Disease overview

Thalassemias are a group of inherited disorders characterized by reduced production of healthy hemoglobin and chronic anemia of varying severity.¹ Thalassemia is caused by genetic defects in the alpha and/or beta globin genes that lead to imbalanced globin chain production.¹ In thalassemia, imbalances in globin chain production lead to increased oxidative stress in RBCs and their precursors, triggering ineƯective erythropoiesis and hemolysis – the key drivers of anemia and downstream complications.¹

Classification

Phenotypically, patients with thalassemia can be classified as NTDT (non–transfusion-dependent thalassemia) or TDT (transfusion-dependent thalassemia).²

NTDT patients do not require regular lifelong transfusions for survival. However, they may need transfusions occasionally (e.g. for surgery, infection, etc.) or frequently for a defined period of time (e.g. in response to poor growth, complications, surgery, infection, etc.).²

TDT patients require regular lifelong blood transfusions to survive.²

Within NTDT and TDT, patients can have alpha- or beta-thalassemia genotypes and there are different forms of alpha (α)– and beta (β)-thalassemia.³

Types of β-thalassemia include: β-thalassemia intermedia, hemoglobin E/beta-thalassemia, and β-thalassemia major.²

There are also individuals classified as alpha- or beta-thalassemia carrier/trait, who may have anemia ranging from very mild to low end of normal and are typically asymptomatic^2,3

Complications

Ineffective erythropoiesis and hemolysis are key drivers of thalassemia pathophysiology, which can lead to serious complications in both NTDT and TDT.^2,4

Ineffective erythropoiesis may lead to primary iron overload, and chronic hemolysis may lead to hypercoagulability. Both processes may also lead to chronic anemia, which further contributes to ineffective erythropoiesis and primary iron overload, and can lead to tissue hypoxia and marrow expansion. ^2,4

All of these factors can contribute to a range of serious complications including, but not limited to: liver disease, diabetes mellitus, growth deficiency, hypothyroidism, bone deformities, osteoporosis, hepatosplenomegaly, extramedullary pseudotumors, leg uclers, thrombotic events, and pulmonary hypertension^2,5 TDT patients can also experience complications related to secondary iron overload from transfusions.⁴

In addition to these complications, thalassemia patients can experience symptoms that may impair quality of life, including fatigue and exercise intolerance.⁵

Risk of complications is associated with hemoglobin (Hb) level ^6,7

In NTDT, each 1 g/dL increase in Hb level was independently associated with a decrease in morbidity risk.^6,7

In TDT, lower pretransfusion Hb thresholds were associated with higher thalassemia-related mortality risk in adults with thalassemia⁸

Disease management and monitoring

Thalassemia International Federation (TIF) guidelines recommend frequent monitoring of patients with thalassemia to identify and manage the development of morbidities and assess quality of life.^2,3,10

TIF guidelines now recommend active management of NTDT patients with hemoglobin

levels < 10 g/dL, challenging the longstanding belief that patients can simply adapt to mild- to-moderate anemia without treatment.⁹

TIF guidelines also recommend maintaining pretransfusion hemoglobin levels 9.5 to 10.5g/dL.¹⁰

The thalassemia treatment landscape continues to evolve, with a number of FDA-approved therapy options available for healthcare providers to consider in their clinical management of patients with thalassemia.

References:

1. Sheth S, Thein SW. Thalassemia: a disorder of globin synthesis. In: Kaushansky K, Lichtman MA, Prchal JT, Levi M, Burns LJ, Linch DC, eds. Williams Hematology. 10th ed. New York, NY:McGraw-Hill; 2021:785-823.
2. Taher AT et al. Guidelines for the Management of Non–Transfusion-Dependent β-Thalassaemia. 3rd ed. Thalassaemia International Federation; 2023
3. Amid A et al, eds. Guidelines for the Management of α-Thalassaemia. Thalassaemia International Federation; 2023
4. Taher AT, Weatherall DJ, Cappellini MD. Thalassemia. Lancet. 2018;391:155-167.
   .doi.org/10.1016/S0140-6736(17)31822-6.
5. Sheth S. Thalassemia syndromes. In: Hoffman R, Benz EJ Jr, Silberstein LE, et al, eds.Hematology. 8th ed. Philadelphia, PA: Elsevier; 2023:555-584.
6. Musallam KM,  Cappellini MD, Taher AT. Variations in hemoglobin level and morbidity burden in non-transfusion-dependent β-thalassemia. Annals of Hematology. 2021;100(7):1903-1905.
   doi:10.1007/s00277-021-04456-5
7. Blunt J, et al. Outcomes and risk factors for complications in deletional haemoglobin H disease: A retrospective longitudinal cohort study in British Columbia, Canada. B J Haematol. 2025;207(5):2204-2209. doi:10.1111/bjh.70123
8. Coates TD. Higher hemoglobin is better in thalassemia. Blood. 2024;143(10):842.
9. Musallam KM, et al. Impact of lifetime anaemia and iron control on outcomes in β-thalassaemia: Data from the longitudinal de-LIGHT study. Br J Haematol. 2025 Jul 31. doi: 10.1111/bjh.70047. Epub ahead of print. PMID: 40745912.
10. Musallam KM, et al. TIF Guidelines for the Management of Transfusion‐Dependent Β‐Thalassemia. HemaSphere. 2025;9(3):e70095. doi:10.1002/hem3.70095