Etiology

Hemoglobin is responsible for carrying oxygen in the bloodstream and is found inside the red blood cell. It is a protein made up of four chains called globins and four iron groups called heme. Each globin chain is composed of a series of building blocks called amino acids that in turn are built from the genetic material known as deoxyribonucleic acid (DNA). The structure of a particular piece of DNA determines the structure of a particular protein. In the case of sickle-cell anemia the structure of the DNA molecule is changed through a single genetic mutation and results in a change in the amino acid composition of the protein chain. This change is a substitution of valine for glutamic acid in the sixth position of the amino end of the molecule. This simple substitution causes marked changes in the solubility and interactive properties of hemoglobin. Under appropriate conditions, this results in a dramatic conformational change in the red cell from a flexible biconcaved disk to an inflexible sickled cell.

Sickling results from a low oxygen state and tends to occur in the acidotic and hypertonic milieu of small blood vessels. It is a two-step process. Initially, small submicroscopic aggregates of hemoglobin form, followed by rapid polymer formation into long tubular helical fibers that twist the red cell into the sickle shape. This fiber formation is reversible and results from noncovalent chemical bonds between hemoglobin molecules.

Sickling is also accompanied by a dynamic process at the cell membrane. Ion fluxes that occur normally at the membrane become disrupted during sickling, and a rapid influx of calcium occurs. This calcium is later pumped out of the cell by an energy-dependent mechanism utilizing an intercellular energy source known as adenosine triphosphate (ATP). Recurrent sickling results in early depletion of ATP and is one contributor to premature cellular death. Recurrent sickling can cause the cellular membrane to become permanently calcified, resulting in rigid, irreversibly sickled cells. These cells are found in all persons afflicted with sickle-cell disease and may represent from 5 to 50 percent of the red cell mass.

Functionally, hemoglobin S has a lower affinity for oxygen especially at low hydrogen-ion concentrations and increased tonicity. This results in early release of oxygen and the inability to oxygenate tissues adequately. In the sickled form, these cells have significant difficulty traversing the small vas-

culature of the capillary bed. Vascular occlusion and destruction of tissues result. The life-span of a single cell is also decreased from 120 to 60 days and is manifested as a hemolytic anemia. This condition results from a combination of acquired membrane abnormalities from recurrent sickling and destruction of irreversibly sickled cells. There is also increased incidence of infection owing to gradual destruction of the spleen and alterations in the immune system.

The presence of other forms of hemoglobin can modify the ability of hemoglobin S to form fibrils. One such hemoglobin is fetal hemoglobin. Hemoglobin F is normally present at birth in large concentrations. After birth its production is decreased and is replaced with adult hemoglobin (hemoglobin A), such that by 6 months of life the individual has hemoglobin in adult percentages. In some individuals, however, hemoglobin F persists in abnormally high levels. This persistence of hemoglobin F alters the final hemoglobin concentration in the red blood cell and reduces the percentage of hemoglobin S in patients with sickle-cell disease. Hemoglobin F is a poor participant in hemoglobin S fibril formation and thus inhibits sickling. Clinically this results in a milder form of the disease and in some patients produces an asymptomatic state.

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