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Hemolytic Anemia Associated with Red Cell Membrane Defects
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Several other hematologic conditions produce elliptocytes, including iron deficiency, thalassemia, sickle disease, myelophthisic anemias, myelofibrosis, and megaloblastic anemia. It is uncommon for these disorders, however, to result in elliptocytosis as the predominant morphology or elliptocytes in the absence of other poikilocytes. Hereditary pyropoikilocytosis (see below) often demonstrates a significant degree of elliptocytosis. A rare hybrid disorder, hereditary spheroelliptocytosis, has features of both HS and HE. Erythrocytes have both mechanical instability and osmotic fragility. This diagnosis must be considered in cases of hemolytic HE.
Inherited Disorders of Red Cell Membrane Proteins
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Hereditary pyropoikilocytosis is a rare disease which presents early in infancy as a severe microcytic hemolytic anemia with bizarre poikilocytic, fragmented, budding, elliptocytic, and spherocytic red cells.91 As seen in hereditary spherocytosis, the osmotic fragility is abnormal, and there is amelioration of the hemolysis following spelenectomy. Of major diagnostic importance is the marked thermal instability of the red cells, which fragment at 46°C, compared to normal red cells which do not fragment until 49°C. It is becoming clear that hereditary pyropoikilocytosis is a variation on the hereditary elliptocytosis theme. In a number of families with hereditary pyropoikilocytosis, there are family members with classical hereditary elliptocytosis. In addition, the molecular pathology of hereditary pyropoikilocytosis appears to be identical to that of the variety of hereditary elliptocytosis with abnormal spectrin self-association.
Rheology of the Hemolytic Anemias
Published in Gordon D. O. Lowe, Clinical Blood Rheology, 2019
In hereditary pyropoikilocytosis (HP) the dramatic blood film appearances of poikilocytosis and fragmentation are morphologically similar to those of thermal injury and Zarkowsky et al.77 demonstrated a lower threshold temperature (45°C) for heat-induced erythrocyte fragmentation in these patients. Again the thermal instability of HP erythrocytes is shown also by isolated spectrin, with denaturation occurring at 44°C.78 A structural defect of the a-chain of spectrin with defective formation of tetramers has now been shown in several patients.79-82 A quantitative reduction of above 30% in membrane spectrin may be associated.83 The molecular defects in HP and HE are very similar, and may be identical, with HP being the more severe form. Indeed, the two disorders may alternate in different generations of the same family.
Screening tools for hereditary hemolytic anemia: new concepts and strategies
Published in Expert Review of Hematology, 2021
Elisa Fermo, Cristina Vercellati, Paola Bianchi
RBC membrane defects are characterized by qualitative or quantitative abnormalities of the erythrocyte cytoskeletal proteins, which constitute a complex structure that determines the erythrocyte shape and deformability, and regulates the hydration state and cell volume. These alterations result in typical abnormalities in RBC morphology that can be observed at peripheral blood smear examination. The most common defects involve alterations in the membrane structural organization; in hereditary spherocytosis (HS), defects of ankyrin, spectrin, protein band 3, and band 4.2 impair the vertical linkage between the cytoskeleton and the membrane lipidic bilayer, leading to the release of microvesicles and loss of surface; conversely, impairment of the horizontal associations of the RBC cytoskeleton due to alterations in spectrin dimers or spectrin-actin-protein 4.1 complexes, results in hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (HPP). Given the constitutional expression and the double function (structural and membrane channel) of band 3, abnormalities in this protein may be associated to the severe form of distal renal tubular acidosis (dRTA), with or without HS [1,2].
Hereditary red blood cell membrane defects. Detection of PIEZO1 mutations associated with SPTA1 mutations. An unusual clinical case of hereditary xerocytosis
Published in Pediatric Hematology and Oncology, 2020
Carmelo Fortugno, Eulalia Galea, Renato Cantaffa, Francesco Gigliotti, Rachele Lucia Fabiano, Valentina Talarico, Giuseppe Raiola, Maria Concetta Galati
Hereditary spherocytosis is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia characterized by sphere-shaped erythrocytes (spherocytes) with increased osmotic fragility. Hereditary spherocytosis can affect all ethnic groups but is more common in people of northern European ancestry where the prevalence is 1 in 1000–2500. Spherocytes are formed because of loss of membrane due to quantitative defects in proteins that link the cytoskeleton to the lipid bilayer (“vertical” linkages). The scaffolding network of the RBC cytoskeleton is assembled by α- and β-spectrin heterodimers self-associating in a head-to-head fashion to form tetramers, bound to the lipid membrane via the anchoring complex of ankyrin, protein 4.2, and band 3. In autosomal dominant Hereditary spherocytosis, which accounts for approximately 75% of cases, mutations of ankyrin (ANK1), band 3 (SLC4A1), and β-spectrin (SPTB) genes predominate. Recessive Hereditary spherocytosis is most often due to compound heterozygosity for defects in the genes encoding ankyrin, α-spectrin (SPTA1), or protein 4.2 (EPB42). Two SPTA1 low expression alleles were identified early-on to be associated with RBC membrane disorders and their study helped to determine the quantitative requirements of the RBC cytoskeleton for α-spectrin. αLELY(Low Expression LYon) has a minor allele frequency (MAF) of 25.5% and consists of the mutation c.6531-12C > T in intron 45, causing partial skipping of exon 46 in half of the transcripts and consequently a 50% decrease in the amount of α-spectrin. αLELYin trans to an SPTA1 allele with a hereditary elliptocytosis (HE)-associated mutation modifies the phenotype from HE to hereditary pyropoikilocytosis. In contrast, αLELYin trans to a null SPTA1 allele causes no disease, indicating that production of ∼25% of normal α-spectrin is enough for normal RBC cytoskeleton assembly.7–9 The severity of Hereditary spherocytosis is directly related to the extent of the surface loss and consequently to the degree of spherocytosis: among the RBC indices, the percentage of microcytes is the best indicator of the disease severity.