Deoxygenated HbS polymerization is the primary trigger of sickle cell disease pathophysiology, and its inhibition is therapeutically important. Polymerization (left) can be averted by (1) increasing HbF levels; (2) increasing hemoglobin-oxygen affinity, as with voxelator; (3) “rehydrating” the sickle cell, thereby decreasing the concentration of HbS.⁹  Polymer-damaged sickle erythrocytes cause vaso-occlusion (top) and hemolysis, a portion of which occurs intravascularly (bottom). ISC, irreversibly sickle cell; N, neutrophil; R, reticulocyte; RBC, sickle erythrocyte. Professional illustration by Somersault18:24.