These findings support the notion that mitapivat treatment should be considered for symptomatic HS.
Topics: Animals; Mice; Disease Models, Animal; Spherocytosis, Hereditary; Erythrocytes; Anemia, Hemolytic
PubMed: 37676741
DOI: 10.1172/jci.insight.172656 -
Stem Cell Research & Therapy Dec 2012Erythrocytes contain oxygen-carrying hemoglobin to all body cells. Impairments in the generation of erythrocytes, a process known as erythropoiesis, or in hemoglobin... (Review)
Review
Erythrocytes contain oxygen-carrying hemoglobin to all body cells. Impairments in the generation of erythrocytes, a process known as erythropoiesis, or in hemoglobin synthesis alter cell function because of decreased oxygen supply and lead to anemic diseases. Thus, understanding how erythropoiesis is regulated during embryogenesis and adulthood is important to develop novel therapies for anemia. The zebrafish, Danio rerio, provides a powerful model for such study. Their small size and the ability to generate a large number of embryos enable large-scale analysis, and their transparency facilitates the visualization of erythroid cell migration. Importantly, the high conservation of hematopoietic genes among vertebrates and the ability to successfully transplant hematopoietic cells into fish have enabled the establishment of models of human anemic diseases in fish. In this review, we summarize the current progress in our understanding of erythropoiesis on the basis of zebrafish studies and highlight fish models of human anemias. These analyses could enable the discovery of novel drugs as future therapies.
Topics: Anemia; Anemia, Dyserythropoietic, Congenital; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Ankyrins; Cation Transport Proteins; Disease Models, Animal; Erythrocytes; Erythropoiesis; Genetic Diseases, X-Linked; Hemochromatosis; Spherocytosis, Hereditary; Zebrafish
PubMed: 23257067
DOI: 10.1186/scrt146 -
Leukemia Research Reports 2022Hereditary spherocytosis (HS) is the most prevalent red blood cell (RBC) membrane disorder. We report a rare case of acquired spherocytosis coinciding with a...
Hereditary spherocytosis (HS) is the most prevalent red blood cell (RBC) membrane disorder. We report a rare case of acquired spherocytosis coinciding with a myelodysplastic syndrome associated mutation, neither found in germline DNA. The diagnosis was confirmed by Eosin-5-Maleimide binding assay and Next Generation Sequencing (NGS). The patient recovered quickly after splenectomy, which confirms that his myelodysplastic syndrome (MDS)-associated mutation did not affect the clinical picture. This case highlights the essence of thoroughly examining the etiology of hemolytic indices, despite bone marrow morphology and myeloid gene panel supporting a diagnosis of MDS with single line dysplasia.
PubMed: 35720514
DOI: 10.1016/j.lrr.2022.100332 -
British Journal of Haematology Jun 2009Splenectomy is indicated in hereditary spherocytosis to relieve symptoms due to anaemia or splenomegaly, reverse growth failure or skeletal changes due to over-robust... (Review)
Review
Splenectomy is indicated in hereditary spherocytosis to relieve symptoms due to anaemia or splenomegaly, reverse growth failure or skeletal changes due to over-robust erythropoiesis, and prevent recurrent gallstones. A life-long risk of bacterial infection has been recognised for many years as a concomitant cost of splenectomy. The scope of this risk has expanded to include a number of organisms beyond the triad of pneumococcus, meningococcus, and haemophilus influenzae. Recently, it has been demonstrated that splenectomy also confers a significant risk of delayed adverse vascular events in patients with hereditary spherocytosis, just as it does in patients undergoing splenectomy for other indications. Further, these same studies demonstrated a benefit of avoiding splenectomy: hereditary spherocytosis patients with a spleen have significantly fewer adverse vascular events than unaffected family members, probably because of the protective effect of chronic, mild anaemia. Accordingly, this review marshals the evidence favouring a conservative approach to splenectomy in spherocytosis.
Topics: Adult; Bacterial Infections; Child; Humans; Myocardial Infarction; Patient Selection; Risk; Spherocytosis, Hereditary; Splenectomy; Treatment Outcome
PubMed: 19388926
DOI: 10.1111/j.1365-2141.2009.07694.x