Sickle Cell Anemia: The Effects of Hydroxyurea on Red Blood Cell Polymerization Reversal

Abstract

Sickle cell anemia – the most common form of sickle cell disease (SCD) – is a debilitating condition that presents with health complications ranging from severe pain due to vaso-occlusion and acute chest syndrome, to a reduced ability to sufficiently transport oxygen through the body due to accelerated hemolysis of red blood cells. The underlying cause of SCD is a genetic mutation in which valine is replaced by glutamic acid at the sixth position of the β-globin chain, leading to the production of an abnormal sickle hemoglobin (hemoglobin S). This abnormal protein within the red blood cells have an increased propensity to polymerize into long fibers when deoxygenated, decreasing red-cell deformability while increasing the rate of cell death by damaging the cell membrane. These sickled red blood cells can then clump together to occlude blood vessels causing pain and organ damage. The impact of SCD has led to the evaluation of different treatment modalities in attempt to cure or ameliorate the manifestations of the disease. This thesis is intended to review the underlying disease process, elucidate the treatment modalities that have been previously proposed, and highlight the effect of hydroxyurea as the primary approved treatment of sickle cell anemia due to its ability to reverse the polymerization of already sickled cells, and increase the levels of fetal hemoglobin (HbF). The increase of HbF levels is a major goal of treatment that can achieved by increasing the expression of gamma-globin genes, therefore we can hypothesize that upregulating the activity of enzyme Demethylase will reverse the methylation of the CpG islands and reverse the binding of Histone deacetylase allowing the transcription of already silenced genes to resume.