β-Thalassemia and Polycythemia vera: Targeting chronic stress erythropoiesis

Abstract

β-thalassemia and Polycythemia vera are genetic disorders which affect the synthesis of red blood cells, also referred to as erythropoiesis. Although essentially different in clinical presentation – patients with β-thalassemia have an impairment in β-globin synthesis leading to defective erythrocytes and anemia, while patients with Polycythemia vera present with high hemoglobin levels because of excessive red blood cell synthesis – both pathologies may characterized by lasting high erythropoietic activity, i.e. chronic stress erythropoiesis. In both diseases, therapeutic strategies targeting chronic stress erythropoiesis may improve the address phenotype and prevent secondary pathology, such as iron overload. The current review will address the basic concepts of these strategies to reduce chronic stress erythropoiesis, which may have significant clinical implications in the near future.

A Red Carpet for Iron Metabolism

“…The ensuing hypoxia triggers EPO release and erythroid precursor proliferation in an unsuccessful attempt to compensate for the anemia, a condition defined as ineffective erythropoiesis (Rivella, 2015). By contrast, polycythemia vera is characterized by excess RBC production (Crielaard and Rivella, 2014). Both disorders exhibit stress erythropoiesis with an increase in the absolute number of erythroid precursors, extramedullary hematopoiesis, and splenomegaly (Crielaard and Rivella, 2014).…”

“…By contrast, polycythemia vera is characterized by excess RBC production (Crielaard and Rivella, 2014). Both disorders exhibit stress erythropoiesis with an increase in the absolute number of erythroid precursors, extramedullary hematopoiesis, and splenomegaly (Crielaard and Rivella, 2014). Diminished hepcidin expression has now been recognized as one of the key mechanisms responsible for the increased iron absorption observed in these disorders (Gardenghi et al, 2007; Weizer-Stern et al, 2006a, 2006b).…”

What can we learn from ineffective erythropoiesis in thalassemia?

“…β-thalassemia is one of the most common causes of congenital anemias with a worldwide annual incidence of 1:100.000 34 . It is caused by several hundred mutations in the β-globin gene or its promoter, which result in impaired production of β-globin chains 55, 67 .…”

Iron age: novel targets for iron overload

“…14 EPO’s regulation of erythropoiesis is mediated by hypoxia-inducible factor 2α (HIF2α) in a process that responds to cellular hypoxia. 15 Under certain conditions, such as at high altitude or after acute blood loss, there is inadequate tissue oxygenation. In this case, the erythropoietic activity expands significantly, a process commonly known as “stress erythropoiesis,” and erythroid development might extend in extramedullary sites such as the liver and spleen, with massive production of erythroid progenitors and RBCs.…”

“…Additional mechanisms play an important role in stress erythropoiesis. 15 One of these mechanisms involves the action of bone morphogenic protein 4 (BMP4), which induces (through SMAD5) the proliferation of stress erythroid progenitors (Figure 2). 17 Macrophages also have a central role in supporting normal and stress erythropoiesis (Figure 2).…”