Pharmacological management of sickle cell disease.

Sickle cell disease is characterized by a structural abnormality in the beta-globin chain of the hemoglobin molecule within the red blood cells (RBCs). The sickle mutation is a single base change (GAT → GTT) in the sixth codon of exon-1 of the betaglobin gene on chromosome 11. This change leads to the synthesis of the beta-globin polypeptide of the hemoglobin molecule. This mutation causes the replacement of the normal glutamic acid with valine acid, thus resulting in the formation of the sickle cell hemoglobin (HbS). This hydrophobic aminoacid substitution causes the hemoglobin to take on a “sickle” shape when in a deoxygenated state. The ability of these sickled cells to adapt to their surroundings is impaired, especially in the microvasculature. These cells hemolyze prematurely, accounting for the chronic anemia frequently encountered by patients with SCD.5 The paucity of sickled cells in newborns with SCD led to the discovery that fetal hemoglobin (HgF) reduces the severity of SCD by preventing the formation of the hemoglobin S polymer.6 Fever, dehydration, hypoxia, acidosis, stress, and a cold environment may precipitate sickling, although a precursor event is not always identified.7,8 The pathophysiology of SCD is considerably complex, involving abnormalities of hemo globin, the RBC’s membrane, erythrocyte hydration, the endothelium, vascular tone, inflammatory responses, leukocytes, and coagulation. This forceful combination of factors results in cell interactions, generating hemolysis and micro vascular obstruction, ultimately leading to damage of nearly all organ systems.9