Chapter 236: Sickle Cell Disease and Hereditary Hemolytic Anemias

INTRODUCTION

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.

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). About 5% of the world’s population are carriers of a clinically significant 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.

SICKLE CELL DISEASE

Sickle cell disease (SCD) is a group of genetic RBC disorders that constitute a worldwide public health problem.^2,3 An estimated 250 million people (approximately 4.5% of the world population) are carriers of the sickle cell gene,¹ with an estimated >250,000 new individuals born each year with SCD.¹ SCD affects predominantly people of African Equatorial descent, although it is also found in persons of Mediterranean, Indian, and Middle Eastern origin.¹ SCD affects approximately 100,000 people in the United States, and about 2 million Americans are sickle cell gene carriers.⁴ One of every 13 African Americans carries the sickle cell gene, and SCD occurs in 1 of every 365 African American births.⁴

Antenatal and neonatal screening, parental education about complications, monitoring in clinics and close follow-up, immunizations, prophylactic penicillin to prevent pneumococcal septicemia, and increased use of drugs such as hydroxyurea counteract the high mortality rate seen with untreated SCD. In the United States, survival to age 18 years approaches 94%, and the overall life expectancy is >50 years.^5,6

PATHOPHYSIOLOGY

SCD is characterized by RBCs that contain at least one abnormal hemoglobin, hemoglobin S. Hemoglobin is made of iron (heme) and protein chains (globin). There are four types of globin molecule chains (alpha, beta, gamma, and delta), which determine the type of hemoglobin present.⁷ Hemoglobin A, the normal constituent of adult hemoglobin (95% to 98%), consists of a pair of alpha and beta chains. HbSS, the hemoglobin of sickle cell anemia, consists of a pair of alpha chains and a pair of sickle beta chains. The hemoglobin of sickle cell trait, HbS, consists of two alpha chains, one normal beta chain, and one sickle beta chain.

The abnormal hemoglobin S results from an adenine-to-thymine DNA substitution in the beta-globin chain of hemoglobin.^3,8 RBCs with normal hemoglobin are donut shaped and flexible enough to move through arterioles and capillaries. RBCs containing hemoglobin S ...