A simple schematic illustrating the redundancy of pathways causally linking the primary red cell defect to cardiac fibrosis. Hemolysis, anemia, and vaso-occlusion represent the proximal stimuli, but so many interrelationships exist across these pathways that connecting arrows were suppressed for clarity. Some mediators clearly lie outside any given pathway, and other connections and mediators remain to be elucidated. Although IL-18 has shown promise as a convergent pathway for fibrosis and arrhythmias in mouse models,^3,4 its suitability as a drug target in humans remains an open question. NO, nitric oxide; PLGF, placentally derived growth factor; RAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; VEGF, vascular endothelial growth factor.