Vascular based therapeutic targets in sickle cell disease (SCD). Several mechanisms have been proposed to contribute to pathological blood flow in SCD: intravascular hemolysis, which releases arginase and hemoglobin (Hb), which respectively reduce levels of the nitric oxide synthase (NOS) substrate arginine and consumes NO; oxygen radicals produced by xanthine oxidoreductase (XO) and NADPH oxidase; sickle hemoglobin polymer formation, inducing stiff, noncompliant red cells; and adhesion of sickle erythrocytes, leukocytes, and platelets to post-capillary venular endothelium. Strategies being tested in clinical trials directed at these pathways are indicated in the boxes and described in detail in the text.