Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr 12:9:880752.
doi: 10.3389/fmed.2022.880752. eCollection 2022.

New Insights Into Pathophysiology of β-Thalassemia

Affiliations

New Insights Into Pathophysiology of β-Thalassemia

Maria Sanchez-Villalobos et al. Front Med (Lausanne). .

Abstract

β-thalassemia is a disease caused by genetic mutations including a nucleotide change, small insertions or deletions in the β-globin gene, or in rare cases, gross deletions into the β-globin gene. These mutations affect globin-chain subunits within the hemoglobin tetramer what induces an imbalance in the α/β-globin chain ratio, with an excess of free α-globin chains that triggers the most important pathogenic events of the disease: ineffective erythropoiesis, chronic anemia/chronic hypoxia, compensatory hemopoietic expansion and iron overload. Based on advances in our knowledge of the pathophysiology of β-thalassemia, in recent years, emerging therapies and clinical trials are being conducted and are classified into three major categories based on the different approach features of the underlying pathophysiology: correction of the α/β-globin disregulation; improving iron overload and reverse ineffective erythropoiesis. However, pathways such as the dysregulation of transcriptional factors, activation of the inflammasome, or approach to mechanisms of bone mineral loss, remain unexplored for future therapeutic targets. In this review, we update the main pathophysiological pathways involved in β-thalassemia, focusing on the development of new therapies directed at new therapeutic targets.

Keywords: GATA1; anemia; inflammasome; thalassemia; β-globin.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Types of thalassemia. Genotype–Phenotype Association. α and β-thalassemias are genetically heterogeneous diseases. The clinical management with RBC transfusions is an essential factor in classifying them as either transfusion-dependent thalassemia (TDT) or non–transfusion-dependent thalassemia (NTDT). Patients with TDT need life-long regular transfusions for survival in early childhood while patients with NTDT do not need life-long regular transfusions for survival and normally have later in childhood or even in adulthood with mild/moderate anemia that requires only occasional or short-course regular transfusions under concrete clinical circumstances during times of erythroid stress (infection, pregnancy, surgery, or aplastic crisis); however, usually present the typical complications of TDT such as extramedullary hematopoiesis, iron overload, leg ulcers, and osteoporosis. Patients with TDT include those with β-thalassemia major or severe forms of β-thalassemia intermedia, HbE/β-thalassemia, or α-thalassemia/HbH disease. NTDT mainly encompasses three clinically distinct forms: β-thalassemia intermedia (β-TI), hemoglobin E/β- thalassemia (mild and moderate forms), and α-thalassemia intermedia (hemoglobin H disease).
Figure 2
Figure 2
Schematic representation of erythropoiesis. During erythroid development, several stages occur in which a complex network of molecules are expressed (EPO, iron, transcription factors) are involved. In early-stage erythropoiesis, EPO is the main regulator after BFU-E formation. In this stage, GATA-1 promotes erythropoiesis and increases the EPO receptor expression. In large-stage erythropoiesis molecules such as transferrin and growth/differentiating factor 11 (GDF11) are involved. Erythroid expansion is negatively regulated by association of FAS to FAS ligand, which has as a consequence the apoptosis on immature erythroid cells, and GDF11 and other members of the TGF-β family, which negatively regulate erythrocyte differentiation and maturation from the early to the late stages.
Figure 3
Figure 3
Clinical complications and pathophysiological mechanisms of β-Thalassemia. In thalassemia, the imbalance α/β-globin synthesis is the fundamental initial pathogenic event. Excess α-globin chains precipitate in the cytoplasm, sequester HSP70 and GATA1 is cleaved by Caspase 3/1 which result in dysfunctional erythropoiesis and imposes metabolic stress on the erythrocytes, specifically in the form of excess generation of reactive oxygen species and increased demand on adenosine triphosphate (ATP)-dependent proteolytic mechanisms to clear excess globin chains. These pathophysiological changes lead to the characteristics of this disease: ineffective erythropoiesis, peripheral hemolysis, and subsequent anemia. Clinical implications of the α- and β-globin imbalance include lack of sufficient RBCs and Hb for effective oxygen transport, and ineffective erythropoiesis and hemolysis, which can lead to splenomegaly, bone marrow expansion (extramedullary hematopoiesis), concomitant bone deformities, and iron overload.
Figure 4
Figure 4
New potential treatments for β-thalassemia. In normal erythroblast, GATA1 levels are regulated through the balance Caspase 3/1 cleavage and HSP70 protecting function in the nucleus. As a consequence, normal and functional erythrocytes are produced. In contrast, in β-thalassemic erythroblast, the lack of functional β-globin chains induces accumulation of free α-globin chains which restrict HSP70 distribution to the cytoplasm and therefore GATA1 is cleaved by Caspase 3/1 which result in fewer functional matured erythrocytes.

Similar articles

  • Emerging Therapies in β-Thalassemia.
    Bou-Fakhredin R, Kuo KHM, Taher AT. Bou-Fakhredin R, et al. Hematol Oncol Clin North Am. 2023 Apr;37(2):449-462. doi: 10.1016/j.hoc.2022.12.010. Hematol Oncol Clin North Am. 2023. PMID: 36907614 Review.
  • Novel Therapeutic Advances in β-Thalassemia.
    Makis A, Voskaridou E, Papassotiriou I, Hatzimichael E. Makis A, et al. Biology (Basel). 2021 Jun 18;10(6):546. doi: 10.3390/biology10060546. Biology (Basel). 2021. PMID: 34207028 Free PMC article. Review.
  • Recent trends in treatment of thalassemia.
    El-Beshlawy A, El-Ghamrawy M. El-Beshlawy A, et al. Blood Cells Mol Dis. 2019 May;76:53-58. doi: 10.1016/j.bcmd.2019.01.006. Epub 2019 Feb 4. Blood Cells Mol Dis. 2019. PMID: 30792169 Review.
  • Beta-thalassemia.
    Cao A, Galanello R. Cao A, et al. Genet Med. 2010 Feb;12(2):61-76. doi: 10.1097/GIM.0b013e3181cd68ed. Genet Med. 2010. PMID: 20098328 Review.
  • Emerging therapies in β-thalassemia: toward a new era in management.
    Bou-Fakhredin R, Tabbikha R, Daadaa H, Taher AT. Bou-Fakhredin R, et al. Expert Opin Emerg Drugs. 2020 Jun;25(2):113-122. doi: 10.1080/14728214.2020.1752180. Epub 2020 Apr 15. Expert Opin Emerg Drugs. 2020. PMID: 32249632 Review.

Cited by

References

    1. Origa R. beta-Thalassemia. Genet Med. (2017) 19:609–19. 10.1038/gim.2016.173 - DOI - PubMed
    1. Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing patterns in the epidemiology of beta-thalassemia. Eur J Haematol. (2020) 105:692–703. 10.1111/ejh.13512 - DOI - PMC - PubMed
    1. Asadov C, Alimirzoeva Z, Mammadova T, Aliyeva G, Gafarova S, Mammadov J. beta-Thalassemia intermedia: a comprehensive overview and novel approaches. Int J Hematol. (2018) 108:5–21. 10.1007/s12185-018-2411-9 - DOI - PubMed
    1. Viprakasit V, Ekwattanakit S. Clinical classification, screening and diagnosis for thalassemia. Hematol Oncol Clin North Am. (2018) 32:193–211. 10.1016/j.hoc.2017.11.006 - DOI - PubMed
    1. Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V. (eds.). Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT). Nicosia: Thalassaemia International Federation; (2014). - PubMed

Publication types

LinkOut - more resources