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Hemoglobin (Hb) is the oxygen-carrying protein within red blood cells (RBCs). It is composed of four globular protein subunits, called globins, and four oxygen-binding heme groups, which are attached to each globin. The two main types of globins are the α-globins and the β-globins, which are made in essentially equivalent amount in precursors of RBCs. Normal adult Hb (Hb A) has two α-globins and two β-globins (α2 β2). Genes on chromosomes 16 and 11 encode the α- and β-globins, respectively. There are also distinct embryonic, fetal, and minor adult analogs of the α- and β-globins, all of which are encoded by separate genes. Most important among these are the γ- and δ-globins, which are the fetal and minor adult analogs of α- and β-globin, respectively. See Chapter 429 for a discussion of the developmental changes in Hb production.

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Disorders of Hb can be classified as qualitative or quantitative disorders. Qualitative abnormalities of Hb arise from mutations that change the amino acid sequence of the globin, thereby producing structural and functional changes in the Hb. There are four ways in which Hb can be qualitatively abnormal: (1) decreased solubility, (2) instability, (3) altered oxygen affinity, and (4) altered oxidation state of the heme-coordinated iron. Qualitative Hb disorders are often referred to as hemoglobinopathies, even though the term can technically apply to both qualitative and quantitative disorders. Quantitative Hb disorders result from the decreased and imbalanced production of generally structurally normal globins. For example, if β-globin production is diminished by a mutation, there will be a relative excess of α-globins. Such imbalanced production of α- and β-globins damages RBCs and their precursors in the bone marrow. These quantitative Hb disorders are called thalassemias. Both qualitative and quantitative disorders of Hb can be subdivided by the particular globin that is affected; for example, there can be α-thalassemias and β-hemoglobinopathies. We begin this chapter with a review of several of the common qualitative Hb disorders and end with a discussion of the thalassemias.

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Sickle cell disease (SCD) is the name for a group of related disorders caused by sickle Hb (Hb S).1 Hb S is a qualitatively abnormal Hb caused by a point mutation of the β-globin gene. The sixth codon of the normal β-globin gene, GAG, codes for glutamic acid. In Hb S, the adenine nucleotide is replaced by thymidine, producing GTG, which is a codon for valine. This mutation replaces a hydrophilic glutamic acid with a hydrophobic valine, permitting abnormal hydrophobic interactions between adjacent deoxyhemoglobin molecules. This change decreases the solubility of Hb S in the deoxygenated state. Thus, as sickle red blood cells (RBCs) traverse the circulation, cycling through oxygenated and deoxygenated states, Hb S repeatedly forms rigid polymers that damage the RBC membrane, causing a hemolytic anemia and, ultimately, the manifestations of SCD.

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Epidemiology

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Sickle cell trait, the heterozygous or carrier state for the ...

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