Sickle cell anemia is caused by a single amino acid substitution in β-globin that results in a tendency for deoxygenated HbS to self-associate into polymers. Normal hemoglobins are tetramers composed of two pairs of similar chains. On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). In patients with sickle cell anemia, HbA is completely replaced by HbS, whereas in heterozygous carriers, only about half is replaced. HbS differs from HbA by having a valine residue instead of a glutamate residue at the 6th amino acid position in β-globin. On deoxygenation HbS molecules undergo a conformational change that allows polymers to form via intermolecular contacts involving the abnormal valine residue. These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape (
Fig. 12.3
The sickling of red cells initially is reversible on reoxygenation. However, membrane distortion produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton. With time, this cumulative damage creates irreversibly sickled cells that rapidly undergo hemolysis.
Three factors are particularly important in determining whether clinically significant polymerization of HbS occurs in patients: • The intracellular levels of hemoglobins other than HbS. In heterozygotes approximately 40% of Hb is HbS and the remainder is HbA, which interacts only weakly with deoxygenated HbS. Because HbA greatly retards HbS polymerization, the red cells of HbS heterozygotes have little tendency to sickle in vivo. Such persons are said to have sickle cell trait. Similarly, because fetal hemoglobin (HbF) interacts weakly with HbS, newborns with sickle cell anemia do not manifest the disease until HbF falls to adult levels, generally around the age of 5 to 6 months. Hemoglobin C (HbC), another mutant β-globin, has a lysine residue instead of the normal glutamic acid residue at position 6. About 2.3% of American blacks are heterozygous carriers of HbC and about 1 in 1250 newborns are compound HbC/HbS heterozygotes. HbC has a greater tendency to aggregate with HbS than does HbA, and as a result HbS/HbC compound heterozygotes have a symptomatic sickling disorder called HbSC disease.
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Fig. 12.3 Sicklecellanemia—peripheralbloodsmear.(A)Lowmagnificationshowssicklecells,anisocytosis,poikilocytosis,andtargetcells.(B)Highermagnificationshowsanirreversiblysickledcellinthecenter.(Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)
The intracellular concentration of HbS. The polymerization of deoxygenated HbS is strongly concentration-dependent. Thus, red cell dehydration, which increases the Hb concentration, facilitates sickling. Conversely, the coexistence of α-thalassemia (described later), which decreases the Hb concentration, reduces sickling.