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INTRODUCTION

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Hereditary anemias result from defects in hemoglobin production, abnormalities in red blood cell (RBC) metabolism, or changes within RBC membrane structure. Increased hemolysis occurs because the RBCs produced are either abnormal or sustain damage after release from the bone marrow, and are removed from the circulation, primarily by the spleen. Depending on the compensatory rate of production, the concentration of circulating erythrocytes may decrease, resulting in anemia.

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Inherited hemoglobin disorders are comprised of two main groups: disorders with abnormal hemoglobin structure (e.g., sickle cell disease) and disorders of abnormal hemoglobin production (e.g., the thalassemias). These disorders are widely prevalent; an estimated 7% of the world's population are carriers of an abnormal hemoglobin gene.1 These genetic abnormalities result in hemoglobin that tends to gel or crystallize, possesses abnormal oxygen-binding properties, or is readily oxidized to methemoglobin, rendering the RBC susceptible to hemolysis.

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SICKLE CELL DISEASE

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Sickle cell disease (SCD) is a worldwide public health problem.2 An estimated 250 million people (approximately 4.5% of the world population) are carriers of the sickle cell gene,3 with 60 million new carriers of sickle cell and 1.2 million new individuals with SCD diagnosed every year.4 SCD affects predominantly people of African Equatorial descent, although it is also found in persons of Mediterranean, Indian, and Middle Eastern origin.5,6 SCD affects approximately 70,000 people in the United States, and about 2 million Americans are sickle cell gene carriers.7

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The overall life expectancy of patients in the United States with SCD is now >50 years,8 an improvement attributed to early diagnosis (antenatal and neonatal screening), parental education about complications, close monitoring in clinics and follow-up, immunizations, prophylactic penicillin to prevent pneumococcal septicemia, and increased use of drugs such as hydroxyurea.9

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PATHOPHYSIOLOGY

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The normal adult RBC contains three forms of hemoglobin: HbA, HbA2, and fetal hemoglobin (HbF) (Table 236-1). Normal hemoglobin consists of a tetramer of four polypeptide chains, which are pairs of dissimilar chains (two α-globin chains and two non–α-globin chains). HbA accounts for approximately 96% to 98% of adult hemoglobin and consists of two α- and two β-globin chains. HbA2 accounts for approximately 2.0% to 3.5% of adult hemoglobin and is composed of two α- and two δ-globin chains. HbF is composed of two α- and two γ-globin chains. HbF production peaks in utero and starts declining just before birth, reaching a baseline of <1% at approximately 48 weeks of age. Because of the 120-day life span of the normal RBC, HbF is the predominant form in the circulation for approximately the first 4 months of life. The α-globin chains are coded by four genes, two each on chromosomes 16, whereas the β-, γ-, and δ-globin chains are coded by two genes, one each on chromosomes 11.

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Table Graphic Jump Location
TABLE 236-1Composition of Normal Human Hemoglobin and Hemoglobin Variants

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