Proposed model of the iron overload/EKLF/PlGF/ ET-1 pathway. Erythroblast expression of PlGF is affected by erythroblast hyperplasia induced by erythropoietin as a compensatory response to hemolytic anemia. PlGF expression is augmented in some patients by excess iron via EKLF as a consequence of repeated therapeutic transfusion of red blood cells. PlGF induces expression of endothelin-1, which promotes pulmonary artery vasoconstriction and eventual pulmonary hypertension. Additional factors are also involved in dysregulation of endothelin-1 expression, such as expression of inflammatory cytokines, and several more pathways contribute to the development of pulmonary hypertension.