Figure 1.

Aspects of SCD pathophysiology that may contribute to clonal hematopoiesis in SCD. Proliferative stress: shortened RBC survival may contribute to high hematopoietic stem cell turnover. Genotoxic stress: free heme, oxidative stress, and other inflammatory mediators damage DNA. Clonal selection: the inflammatory environment may select for clones able to tolerate an unfavorable bone marrow microenvironment. Three processes drive chronic inflammation in SCD: (1) RBC abnormalities; sickle red blood cells (sRBC) damage the endothelium directly through mechanical injury and adhesion. (2) Release of free hemoglobin and heme secondary to sRBC chronic hemolysis; fragile, rigid sRBC have a shortened lifespan, 20 days compared to 120 days. Free hemoglobin and heme result in chronic inflammation, oxidative stress, and vascular damage. The abnormal sRBCs and activated endothelial cells produce a proinflammatory environment; circulating leukocytes and platelets also have an activated phenotype. (3) Ischemia-reperfusion injury secondary to ongoing, intermittent microvascular occlusions promotes chronic inflammation in SCD [8]. Ischemic cells accumulate calcium, exhibit mitochondrial dysfunction and cell swelling, and release major inflammatory-damage-associated molecular patterns (DAMPs) that promote multiple inflammatory pathways, including neutrophil extracellular trap formation and inflammasome assembly [9]. Reperfusion causes further damage due to the production of reactivated oxygen species and calcium overload. Ischemia/reperfusion injury activates invariant natural killer T cells, which trigger interferon gamma (IFN-γ) and IFN-γ-inducible chemokines [10]. Upward arrow indicates levels are higher in SCD than in healthy individuals.