A working model showing the link between increased erythropoiesis in SCD and inflammation. In SCD, increased sickling of RBCs leads to vaso-occlusion, which has been suggested to activate leukocytes. Alternatively, we propose that increased PlGF, resulting from erythroid hyperplasia and increased erythropoietin levels in SCD, activates leukocytes, specifically monocytes, and results in elevated proinflammatory cytokines and chemokines. These cytokines have been previously shown to up-regulate expression of VCAM and ICAM-1 in cultured endothelial cells and thereby increase the adherence of sickle RBCs and leukocytes through their counterreceptors. The increased adherence of these cells to endothelium has also been shown to cause vaso-occlusion in in vivo models. In this proposed schema of events in SCD, previously published associations are shown in blue, speculations are indicated with a dashed blue line, and our data and its interpretations are depicted in red. We conclude that erythroid cells intrinsically release a factor, PlGF, which directly activates leukocytes, specifically monocytes, to modulate the inflammatory tone and clinical severity of SCD.