ESSENTIALS OF DIAGNOSIS
Recurrent pain episodes.
Positive family history and lifelong history of hemolytic anemia.
Irreversibly sickled cells on peripheral blood smear.
Hemoglobin S is the major hemoglobin seen on electrophoresis.
Sickle cell anemia is an autosomal recessive disorder in which an abnormal hemoglobin leads to chronic hemolytic anemia with numerous clinical consequences. A single DNA base change leads to an amino acid substitution of valine for glutamate in the sixth position on the beta-globin chain. The abnormal beta chain is designated betas and the tetramer of alpha-2betas-2 is designated hemoglobin SS (eFigure 15–13). Hemoglobin S is unstable and polymerizes in the setting of various stressors, including hypoxemia and acidosis, leading to the formation of sickled RBCs. Sickled cells result in hemolysis and the release of ATP, which is converted to adenosine. Adenosine binds to its receptor (A2B), resulting in the production of 2,3-biphosphoglycerate and the induction of more sickling, and to its receptor (A2A) on natural killer cells, resulting in pulmonary inflammation. The free hemoglobin from hemolysis scavenges nitric oxide causing endothelial dysfunction, vascular injury, and pulmonary hypertension.
Sickle cell disease, peripheral blood smear. In this patient with hemoglobin SS disease, there are two characteristic cells (arrows). One is the classic crescent shaped cell pathognomonic of sickle cell disease. The other is an elliptical RBC with condensation of hemoglobin leaving a paler outer rim of cytoplasm, also characteristic of hemoglobin SS. Also present in the center of the smear are two target cells. (Reproduced, with permission, from Lichtman MA, Shafer MS, Felgar RE, Wang N. Lichtman's Atlas of Hematology. McGraw-Hill, 2016.)
The rate of sickling is influenced by the intracellular concentration of hemoglobin S and by the presence of other hemoglobins within the cell. Hemoglobin F cannot participate in polymer formation, and its presence markedly retards sickling. Factors that increase sickling are RBC dehydration and factors that lead to formation of deoxyhemoglobin S (eg, acidosis and hypoxemia), either systemic or local in tissues. Hemolytic crises may be related to splenic sequestration of sickled cells (primarily in childhood before the spleen has been infarcted as a result of repeated sickling) or with coexistent disorders such as G6PD deficiency.
The betaS gene is carried in 8% of American Blacks, and 1 of 400 American Black children will be born with sickle cell anemia; prenatal diagnosis is available when sickle cell anemia is suspected. Genetic counseling should be made available to patients.
The disorder has its onset during the first year of life, when hemoglobin F levels fall as a signal is sent to switch from production of gamma-globin to beta-globin. Chronic hemolytic anemia ...