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Chapter 33 Pathobiology of the Human Erythrocyte and Its Hemoglobins 457

SUGGESTED READINGS
TABLE Classification of Hemoglobinopathies and
33.1 Thalassemias
Bank A: Regulation of human fetal hemoglobin: new players, new complexi-
Structural hemoglobinopathies—mutations altering the amino acid ties. Blood 107:435, 2006.
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properties of the hemoglobin tetramer in such a way that function is viability in red cell aging and in hemolytic anemia. Proc Natl Acad Sci
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Abnormal Hemoglobin Polymerization—Sickle Cell Hemoglobin (HbS); Burgess-Beusse B, Farrell C, Gaszner M, et al: The insulation of genes from
Hemolysis, Vasoocclusion external enhancers and silencing chromatin. Proc Natl Acad Sci USA
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High oxygen affinity—polycythemia (Hb Zurich) Cantor AB, Orkin SH: Transcriptional regulation of erythropoiesis: an affair
Low oxygen affinity—cyanosis (Hb Kansas) involving multiple partners. Oncogene 21:3368, 2002.
Hbs that oxidize or precipitate too readily—unstable Hbs (Hb Köln) Chakalova L, Carter D, Debrand E, et al: Developmental regulation of the
M Hbs—methemoglobinemia, cyanosis (e.g., Hb Milwaukee) beta-globin gene locus. Prog Mol Subcell Biol 38:183, 2005.
Thalassemia—Defective Production of Globin Chains With Hypochromia, Chiu CH, Schneider H, Slightom JL, et al: Dynamics of regulatory evolution
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β-Thalassemia Dzierzak E: The emergence of definitive hematopoietic stem cells in the
δβ-Thalassemias, γδβ-thalassemias, αβ-thalassemias mammal. Curr Opin Hematol 12:197, 2005.
“Thalassemic” Hemoglobinopathies and Dominantly Inherited Feng L, Zhou S, Gu L, et al: Structure of oxidized alpha-haemoglobin bound
Thalassemias—Mutations Altering the Synthesis and Structure or Function to AHSP reveals a protective mechanism for haem. Nature 435:697, 2005.
of the Hemoglobin Gene Products (e.g., HbE, Hb Terre Haute, Hb Lepore, Hb Gibbons RJ, Picketts DJ, Villard L, et al: Mutations in a putative global tran-
Constant Spring) scriptional regulator cause X-linked mental retardation with α-thalassemia
Hereditary persistence of fetal hemoglobin (HbF)—persistence of (ATR-X syndrome). Cell 80:837, 1995.
high levels of HbF into adult life Gladwin MT, Wang X, Reiter CD, et al: S-nitrosohemoglobin is unstable in
Pancellular—high HbF levels in all RBCs the reductive erythrocyte environment and lacks O 2 /NO-linked allosteric
Nondeletion forms function. J Biol Chem 277:27818, 2002.
Deletion forms Gow AJ, Stamler JS: Reactions between nitric oxide and haemoglobin under
Hb Kenya physiological conditions. Nature 391:169, 1998.
Heterocellular—inherited increases in the percentage of F cells Hardison R, Riemer C, Chui DH, et al: Electronic access to sequence align-
Acquired hemoglobinopathies ments, experimental results, and human mutations as an aid to studying
Methemoglobinemia Caused by Toxic Exposures globin gene regulation. Genomics 47:429, 1998.
Sulfhemoglobinemia caused by toxic exposures Higgs DR, Garrick D, Anguita E, et al: Understanding alpha-globin gene
Carboxyhemoglobinemia caused by toxic exposures regulation: Aiming to improve the management of thalassemia. Ann N Y
HbH in erythroleukemias Acad Sci 1054:92, 2005.
Acquired elevations in F cells and HbF Jenuwein T, Allis CD: Translating the histone code. Science 293:1074, 2001.
