Chapter 17: Hemoglobinopathies Associated with Unstable Hemoglobin

DEFINITION

• The unstable hemoglobins discussed here result from a mutation that changes the amino acid sequence of one of the globin chains, leading to instability and precipitation of the hemoglobin molecule.

• Homotetramers of normal β chains (hemoglobin H) or, less often, 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, impeding the ability to negotiate the splenic sinuses; “pitting” of Heinz bodies causes loss of membrane area and ultimately destruction of red cells, reflected in a hemolytic anemia.

INHERITANCE

• These are autosomal dominant disorders. The patients are heterozygotes and have a combination of hemoglobin A and unstable hemoglobin in their red cells. Homozygous and compound heterozygotes are not observed; the conditions are thought to be lethal.

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

CLINICAL FEATURES

• Decreased hemoglobin concentration is variable from virtually normal to severely decreased. Patients may have reticulocytosis, elevated indirect bilirubin, elevated lactic dehydrogenase, and decreased to absent haptoglobin. The blood film shows polychromasia, anisocytosis, poikilocytosis, and, sometimes, basophilic stippling (Heinz bodies).

• Hemolysis is usually compensated. A patient with an unstable hemoglobin with high oxygen affinity may have a hemoglobin level in the upper normal range.

• The treatment with oxidant drugs may precipitate hemolytic episodes, making the diagnosis apparent.

• In β-chain mutations, chronic hemolytic anemia becomes evident after neonatal period, because during the first year of life γ chains (fetal hemoglobin) are replaced by mutant β chains.

• 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

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

• Blood film may show hypochromia, poikilocytosis, polychromasia, anisocytosis, and basophilic stippling.

• Heinz bodies are commonly found in circulating red cells; after splenectomy they become more frequent.

• Reticulocytosis is often disproportionate to the severity of the anemia, particularly when the abnormal hemoglobin has a high oxygen affinity.

• Diagnosis of an unstable hemoglobin is confirmed by one of the following:

  — Isopropanol precipitation test: a simple screening test that ...