Sickle cell disease at the dawn of the molecular era

Recent investigations have identified a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease (SCD), which features severe hemolytic anemia that leads to scavenging of nitric oxide (NO) and its biochemical precursor arginine. This diminished bioavailability of NO promotes several clinical sequelae, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules and leukocytes, as well as oxidative stress-related pathways. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of NO synthase. Our current understanding of the dysregulated vascular biology pathways in SCD provides a basis for new clinical trials investigating promising targeted therapeutics.