Agents targeting the hemolysis-vascular endothelial axis. In SCD, one-third of the chronic hemolysis happens to be intravascular. This is also associated with the release of erythroid microparticles, which also contains heme. Thus, the consumption of physiologic binding proteins respectively haptoglobin for hemoglobin and Hpx for heme, results increased level of free hemoglobin and free heme into the peripheral circulation, promoting a plasmatic pro-oxidant environment. This contributes to chronic, unresolved inflammation characterizing SCD resulting in the upregulation of proinflammatory cytokines (Il-1β, IL-6, and TNF-α) and makers of vascular endothelial activation such as vascular cell adhesion molecule-1 (VCAM-1) or selectin. To counteract the detriment effects of free heme and to limit inflammatory vasculopathy, the following novel therapeutic strategies are under evaluation in clinical trials in patients with SCD (Table 1): (1) recombinant ADAMTS13 (r-ADAMTS13) for the relative ADAMTS13 functional deficiency; (2) crovalimab as anti-C5 inhibitor to block the overactivation of the complement alternative pathway; (3) l-Arginine to support NO synthesis; (4) anti–P-selectin antibodies to prevent cell-cell adhesion between red cells and neutrophils to vascular endothelial cells; (5) blockers of the proinflammatory cytokines (anti–IL-1b, –IL-6, or –TNF-α antibodies); and (6) multitarget approach by ω-3 fatty acid supplementation. IL-1, interlukin-1; TNF-α, tumor necrosis factor α.