Erythropoiesis is essentially a two-phase process, erythropoietin (EPO) driving the initial proliferative phase, leading to stimulation of the stem cell toward the erythroid lineage, and proliferation through the BFU-E and CFU-E phases. The second stage is one of differentiation and maturation, with the proerythroblasts moving through the different erythroblast phases, into reticulocytes and eventually mature red cells (Fig. 1).

Fig1. NORMAL AND INEFFECTIVE ERYTHROPOIESIS. (A) Schema of normal erythropoiesis, showing proliferation, differentiation, and maturation phases. (B) Schema of ineffective erythropoiesis, showing an expanded proliferative phase but a block of differentiation and maturation. EPO, Erythropoietin.

As described, the basic molecular abnormality in β-thalassemia is the imbalance between alpha and beta globin production, with reduction in beta globin production and thus a decrease in HbA ( α 2 β 2 ) production. The ratio of β - to α -globin is typically close to 1. When abnormal, this ratio has a direct correlation with clinical severity in β -thalassemia patients. In β -thalassemia heterozygotes, β -globin synthesis is approximately half-normal, with the ratio of β - to α -chain mRNA ( β / α ratio) of 0.5 to 0.7 (normal = 1.0). In homozygotes for β0 -thalassemia, which account for approximately one-third of patients, β -globin synthesis is absent. β -globin synthesis is reduced to 5% to 30% of normal levels in β +-thalassemia homozygotes or β +/ β °-thalassemia compound heterozygotes, which together account for approximately two-thirds of cases.  The excess α-globin chains may be stabilized by alpha Hb stabilizing protein, which is a chaper one-like protein that assists in binding free α -globin chains. Higher levels of alpha Hb stabilizing protein result in more IE, and thus a more severe clinical phenotype.

The decreased or absent synthesis of HbA ( α 2 β 2 ) results in the production of smaller red cells and depending on the severity of the deficiency, hypochromia as well. RBCs are always microcytic in the thalassemias across the spectrum, and usually hypochromic though not so much in heterozygotes. γ -Chain synthesis is partially reactivated, and there is some upregulation of δ chain synthesis, though not enough to replace the deficiency of β -chains, and thus the red cells may contain relatively large proportions of HbF ( α 2 γ 2 ) and some HbA2 ( α 2 δ 2 ).

Individuals inheriting two β -thalassemic alleles experience a more profound deficit of β -chain production. Little or no HbA is produced, and importantly, the imbalance of α - and β -globin production is far more severe ( Fig. 2). In the BM, the limited capacity of the red cell precursors to proteolyze the excess α -globin chains, a capacity that probably exerts a protective effect in heterozygous β -thalassemia, is overwhelmed in homozygotes. Free α -globin accumulates, and unpaired α -chains aggregate and precipitate to form inclusions called Fessas bodies and hemichromes with the addition of heme iron, which cause oxidative membrane damage leading to apoptosis and destruction of immature developing erythroblasts in the BM (intramedullary hemolysis). Consequently, relatively few of the erythroid precursors undergoing erythroid maturation in the BM survive long enough to be released into the bloodstream as erythrocytes, leading to anemia. Thus, in β -thalassemia, the defect in the erythropoietic pathway is one of impaired differentiation and maturation of the developing erythroid precursors, beginning at the time globin genes begin expression in the proerythroblast-basophilic erythroblast stages. Erythropoiesis is ineffective, and the severity of this IE worsens as the imbalance between β- and α-globin synthesis deepens. The occasional erythrocytes that are formed during erythropoiesis bear a burden of inclusion bodies. The reticuloendothelial cells in the spleen, liver, and BM remove these abnormal cells prematurely, which reduces RBC survival as a consequence of this hemolytic anemia.

Fig2. FEATURES OF INEFFECTIVE ERYTHROPOIESIS (IE). Intramedullary apoptosis of abnormally maturing erythroid precursors and a reduction in the lifespan of red cells produced, lead to anemia, the hallmark of IE.

IE is thus the hallmark of β -thalassemia, triggering a cascade of compensatory mechanisms and resulting in clinical sequelae such as erythroid BM expansion, extramedullary hematopoiesis (EMH), and splenomegaly. The master iron regulatory hormone hepcidin plays an integral and critical role in the pathophysiology of the dis ease as well. Erythroferrone (ERFE) is a protein which is produced during erythropoiesis, which has the effect of reducing hepcidin production, likely through the BMP/SMAD signaling pathway. During stress erythropoiesis, increased ERFE results in decreased hepcidin which in turn leads to increased iron absorption through the transporter ferroportin at the basolateral side of the intestinal enterocyte, the body mistakenly sensing anemia as being a result of iron deficiency. The greater the erythropoietic activity, the higher ERFE levels rise to, and the greater the suppression of hepcidin. In thalassemia, where IE is a significant feature, ERFE levels are high and therefore hepcidin levels are inappropriately low. Such patients become iron overloaded as a result of increased iron absorption even in the absence of transfusional iron loading. The critical role of hepcidin in iron trafficking is also a factor in iron toxicity in thalassemia. In the absence of IE, hepcidin levels are increased when there is iron overload, thus reducing iron absorption, and also safely sequestering iron in storage sites and preventing deposition in vulnerable tissues. The relatively lower levels of hepcidin driven by ERFE in ineffective erythropoiesis result in iron being able to be more easily redistributed, leading to organ toxicity. When hepcidin production is inappropriately low as a result of increased IE, tissues such as the heart and endocrine organs are exposed to more circulating iron and this results in uptake and organ dysfunction as a result of iron toxicity.

As a result of the anemia, there is increased secretion of EPO, and further proliferation, once again, without maturation. Accumulation of molecules belonging to the transforming growth factor-beta (TGF- β) superfamily of ligands has been described, which inhibits maturation and differentiation. Trapping these ligands has been the focus of a therapeutic intervention to try and improve IE by removing the block on maturation, and promoting more effective erythropoiesis. Massive BM expansion does occur, but very few erythrocytes are actually supplied to the circulation. The BM becomes packed with immature erythroid precursors, which die from their burden of precipitated α -globin chains before they reach the reticulocyte stage. Profound anemia persists, driving erythroid hyperplasia to still higher levels. In some cases, erythropoiesis is so exuberant that masses of extramedullary erythropoietic tissue form in the chest, abdomen, or pelvis.

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