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INTRODUCTION

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CASE HISTORY • Part 1

A 22-year-old African American woman presents to her obstetrician for prenatal care. She reports that she has been anemic since childhood but is unclear as to what kind of anemia. Past medical history is positive for splenectomy following blunt trauma to the abdomen in a car accident at age 16. Otherwise review of systems negative. A routine CBC shows the following results:

CBC: Hematocrit/hemoglobin - 33%/11 g/dL (IU - 110 g/L)

MCV - 75 fL MCH - 28 pg MCHC - 30 g/dL

RDW-CV - 16%

WBC count - 7,400/μL

Platelet count - 245,000/μL

SMEAR MORPHOLOGY

Findings on the blood smear include microcytosis, targeting, sickle cell forms, and both the occasional nucleated red blood cell (not shown) and red cells with Howell-Jolly bodies (also not shown).

Reticulocyte count - 4.5%/3.0 Index - 1.5–2

Image not available.

Questions
  • How should this anemia be described/categorized?

  • Do the smear abnormalities indicate a specific abnormality?

  • What additional tests should be ordered?

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Inherited defects in globin structure are common in individuals of African, Indian, Asian, and Mediterranean descent. Most of these involve a single amino acid substitution in one of the globin chains. The resulting structural defect can be clinically silent or produce a significant anemia. Sickle cell disease, secondary to the substitution of valine for glutamic acid in position 6 of the β-globin chain, is the paradigm of the hemoglobinopathies. It has a worldwide distribution with a very high frequency, and it was the first hemoglobinopathy to be defined at a molecular level.

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Management of a patient with a hemoglobinopathy depends not only on an accurate diagnosis of the disorder but also on an understanding of the clinical expression of the defect. In addition, there is an obligation for screening and genetic counseling of populations with any increased prevalence of a hemoglobinopathy.

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NORMAL GLOBIN CHEMISTRY

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The globin portion of the hemoglobin molecule can be defined according to combinations of α-globin and β-, γ-, or δ-globin chains; the amino acid sequence of the individual chains; and the 3-dimensional structure of the folded molecule. As discussed in Chapter 6, genetic defects resulting in impaired globin chain synthesis produce microcytic, hypochromic anemias and distinctive changes in pairing of the several globin chains. In contrast, amino acid substitutions in either the α-globin or β-globin chains can disrupt the molecular structure and function of hemoglobin.

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Normal globin is made up of 2 α-globin chains, each with 141 amino acids, and 2 β-globin chains, each with 146 amino acids. The 4 polypeptide chains form a helical structure with hydrophobic pockets holding 4 heme groups. A central cavity between the two β-globin chains houses 2,3-diphosphoglycerate (2,3-DPG) (Figure 7-1). This complex structure is essential to hemoglobin function.

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FIGURE 7-1

Hemoglobin structure. Each hemoglobin molecule is composed of 2 α-globin (light shading) and 2 β-globin chains (dark shading), each of ...

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