Due to increased erythropoiesis in SCD as a compensatory response to severe hemolytic anemia, Erythropoietin (Epo) is released at high levels which targets erythroid cells to secrete PlGF. Released PlGF in circulation can target blood cells, e.g. MNCs and vascular endothelium (endothelial cells). PlGF causes activation of HIF-1α, independent of hypoxia and stimulates expression of cytochemokines, leukotriene formation via activation of lipoxygenase enzymes, and expression of ET-1 and PAI-1, the latter is involved in pulmonary hypertension in SCD.