Pathophysiology and Complications of Thalassemia

Hemolysis and ineffective erythropoiesis are the primary drivers of downstream complications, including chronic anemia1-3

Genetic mutations in the α- and/or β-globin chains of hemoglobin lead to an accumulation of excess unpaired globin chains that form precipitates and aggregates. This facilitates the generation of reactive oxidative species (ROS) and induction of oxidative stress, increasing ATP demand within red blood cells.1,4

Consequently, oxidative stress and globin chain aggregates can trigger a series of pathophysiological events, including destabilization of the cell membrane and ineffective erythropoiesis and hemolysis, which result in chronic anemia.1,5

Ineffective erythropoiesis and hemolysis can lead to chronic anemia, iron overload, and more complications.

ATP=adenosine triphosphate; RBC=red blood cell.

Hemolysis and ineffective erythropoiesis cause chronic anemia, which can lead to serious complications2,6

If left untreated, hemolysis and ineffective erythropoiesis can lead to thalassemia complications such as2,6:

Heart disease

  • Heart failure

  • Arrhythmias

Vascular disease

  • Pulmonary hypertension

  • Thrombosis

  • Leg ulcers

  • Silent cerebral infarct

Liver disease

Other hematologic

  • Extramedullary hematopoietic pseudotumors

Renal disease

Bone disease

  • Osteoporosis

  • Fractures

  • Bony changes

Endocrinopathy

  • Diabetes mellitus

  • Hypothyroidism

  • Hypoparathyroidism

  • Hypogonadism

Hepatosplenomegaly

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References:
1. Kuo KHM. Pyruvate kinase activators: targeting red cell metabolism in thalassemia. Hematology Am Soc Hematol Educ Program. 2023;2023(1):114-120. doi:10.1182/hematology.2023000468 2. Taher AT, Musallam KM, Cappellini MD. Guidelines for the Management of Non-Transfusion-Dependent β-Thalassemia. 3rd ed. Nicosia, Cyprus: Thalassemia International Federation; 2023. 3. Musallam KM, Taher AT, Cappellini MD, et al. Untreated anemia in nontransfusion-dependent β-thalassemia: time to sound the alarm. Hemasphere. 2022;6(12):e806. doi:10.1097/HS9.0000000000000806 4. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155-167. doi:10.1016/S0140-6736(17)31822-6 5. Nienhuis AW, Nathan DG. Pathophysiology and clinical manifestations of the ß-thalassemias. Cold Spring Harb Perspect Med. 2012;2(12):a011726. doi:10.1101/cshperspect.a011726 6. Taher AT, Musallam KM, Cappellini MD. ß-Thalassemias. N Engl J Med. 2021;384(8):727-743. doi:10.1056/NEJMra2021838