Spectrum of sickle cell subphenotypes affected by hemolytic rate. The viscosity–vaso-occlusion subphenotype is associated with a lower hemolytic rate, marked by a higher hemoglobin level, and low plasma hemoglobin, lactate dehydrogenase (LDH), bilirubin and arginase levels. Patients with these features have a higher incidence of vaso-occlusive pain crises, acute chest syndrome, and osteonecrosis. In contrast, patients with the hemolysis-endothelial dysfunction subphenotype exhibit markers of high hemolytic rate, including low hemoglobin level, high plasma hemoglobin, LDH, bilirubin, and arginase, culminating in low nitric oxide bioavailability and high prevalence of pulmonary hypertension, leg ulceration, priapism, and stroke. Co-inheritance of α-thalassemia trait with sickle cell disease reduces the hemolytic rate, minimizes the risk of hemolysis-associated complications and increasing the risk of viscosity-related complications. Adapted with permission from Kato GJ, Gladwin MT, and Steinberg MH. ⁵²