Proposed mechanism of hemolysis-mediated regulation of SCD alloimmunization through inhibition of B-cell differentiation. In allo-negative SCD patients, hemolysis can inhibit B-cell differentiation and subsequent alloimmunization through DOCK8 and HO-1 enzyme activity. In contrast, B cells from allo-positive SCD patients are insensitive to inhibitory effects of hemolysis that results from altered DOCK8 and HO-1 signaling pathways. Heme plus QA can inhibit B-cell activation in both allo-positive and allo-negative patients by targeting HO-1. BCR, B-cell receptor.