The role of ineffective erythropoiesis in non-transfusion-dependent thalassemia

Abstract

Ineffective erythropoiesis is the hallmark of beta-thalassemia that triggers a cascade of compensatory mechanisms resulting in clinical sequelae such as erythroid marrow expansion, extramedullary hematopoiesis, splenomegaly, and increased gastrointestinal iron absorption. Recent studies have begun to shed light on the complex molecular mechanisms underlying ineffective erythropoiesis and the associated compensatory pathways; this new understanding may lead to the development of novel therapies. Increased or excessive activation of the Jak2/STAT5 pathway promotes unnecessary disproportionate proliferation of erythroid progenitors, while other factors suppress serum hepcidin levels leading to dysregulation of iron metabolism. Preclinical studies suggest that Jak inhibitors, hepcidin agonists, and exogenous transferrin may help to restore normal erythropoiesis and iron metabolism and reduce splenomegaly; however, further research is needed.

Fig. 1

Excess production of free α-globin chains causes ineffective erythropoiesis and a variety of clinical sequelae. Primary disease processes are shown in orange, and compensatory mechanisms in yellow. Reprinted with permission from Olivieri NF. N Engl J Med 1999;341:99–109. Copyright © 1999 Massachusetts Medical Society. All rights reserved.

Fig. 2

Mechanisms responsible for ineffective erythropoiesis and compensatory mechanisms. Reprinted from Hematol Oncol Clin North Am Vol 24, Gardenghi S, Grady RW, Rivella S. Anemia, Ineffective Erythropoiesis, and Hepcidin: Interacting Factors in Abnormal Iron Metabolism Leading to Iron Overload in β-Thalassemia. p1089–1107, © 2010 with permission from Elsevier.

Fig. 3

Role of phosphoJAK in ineffective erythropoiesis. Abbreviations: Retics, reticulocytes; RBC, red blood cells. Reprinted from Melchiori L, et al. Adv Hematol 2010;2010:938640. Epub 2010 May 19.