Pathophysiology of alpha thalassemia
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Section Editors
- William C Mentzer, MD
William C Mentzer, MD
- Section Editor — Red Cell Disorders
- Professor of Pediatrics
- University of California, San Francisco
- Donald H Mahoney, Jr, MD
Donald H Mahoney, Jr, MD
- Section Editor — Pediatric Hematology
- Professor of Pediatrics
- Baylor College of Medicine
The major hemoglobin in children and adults is hemoglobin A (adult hemoglobin, HbA), a heterotetramer consisting of one pair of alpha globin chains and one pair of beta globin chains. These chains are derived from two copies of the alpha globin gene on chromosome 16 and a single beta globin gene on chromosome 11 (figure 1). In normal adults, globin chain synthesis is very tightly controlled such that the ratio of production of alpha to beta globin chains is 1.00±0.05. (See "Structure and function of normal hemoglobins".)
The pathophysiology of alpha thalassemia, in which this delicate balance is disrupted, will be reviewed here. This discussion will focus on the mechanisms by which the excess unmatched beta globin chain synthesis in alpha thalassemia leads to increased red blood cell destruction (hemolysis). The accumulation of excess beta chains in erythroid precursors within the bone marrow and in extramedullary sites, such as the liver and spleen, also leads to a certain amount of ineffective erythropoiesis.
The molecular pathology of the thalassemias and the pathophysiology of beta thalassemia are discussed separately. (See "Molecular pathology of the thalassemic syndromes" and "Pathophysiology of beta thalassemia".)
OVERVIEW OF THE THALASSEMIAS
Thalassemia refers to a spectrum of disorders characterized by reduced or absent production of one (or, rarely, two or more) of the globin chains, thus disrupting the delicate balance between the production of alpha and non-alpha (eg, gamma or beta) globin chains. The two most common forms are:
●Alpha thalassemia – Alpha thalassemia is due to impaired or absent production of alpha globin chains, which leads to a relative excess of gamma globin chains in the fetus and newborn, and excess beta globin chains in children and adults. While the excess beta globin chains are capable of forming soluble homotetramers (beta-4, HbH), they are unstable and some precipitate within the cell, leading to a variety of clinical manifestations. Since all normal hemoglobins of postnatal life contain alpha chains, homozygous alpha (0) thalassemia, in which no alpha globin chains can be produced, is incompatible with extrauterine life, leading to hydrops fetalis and death shortly after delivery.
- Yuan J, Bunyaratvej A, Fucharoen S, et al. The instability of the membrane skeleton in thalassemic red blood cells. Blood 1995; 86:3945.
- Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood 2003; 101:791.
- Chen FE, Ooi C, Ha SY, et al. Genetic and clinical features of hemoglobin H disease in Chinese patients. N Engl J Med 2000; 343:544.
- Weatherall D. The molecular basis for phenotypic variability of the common thalassaemias. Mol Med Today 1995; 1:15.
- Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program 2009; :26.
- Fucharoen S, Winichagoon P. Thalassemia in SouthEast Asia: problems and strategy for prevention and control. Southeast Asian J Trop Med Public Health 1992; 23:647.
- Nguyen VH, Sanchaisuriya K, Wongprachum K, et al. Hemoglobin Constant Spring is markedly high in women of an ethnic minority group in Vietnam: a community-based survey and hematologic features. Blood Cells Mol Dis 2014; 52:161.
- Clegg JB, Weatherall DJ. Thalassemia and malaria: new insights into an old problem. Proc Assoc Am Physicians 1999; 111:278.
- Flint J, Hill AV, Bowden DK, et al. High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature 1986; 321:744.
- Williams TN, Maitland K, Bennett S, et al. High incidence of malaria in alpha-thalassaemic children. Nature 1996; 383:522.
- Allen SJ, O'Donnell A, Alexander ND, et al. alpha+-Thalassemia protects children against disease caused by other infections as well as malaria. Proc Natl Acad Sci U S A 1997; 94:14736.
- Mockenhaupt FP, Ehrhardt S, Gellert S, et al. Alpha(+)-thalassemia protects African children from severe malaria. Blood 2004; 104:2003.
- Pattanapanyasat K, Yongvanitchit K, Tongtawe P, et al. Impairment of Plasmodium falciparum growth in thalassemic red blood cells: further evidence by using biotin labeling and flow cytometry. Blood 1999; 93:3116.
- RIGAS DA, KOLER RD, OSGOOD EE. Hemoglobin H; clinical, laboratory, and genetic studies of a family with a previously undescribed hemoglobin. J Lab Clin Med 1956; 47:51.
- Gouttas A, Fessas PH, Tsevrenis H, et al. Description d'une nouvelle variété d'anémie hémolytique congénitale. Vox Sang 1955; 26:911.
- DANCE N, HUEHNS ER, BEAVEN GH. The abnormal haemoglobins in haemoglobin-H disease. Biochem J 1963; 87:240.
