Proposed mechanism for blocking mechanical bending-associated mature erythrocyte adhesion. Low-level adhesion and high deformability of mature erythrocytes are favorable for SCD. HbS does not disrupt SMase activity under normoxia. However, under hypoxia, HbS polymerization increases the accumulation of bending energy and initiates a cascade that leads to sulfatide exposure via SMase upregulation. Therefore, mature erythrocytes become highly adhesive, suggesting poor biophysical properties. Inhibition of mature erythrocyte adhesion is possible with antibodies against sulfatide; however, inhibition of SMase activity could also improve other biophysical properties of mature erythrocytes, such as deformability, while preventing abnormal adhesion as well.