Pathophysiologically based drug treatment of sickle cell disease

Trends Pharmacol Sci. 2006 Apr;27(4):204-10. doi: 10.1016/ Epub 2006 Mar 13.


Sickle cell disease is a systemic disorder that is caused by a mutation (Glu6Val) in the gene that encodes beta globin. The sickle hemoglobin molecule (HbS) is a tetramer of two alpha-globin chains and two sickle beta-globin chains, and has the tendency to polymerize when deoxygenated. HbS facilitates abnormal interactions between the sickle erythrocyte and leukocytes and endothelial cells, which trigger a complex pathobiology. This multifaceted pathophysiology provides the opportunity to interrupt the disease at multiple sites, including polymerization of HbS, erythrocyte density and cell-cell interactions. For example, it is possible to induce higher concentrations of fetal hemoglobin, which disrupts the pathology-initiating step of HbS polymerization. Furthermore, it is possible to improve the hydration of sickle erythrocytes and it might be feasible to counteract the endothelial, inflammatory and oxidative abnormalities of sickle cell disease. A therapeutic approach that targets several sites of pathobiology might be most promising.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Anemia, Sickle Cell / blood
  • Anemia, Sickle Cell / drug therapy*
  • Anemia, Sickle Cell / physiopathology*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Antisickling Agents / pharmacology
  • Antisickling Agents / therapeutic use*
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use*
  • Cell Adhesion
  • Drug Therapy, Combination
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Fetal Hemoglobin / biosynthesis*
  • Fetal Hemoglobin / genetics
  • Gene Expression Regulation
  • Hemoglobin, Sickle / genetics
  • Hemoglobin, Sickle / metabolism*
  • Humans
  • Hydroxyurea / therapeutic use*
  • Pyrrolidonecarboxylic Acid / pharmacology
  • Pyrrolidonecarboxylic Acid / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Symporters / antagonists & inhibitors
  • Symporters / metabolism


  • Anti-Inflammatory Agents
  • Antisickling Agents
  • Hemoglobin, Sickle
  • Symporters
  • potassium-chloride symporters
  • Fetal Hemoglobin
  • Azacitidine
  • Pyrrolidonecarboxylic Acid
  • Hydroxyurea