- Wood WG, Stamatoyannopoulos G. synthesis during erythroid cell maturation in alpha thalassemia. Hemoglobin 1976-77; 1:135.
- Lehmann H. Different types of alpha-thalassemia and significance of haemoglobin Bart's in neonates. Lancet 1970; 2:78.
- Gabuzda TG. Hemoglobin H and the red cell. Blood 1966; 27:568.
- Nathan DG, Gunn RB. Thalassemia: the consequences of unbalanced hemoglobin synthesis. Am J Med 1966; 41:815.
- RIGAS DA, KOLER RD. Decreased erythrocyte survival in hemoglobin H disease as a result of the abnormal properties of hemoglobin H: the benefit of splenectomy. Blood 1961; 18:1.
- BENESCH R, BENESCH RE. PROPERTIES OF HAEMOGLOBIN H AND THEIR SIGNIFICANCE IN RELATION TO FUNCTION OF HAEMOGLOBIN. Nature 1964; 202:773.
- GABUZDA TG, NATHAN DG, GARDNER FH. THE METABOLISM OF THE INDIVIDUAL C14 LABELED HEMOGLOBINS IN PATIENTS WITH H-THALASSEMIA, WITH OBSERVATIONS ON RADIOCHROMATE BINDING TO THE HEMOGLOBINS DURING RED CELL SURVIVAL. J Clin Invest 1965; 44:315.
- Schrier SL, Rachmilewitz E, Mohandas N. Cellular and membrane properties of alpha and beta thalassemic erythrocytes are different: implication for differences in clinical manifestations. Blood 1989; 74:2194.
- Bunyaratvej A, Sahaphong S, Bhamarapravati N, Wasi P. Different patterns of intraerythrocytic inclusion body distribution in the two types of haemoglobin H disease. An ultrastructural study. Acta Haematol 1983; 69:314.
- Bunyaratvej A, Butthep P, Fucharoen S, Saw D. Erythrocyte volume and haemoglobin concentration in haemoglobin H disease: discrimination between the two genotypes. Acta Haematol 1992; 87:1.
- PEARSON HA, McFARLAND W. Erythrokinetics in thalassemia. II. Studies in Lepore trait and hemoglobin H disease. J Lab Clin Med 1962; 59:147.
- Malamos B, Gyftaki E, Binopoulos D, et al. Studies of haemoglobin synthesis and red cell survival in haemoglobinopathy. Acta Haematol 1962; 28:124.
- Papassotiriou I, Traeger-Synodinos J, Kanavakis E, et al. Erythroid marrow activity and hemoglobin H levels in hemoglobin H disease. J Pediatr Hematol Oncol 1998; 20:539.
- Rees DC, Williams TN, Maitland K, et al. Alpha thalassaemia is associated with increased soluble transferrin receptor levels. Br J Haematol 1998; 103:365.
- Schrier SL, Bunyaratvej A, Khuhapinant A, et al. The unusual pathobiology of hemoglobin constant spring red blood cells. Blood 1997; 89:1762.
- Adirojnanon P, Wasi P. Levels of haemoglobin H and proportions of red cells with inclusion bodies in the two types of haemoglobin H disease. Br J Haematol 1980; 46:507.
- Wickramasinghe SN, Lee MJ, Furukawa T, et al. Composition of the intra-erythroblastic precipitates in thalassaemia and congenital dyserythropoietic anaemia (CDA): identification of a new type of CDA with intra-erythroblastic precipitates not reacting with monoclonal antibodies to alpha- and beta-globin chains. Br J Haematol 1996; 93:576.
- Rachmilewitz EA, Peisach J, Bradley TB, Blumberg WE. Role of haemichromes in the formation of inclusion bodies in haemoglobin H disease. Nature 1969; 222:248.
- Waugh SM, Low PS. Hemichrome binding to band 3: nucleation of Heinz bodies on the erythrocyte membrane. Biochemistry 1985; 24:34.
- Hebbel RP. Auto-oxidation and a membrane-associated 'Fenton reagent': a possible explanation for development of membrane lesions in sickle erythrocytes. Clin Haematol 1985; 14:129.
- Allen TM, Williamson P, Schlegel RA. Phosphatidylserine as a determinant of reticuloendothelial recognition of liposome models of the erythrocyte surface. Proc Natl Acad Sci U S A 1988; 85:8067.
- Kuypers FA, Yuan J, Lewis RA, et al. Membrane phospholipid asymmetry in human thalassemia. Blood 1998; 91:3044.
- Chinprasertsuk S, Wanachiwanawin W, Pattanapanyasat K, et al. Relation of haemolytic anaemia and erythrocyte-bound IgG in alpha- and beta-thalassaemic syndromes. Eur J Haematol 1997; 58:86.
- Wiener E, Wanachiwanawin W, Kotipan K, et al. Erythroblast- and erythrocyte-bound antibodies in alpha and beta thalassaemia syndromes. Transfus Med 1991; 1:229.
