Chapter 17: Unstable Hemoglobins and Hemoglobins with Altered Oxygen Affinity

UNSTABLE HEMOGLOBINS

Definition

• The unstable hemoglobins discussed here result from different mutations that change the amino acid sequence of a globin chain, leading to instability and precipitation of the hemoglobin molecule.

• Homotetramers of normal β chains (hemoglobin H) or γ chains (hemoglobin Bart’s) are also unstable. These hemoglobins are found in α-thalassemia (see Chap. 15).

Etiology and Pathogenesis

• The tetrameric hemoglobin molecule has numerous noncovalent interactions that maintain the structure of each subunit and bind the subunits to each other.

• Amino acid substitutions or indels that weaken noncovalent interactions allow hemoglobin to denature and precipitate as insoluble globins, which may attach to the cell membrane, forming Heinz bodies.

• Heinz bodies impair erythrocyte deformability by binding to the red cell cytoskeleton (Chap. 13), impeding the cell’s ability to negotiate the splenic sinuses; “pitting” of Heinz bodies causes membrane loss and ultimately destruction of red cells, resulting in a hemolytic anemia.

Inheritance

• These disorders have autosomal dominant inheritance. Affected individuals are heterozygotes for their globin mutation and have a combination of hemoglobin A and unstable hemoglobin in their red cells. Homozygotes and compound heterozygotes are not observed; these conditions are thought to be lethal.

• Affected individuals may develop an unstable hemoglobin as a de novo mutation. More than 80% of individuals with unstable hemoglobins have a defect in the β-globin chain. Defects in the α-globin chain are less likely to cause a clinical disorder because the genome has four α-globin genes (Chap. 15), and a mutation in one α-globin gene results in a minor proportion of abnormal globin in the cell.

Clinical Features

• As a result of hemolysis, affected individuals may have reticulocytosis, elevated indirect bilirubin, elevated lactate dehydrogenase, and decreased to absent haptoglobin.

• Hemolysis is usually compensated. An individual with an unstable hemoglobin with high oxygen affinity (see below) may have a hemoglobin level in the upper normal range.

• Treatment with oxidant drugs may further precipitate hemolysis, making the diagnosis apparent.

• In β-globin mutations, chronic hemolytic anemia becomes evident after the neonatal period, because during the first 6 months of life γ chains (fetal hemoglobin) are replaced by mutant β-globins, while α-globin mutations are apparent since birth. Those with rare γ-globin mutations have a transient hemolytic phenotype at birth that resolves by 6 months of age.

• Physical findings may include pallor, jaundice, and splenomegaly.

• Some patients have dark urine, probably from the catabolism of free heme groups or Heinz bodies.

Laboratory Features

• Intracellular hemoglobin concentration is variable, from virtually normal to severely decreased.

• Hemoglobin concentration may be normal or decreased. The mean corpuscular hemoglobin may be decreased because of loss of hemoglobin from denaturation and pitting.

• The blood film may show hypochromia, poikilocytosis, polychromasia, anisocytosis, and Heinz bodies.

• Heinz bodies are ...