How to Cite This Chapter: Laureano M, Rosart R, Verhovsek M. Thalassemia. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed May 24, 2024.
Last Updated: July 8, 2019
Last Reviewed: August 17, 2020
Chapter Information

Definition, Etiology, PathogenesisTop

Thalassemia is a chronic inherited anemia, most commonly caused by reduced (+) or absent (0) synthesis of alpha-globin and/or beta-globin chains, the key protein components of the adult hemoglobin (Hb) tetramer, HbA (alpha2beta2) (Table 1).

The thalassemias comprise the most common monogenetic disorder worldwide, resulting from inheritance of mutant or deleted copies of globin genes (2 alpha-globin genes on chromosome 16 [4 genes], one beta-globin gene on chromosome 11 [2 genes]). Thalassemia prevalence is highest in populations from Southeast Asia, the Middle East, North and Central Africa, and Mediterranean regions.

The imbalanced production of globin chains leads to excess of the unaffected globin chain (eg, excess alpha-globin chains in beta thalassemia), which is unstable, resulting in ineffective intramedullary erythropoiesis (decreased Hb production) and extramedullary hemolysis (reduced red blood cell [RBC] survival).

Clinical FeaturesTop

The clinical spectrum of thalassemia is broad, ranging from clinically silent (no symptoms or signs) to severe, lifelong, potentially fatal anemia (Table 1). Disease manifestations may include:

1) Anemia.

2) Ineffective erythropoiesis stimulating extramedullary hematopoiesis and leading to proliferation of marrow cavities (eg, frontal bossing), hepatosplenomegaly, and increased risk of osteoporosis.

3) Chronic hemolysis (jaundice, gallstones, splenomegaly, leg ulcers, aplastic crisis).

4) Increased intestinal iron absorption with or without chronic blood transfusions can result in iron overload (cirrhosis, cardiomyopathy, endocrinopathies including hypopituitarism, diabetes mellitus, testicular or ovarian failure).

5) Affected offspring: Offer preconception genetic counselling to individuals with thalassemia and their partners to ensure understanding of genetic risk for future children.


In patients with suspected thalassemia perform complete blood count (CBC), peripheral blood film, and Hb electrophoresis. The diagnosis of thalassemia is confirmed with globin gene testing (molecular studies).

Diagnostic Tests

1. CBC: Low Hb level, low mean corpuscular volume (MCV), elevated reticulocyte count.

2. Peripheral blood film: Microcytosis, hypochromia, target cells, basophilic stippling, nucleated RBCs.

3. Hb electrophoresis: Increased levels of hemoglobin A2 (HbA2) >3.5% (beta thalassemia), hemoglobin H (HbH) preparation (presence of HbH inclusion bodies suggests alpha thalassemia); this test does not detect alpha-thalassemia silent carrier or trait (ie, a defect in 1 or 2 out of 4 genes; molecular testing is needed) but does detect thalassemic-variant Hbs (eg, HbE, Hb Constant Spring, Hb Lepore).

4. Molecular genetic testing for thalassemia.

5. Other studies: Ferritin, zinc protoporphyrin IX (normal in thalassemia, elevated in iron-deficient erythropoiesis) to distinguish thalassemia from iron deficiency anemia or anemia of chronic disease.

Differential Diagnosis

Iron deficiency, anemia of chronic disease, enzymopathies (pyruvate kinase deficiency).


Management should be tailored to the patient’s disease phenotype and clinical manifestations. Patients with thalassemia trait usually have microcytosis with or without anemia that does not require hematology consultation or treatment.

1. General measures:

1) Referral to a hematology center for individuals with moderate or severe anemia.

2) Genetic counseling and prenatal family planning.

2. RBC transfusions: Patients with thalassemia major require chronic transfusions. A pretransfusion Hb level target of 90 to 105 g/L is used with the aim of preventing extramedullary hematopoiesis. Patients with non–transfusion-dependent thalassemia may require transfusion support during acute illness or physiologic stress (eg, pregnancy).

3. Iron overload: Ferritin levels should be measured on a regular basis. Liver and myocardial iron content should be assessed. This can be done through biopsy or, preferably, by specialized noninvasive techniques such as R2 or T2* magnetic resonance imaging (MRI). Patients with non–transfusion-dependent thalassemia can also develop iron overload through increased intestinal iron absorption. Chelators used in the treatment of iron overload include deferoxamine, deferiprone, and deferasirox. Therapy should be tailored to individual patient characteristics, including the area of iron deposition, preferred route of chelator administration, and coexisting medical concerns. Chelator therapy is considered at the time of starting chronic transfusions or detecting marked elevations of ferritin or iron stores in organs that exceed predefined levels.

4. Splenectomy: Possible indications include a significant increase in transfusion requirements, symptomatic splenomegaly, and hypersplenism causing cytopenias. Splenectomy should only be considered in carefully selected patients given the risks that include infection, hypercoagulability, and pulmonary hypertension.

5. Allogeneic hematopoietic stem cell transplant: This can be considered in selected patients as a curative therapy.


Consider the following investigations for patients with thalassemia major and intermedia:

1) Annual blood tests: CBC, reticulocyte count, creatinine, urine albumin-to-creatinine ratio, ferritin, calcium, vitamin D, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (women), testosterone (men), fasting glucose, liver enzymes, HIV testing, and hepatitis B and C serologic testing.

2) Imaging studies:

a) Hepatic and cardiac MRI: Performed as needed for the assessment of iron overload.

b) Bone mineral density: Performed at baseline, then every 1 to 5 years as needed.

c) Echocardiography: Performed at baseline, then every 1 to 3 years as needed.

3) Regular audiometry and ophthalmology evaluations in patients treated with iron chelators.


Table 9.1-1. Examples of genotype and phenotype correlation in thalassemia




Clinical manifestations

Beta thalassemia



Mild microcytic anemia

Intermedia (non–transfusion-dependent thalassemia)



Moderate to severe microcytic anemia

Major (transfusion-dependent thalassemia)


Severe anemia; transfusion-dependent

Alpha thalassemia


-alpha/alpha alpha

Asymptomatic; MCV normal or mild microcytosis


--/alpha alpha


Mild anemia with microcytosis

Hemoglobin H disease


Mild to moderate microcytic anemia

Bart hydrops fetalis


May be fatal in utero or neonatal period

-, loss of alpha chain; alpha, functional alpha chain; beta0, no beta-globin chain production; beta+, reduced beta-globin chain production; MCV, mean corpuscular volume.

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