Mechanisms of vasculopathy. Hemolysis, arginine dysregulation, oxidative stress and uncoupled nitric oxide synthase (NOS) are key mechanisms that contribute to the complex vascular pathophysiology of sickle cell disease (SCD). These events limit nitric oxide (NO) bioavailability through several paths that ultimately provoke increased consumption and decreased production of the potent vasodilator, NO. Although often discussed independently, there is significant overlap closely linking these pathways of endothelial dysfunction that prohibit determining cause and effect. The contribution of inflammation coupled with antioxidant, glutathione and Apolipoprotein A-1 (Apo A) depletion, ischemia-reperfusion injury, and acute as well as chronic end-organ damage obscure mechanistic boundaries further. During hemolysis, cell free hemoglobin and arginase are simultaneously released from the erythrocyte and profoundly contribute to low NO bioavailability. Lactate dehydrogenase (LDH) is also released from the erythrocyte and represents a convenient biomarker of hemolysis that delineates the subphenotypes of SCD.