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INTRODUCTION

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LEARNING OBJECTIVES

After studying this chapter, you should understand:

  • The inheritance of sickle cell disease and the difference between hemoglobin SS homozygotes, hemoglobin AS heterozygotes, and compound heterozygotes (hemoglobin SC and hemoglobin S/β-thalassemia).

  • The molecular basis for polymerization of deoxyhemoglobin S.

  • The process of sickle vaso-occlusion.

  • The clinical manifestations of sickle cell disease: acute pain crises and progressive organ damage.

  • The treatment of sickle cell disease: supportive care and prevention of sickling.

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In 1910, Dr. James Herrick, while teaching a course in laboratory medicine, noted that a student from the West Indies had blood with normal-appearing red cells along with a population of “thin sickle-shaped and crescent-shaped red cells” similar to what is shown in Figure 9-1. Dr. Herrick found that this student was anemic and had breathlessness, palpitations, and occasional bouts of icterus. During the ensuing decade, a number of similar cases were reported, nearly all of them individuals of African ancestry. Most of these patients complained of intermittent attacks of severe pain. In vitro studies demonstrated that when blood from these patients was deoxygenated, all of the red cells were transformed into irregular and elongated “sickle cells.”

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FIGURE 9-1

Peripheral blood film of a patient with sickle cell anemia.

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In the late 1940s, the era of molecular medicine was launched with the discovery by Linus Pauling that the hemoglobin from sickle cell anemia patients had an abnormal electrophoretic mobility, indicating that its structure was different from that of normal hemoglobin. Moreover, Pauling found that healthy relatives of these patients often had a 50:50 mixture of the normal and abnormal hemoglobins.

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In 1957, Vernon Ingram showed that hemoglobin (Hb) S was identical to normal Hb A except for the replacement of glutamic acid, the sixth amino acid in beta (β)-globin, with valine. This was the first demonstration of a human disease arising from a single structural mutation.

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GENETICS

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Careful observations of families showed that sickle cell anemia is inherited in an autosomal recessive manner, as shown in Figure 9-2.

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FIGURE 9-2

Inheritance of sickle cell disease. A) When both parents have sickle cell trait (Hb AS), half of their offspring are expected to have sickle cell trait and one-fourth to have homozygous sickle cell anemia. B) When one parent has sickle cell trait and the other has β-thalassemia trait, one-fourth of their offspring are expected to be compound heterozygotes (Hb S/β-thalassemia) with a symptomatic sickling disorder.

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SICKLE TRAIT

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About 10% of black Americans are heterozygotes, inheriting a sickle globin gene (βS) from one parent and a normal (βA) gene from the other, and are said to have sickle cell trait. ...

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