Erythroid stress (e.g., recovery from BM suppression) Kato GJ, McGowan V, Machado RF, et al: Lactate dehydrogenase as a
BM dysplasias biomarker of hemolysis-associated nitric oxide resistance, priapism, leg
Exposure to agents altering stem cells or gene expression (e.g., ulceration, pulmonary hypertension, and death in patients with sickle
hydroxyurea, butyric acid) cell disease. Blood 107:2279, 2006.
Kihm AJ, Kong Y, Hong W, et al: An abundant erythroid protein that
BM, Bone marrow; Hb, hemoglobin; RBC, red blood cell.
stabilizes free alpha-haemoglobin. Nature 417:758, 2002.
Li Q, Peterson KR, Fang X, et al: Locus control regions. Blood 100:3077,
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NOSOLOGY OF HEMOGLOBINOPATHIES Miller IJ, Bieker JJ: A novel erythroid cell-specific murine transcription factor
that binds to the CACCC element and is related to the Kruppel family
Inherited abnormalities of the Hb molecules that cause morbidity are of nuclear proteins. Mol Cell Biol 13:2776, 1993.
called hemoglobinopathies and thalassemias. Many of these condi- Rother RP, Bell L, Hillmen P, et al: The clinical sequelae of intravascular
tions produce diseases (e.g., sickle cell anemia, thalassemia, unstable hemolysis and extracellular plasma hemoglobin: a novel mechanism of
Hbs, Hbs with altered oxygen affinity, M Hbs) that are especially human disease. JAMA 293:1653, 2005.
important to hematologists. A few acquired conditions lead to modi- Stamatoyannopoulos G: Control of globin gene expression during develop-
fications of Hb (e.g., carbon monoxide exposure, producing carboxy- ment and erythroid differentiation. Exp Hematol 33:259, 2005.
hemoglobinemia, nitrite exposure causing methemoglobinemia) that Stamler JS, Jia L, Eu JP, et al: Blood flow regulation by S-nitrosohemoglobin
produce clinical abnormalities. These situations are summarized by in the physiological oxygen gradient. Science 276:2034, 1997.
the term acquired hemoglobinopathies or dyshemoglobinemias. Steinberg MH, Forget BG, Higgs DR, et al: Disorders of hemoglobin: genet-
Most of the more than 1200 mutations of the globin gene that ics, pathophysiology, and clinical management, ed 2, Cambridge, 2009,
have been described produce no disease or only trivial clinical effects. Cambridge University Press.
The remainder can be classified according to the hematologic and Viprakasit V, Tanphaichitr VS, Chinchang W, et al: Evaluation of alpha
clinical phenotypes that cause reduced solubility with hemolytic hemoglobin stabilizing protein (AHSP) as a genetic modifier in patients
anemia (unstable Hbs and polymerizing Hbs, such as sickle Hb); Hbs with beta thalassemia. Blood 103:3296, 2004.
with altered oxygen affinity; Hbs predisposing to methemoglobin Walsh M, Lutz RJ, Cotter TG, et al: Erythrocyte survival is promoted by
formation; and the thalassemias involving abnormal synthesis of one plasma and suppressed by a Bak-derived BH3 peptide that interacts with
or more globin chains with anemia, hemolysis, and alterations of membrane-associated Bcl-X(L). Blood 99:3439, 2002.
erythropoiesis. Some mutations, such as that responsible for HbE, Weatherall DJ, Clegg JB: The thalassaemia syndromes, ed 4, Oxford, 2001,
can alter the structure and synthesis of the molecule. A classification Blackwell Science Limited, p 818.
of hemoglobinopathies and thalassemias is provided in Table 33.1. Weiss MJ, Zhou S, Feng L, et al: Role of alpha-hemoglobin-stabilizing
Individual conditions are discussed in the chapters already cross- protein in normal erythropoiesis and beta-thalassemia. Ann N Y Acad
referenced in earlier sections of this chapter. Sci 1054:103, 2005.