Chapter 231

Hereditary hemolytic anemias result primarily from a defect in hemoglobin (Hb) production, red blood cell (RBC) metabolism, or the structure of the RBC membrane. Hemolysis, primarily in the spleen, is a normal process whereby abnormal, damaged, and aged RBCs are removed from the circulation. If an increased number of abnormal RBC are produced, hemolytic activity is enhanced, and, depending on the ability rate of production, the concentration of circulating RBC may decrease, manifesting as anemia.

Inherited Hb disorders are classified into two main groups: disorders with abnormal Hb structure [e.g., sickle cell disease (SCD)] and disorders of abnormal Hb production (e.g., the thalassemias). These disorders are widely prevalent, and it is thought that 7% of the world’s population are carriers of an abnormal Hb gene.1 Most of these inherited Hb disorders are the result of point mutation in the genes that code for the globin chains of the Hb molecule, along with other variations, such as deletions, insertions, extended chains, and fusions. These genetic abnormalities result in Hb that tends to gel or crystallize, possesses abnormal oxygen-binding properties, or is readily oxidized to methemoglobin, rendering the RBC susceptible to hemolysis. Disorders of RBC metabolism or cell membrane function also render the cell more sensitive to hemolysis.

### Epidemiology

SCD is a significant public health problem. Sixty million carriers of sickle cell and 1.2 million sickle cell homozygotes are added every year worldwide.2 An estimated 250 million people (approximately 4.5% of the world population) are carriers of the sickle cell gene.3 Sickle cell disorders account for approximately 70% of congenital Hb disorders seen worldwide.3 SCD affects predominantly people of African Equatorial descent, although it is also found in persons of Mediterranean, Indian, and Middle Eastern origin.4 SCD affects approximately 70,000 people in the U.S., and approximately 2 million Americans have the sickle cell trait.5

During the last few decades, the overall life expectancy of patients with SCD has improved from 14 to >50 years.6 This can be attributed to early diagnosis (antenatal and neonatal screening), parental education about complications, close monitoring in clinics and follow-up, prophylactic penicillins to prevent pneumococcal septicemia, and increased usage of drugs such as hydroxyurea.

### Pathophysiology

The normal adult RBC contains three forms of Hb: HbA, HbA2, and fetal Hb (HbF) (Table 231-1). All normal Hb 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 Hb and consists of two α- and two β-globin chains. HbA2 accounts for approximately 2.0% to 3.5% of adult Hb 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 and continues to decline, reaching ...

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