- Wiener E, Wanachiwanawin W, Chinprasertsuk S, et al. Increased serum levels of macrophage colony-stimulating factor (M-CSF) in alpha- and beta-thalassaemia syndromes: correlation with anaemia and monocyte activation. Eur J Haematol 1996; 57:364.
- Advani R, Sorenson S, Shinar E, et al. Characterization and comparison of the red blood cell membrane damage in severe human alpha- and beta-thalassemia. Blood 1992; 79:1058.
- Sancar GB, Cedeno MM, Rieder RF. Rapid destruction of newly synthesized excess beta-globin chains in HbH disease. Blood 1981; 57:967.
- Pootrakul P, Winichagoon P, Fucharoen S, et al. Homozygous haemoglobin Constant Spring: a need for revision of concept. Hum Genet 1981; 59:250.
- Schrier SL, Mohandas N. Globin-chain specificity of oxidation-induced changes in red blood cell membrane properties. Blood 1992; 79:1586.
- Scott MD, Rouyer-Fessard P, Ba MS, et al. Alpha- and beta-haemoglobin chain induced changes in normal erythrocyte deformability: comparison to beta thalassaemia intermedia and Hb H disease. Br J Haematol 1992; 80:519.
- Cheng ML, Ho HY, Tseng HC, et al. Antioxidant deficit and enhanced susceptibility to oxidative damage in individuals with different forms of alpha-thalassaemia. Br J Haematol 2005; 128:119.
- Nathan DG, Stossel TB, Gunn RB, et al. Influence of hemoglobin precipitation on erythrocyte metabolism in alpha and beta thalassemia. J Clin Invest 1969; 48:33.
- Prasartkaew S, Bunyaratvej A, Fucharoen S, Wasi P. Comparison of erythrocyte antioxidative enzyme activities between two types of haemoglobin H disease. J Clin Pathol 1986; 39:1299.
- Shinar E, Rachmilewitz EA, Lux SE. Differing erythrocyte membrane skeletal protein defects in alpha and beta thalassemia. J Clin Invest 1989; 83:404.
- Shalev O, Shinar E, Lux SE. Isolated beta-globin chains reproduce, in normal red cell membranes, the defective binding of spectrin to alpha-thalassaemic membranes. Br J Haematol 1996; 94:273.
- Pootrakul P, Sirankapracha P, Hemsorach S, et al. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassemia. Blood 2000; 96:2606.
- Fessas P, Yatachanas X. Intraerythroblastic instability of hemoglobin beta-4 (Hgb H). Blood 1968; 31:323.
- Wickramasinghe SN, Hughes M, Fucharoen S, Wasi P. The fate of excess beta-globin chains within erythropoietic cells in alpha-thalassaemia 2 trait, alpha-thalassaemia 1 trait, haemoglobin H disease and haemoglobin Q-H disease: an electron microscope study. Br J Haematol 1984; 56:473.
- Chui DH, Waye JS. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood 1998; 91:2213.
- Pászty C, Mohandas N, Stevens ME, et al. Lethal alpha-thalassaemia created by gene targeting in mice and its genetic rescue. Nat Genet 1995; 11:33.
- Randhawa ZI, Jones RT, Lie-Injo LE. Human hemoglobin Portland II (zeta 2 beta 2). Isolation and characterization of Portland hemoglobin components and their constituent globin chains. J Biol Chem 1984; 259:7325.
- Brandenburg H, Bartelings MM, Wisse LJ, et al. Increased expression of vascular endothelial growth factor in cardiac structures of fetus with hydrops as compared to nonhydropic controls. Fetal Diagn Ther 2006; 21:84.
- Ng PC, Fok TF, Lee CH, et al. Is homozygous alpha-thalassaemia a lethal condition in the 1990s? Acta Paediatr 1998; 87:1197.
- Hayward A, Ambruso D, Battaglia F, et al. Microchimerism and tolerance following intrauterine transplantation and transfusion for alpha-thalassemia-1. Fetal Diagn Ther 1998; 13:8.
- OVERVIEW OF THE THALASSEMIAS
- Alpha (0) thalassemia
- Alpha (+) thalassemia
- Complex alpha thalassemia variants
- Protection against severe malaria
- HEMOGLOBIN H DISEASE
- Consequences of impaired alpha globin synthesis
- - Red blood cell size and shape
- - Red blood cell hydration
- - Hemolytic anemia
- Removal of alpha thalassemic red blood cells by spleen and macrophages
- - Reduced RBC deformability
- - Abnormal RBC membrane features
- Increased membrane rigidity
- Increased RBC membrane stability
- Red blood cell inclusions
- Phosphatidylserine signaling
- Membrane IgG and complement
- Macrophage colony-stimulating factor
- Biochemical and cellular alterations leading to hemolysis
- - Membrane bound beta globin chains
- - Role of oxidant injury
- - Other evidence of RBC membrane damage
- Ineffective erythropoiesis
- HYDROPS FETALIS AND HEMOGLOBIN BART'S
- SOCIETY GUIDELINE LINKS