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Characteristics of ineffective erythropoiesis

Normal erythropoiesis proceeds with tight regulation of maturation and apoptosis to maintain red blood cell homeostasis and normal oxygen levels.4 However, ineffective erythropoiesis is an ongoing pathological state where increased erythroid proliferation is unable to restore red blood cell count due to increased apoptosis of immature erythroid cells and impaired late-stage maturation.1,4

Implications of ineffective erythropoiesis

Chronic anemia

  • Ineffective erythropoiesis may result in chronic anemia and its associated symptoms, such as cardiac failure, fatigue, dyspnea, tachycardia, hypotension, low body temperature and an enlarged spleen4-6

Iron overload

  • Hepcidin, an iron metabolism regulator, may be suppressed in the liver due to ineffective erythropoiesis, leading to unrestrained intestinal iron uptake1
  • Increased iron levels may result in the saturation of plasma transferrin and the accumulation of non-transferrin-bound iron in the body, creating iron deposits in various organs1,7
    • This results in a range of clinical complications including pituitary damage, hyperthyroidism, liver disease, heart failure and diabetes6,7,8

Abnormal erythroid marrow expansion

  • Bone deformities may appear in the skull and face, as observed in patients with thalassemias8

Hypercoagulability

  • This state is linked to a high prevalence of thromboembolic and cerebrovascular events associated with ineffective erythropoiesis8

Ineffective erythropoiesis contributes to a variety of symptoms and complications that are characteristic of certain hematological disorders1

Erythroid maturation defects in hematological diseases

Erythroid maturation defects (EMDs) form the underlying mechanism of ineffective erythropoiesis. EMDs may induce changes in cellular and molecular signalling pathways linked to ineffective erythropoiesis and contribute to chronic anemia observed in certain hematological diseases.1

Reduced HSP70 and GATA-1 concentrations

HSP70 and GATA-1 form complexes to promote erythroid differentiation and maturation. HSP70 is regulated by EPO and is important to protect free GATA-1 factors from cleavage. However, in diseases such as β‑thalassemia and MDS, low concentrations of HSP70 – GATA-1 complexes were observed due to reduced EPO concentrations. The free, unprotected GATA-1 factors then become prone to cleavage and result in decreased erythroid differentiation and maturation, leading to ineffective erythropoiesis.9

Elevated TGF-β concentrations

TGF-β superfamily members may produce EMDs that cause dysregulation of signalling pathways in diseases such as sickle cell anemia and MDS. Elevated levels of selected TGF-β superfamily members have been observed in patients with sickle cell anemia.10

In bone marrow samples from patients with MDS, altered TGF‑β superfamily signalling, mediated by the over-activation of the SMAD pathway, has been shown to contribute to ineffective erythropoiesis and chronic anemia.11

The process of erythroid maturation involves a complex network of transcription factors and epigenetic regulators. EPO is the key regulator of early-stage erythropoiesis, whereas some members of the TGF‑β superfamily are involved in the regulation of late-stage erythropoiesis.10,12 Overactivation of TGF‑β signalling, mediated by selected SMAD proteins, is implicated in impaired erythroid maturation, contributing to EMDs and ineffective erythropoiesis.12

Research into the molecular mechanisms of ineffective erythropoiesis revealed that EMD is implicated in the pathogenesis of anemia in certain hematological disorders.9

RBC: Red blood cells, HSP: Heat shock protein, Baso‑E: Basophilic erythroid, BFU‑E: Burst-forming unit-erythroid, CFU-E: Colony-forming unit-erythroid, EMD: Erythroid maturation defect, EPO: Erythropoietin, Ortho-E: Orthochromatophilic, Poly‑E: Polychromatophilic, Pro‑E: Proerythroblasts, TGF: Transforming growth factor.

References

  1. Liang R, Ghaffari S. Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease. Br J Haematol 2016;174:661-673.
  2. Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Semin Hematol 2015;52:348-356.
  3. Gupta R, Mussallam KM, Taher AT, et al. Ineffective erythropoiesis, anemia and iron overload. Hematol Oncol Clin North Am 2018;32:213–221.
  4. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. Br J Haematol 2016;172:512-523.
  5. Prochaska MT, Newcomb R, Block G, et al. Association between anemia and fatigue in hospitalized patients: Does the measure of anemia matter? J Hosp Med 2017;12:898-904.
  6. Gattermann N. Iron overload in myelodysplastic syndromes (MDS). Int J Hematol 2018;107:55-63.
  7. Munoz M, Villar I, Garcia-Erce JA. An update on iron physiology. World J Gastroenterol 2009;15:4617-4626.
  8. Sleiman J, Tarhini A, Bou-Fakhredin R, et al. Non-transfusion-dependent thalassemia: An update on complications and management. Int J Mol Sci 2018;19: 182.
  9. Oikonomidou PR, Rivella S. What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev 2018;32:130-143.
  10. Torres LDS, Okumura JV, da Silva DG, et al. Plasma levels of TGF-β1 in homeostasis of the inflammation in sickle cell disease. Cytokine 2016;80:18-25.
  11. Zhou L, Nguyen AN, Sohal D, et al. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood 2008;112:3434-3443.
  12. Valent P, Büsche G, Theurl I, et al. Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts. Haematologica 2018;103:1593-1603.

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