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Last updated: July 26, 2021

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Thalassemias are a group of hereditary hemoglobin disorders characterized by mutations on the α- or β-globin chains (resulting in alpha or beta thalassemia). Thalassemias can be further classified according to the specific genotype: the α-chain is coded by four alleles, resulting in four possible variants depending on the number of alleles affected, while the β-chain is coded by two alleles, resulting in two possible variants. The number of alleles affected is directly related to the severity of the disease (minor/intermedia/major). Thalassemia mutations are generally more frequent in areas where malaria is endemic; alpha thalassemias occur most commonly in individuals of Asian or African descent, whereas beta thalassemias are predominant in individuals of Mediterranean descent. The key feature in all forms of thalassemia is microcytic hypochromic anemia (which may be very mild in minor forms), but more severe forms may also manifest with hemolysis, splenomegaly, delay in growth and development, and skeletal deformities. The diagnostic workup for suspected thalassemia includes a blood smear, hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), and, possibly, genetic testing. Minor forms of thalassemia usually require no treatment, while patients with thalassemia intermedia/major typically require regular blood transfusions and management of disease and treatment-related complications (e.g., chelating agent for transfusion-mediated iron overload).

  • Beta thalassemia: most commonly seen in people of Mediterranean descent
  • Alpha thalassemia: most commonly seen in people of Asian and African descent
  • Thalassemia provides partial resistance against malaria.

Alpha thalassemia is common in Asia and Africa.

Epidemiological data refers to the US, unless otherwise specified.


Beta thalassemia

In a normal cell, the β-globin chains are coded by a total of two alleles. Thus, there are two main forms of the disease.

Alpha thalassemia

In a normal cell, the α-globin chains are coded by a total of four alleles. Thus, there are four forms of the disease. The severity of alpha thalassemia depends on the number of defective α-globin alleles.

  • Silent carrier (minima form): one defective allele (-α/αα)
  • Alpha thalassemia trait (minor form)
    • Two defective alleles (-α/-α or --/αα)
    • Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
    • Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart.
  • Hemoglobin H disease (intermedia form): three defective alleles (--/-α) → results in excessive production of pathologically altered HbH
  • Hemoglobin Bart disease (major form): four defective alleles (--/-‑) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers))


Anemia results from a combination of inefficient erythropoiesis and increased hemolysis. The degree to which both mechanisms contribute to the severity of the disease depends on a patient's exact genotype.


Beta thalassemia

Alpha thalassemia


Pretest probability [15][16]

The presentation of thalassemia is highly variable, ranging from incidental findings to life-threatening forms.Thalassemia is more like to be diagnosed in patients with the following:

Family history plays an important role in diagnosing patients with clinically silent thalassemia. Consider the possibility of minor forms/traits if a family member is diagnosed with a more severe form.

Initial investigations [15][16]

CBC parameters can help differentiate thalassemia minor/trait from iron deficiency anemia. IDA is frequently associated with a high RDW, low RBC count, and low MCV typically occurring once the Hb is < 10 g/dL. In thalassemia, microcytosis is always present regardless of the Hb level, the RDW is typically normal, and compared to IDA, the RBC count is higher and the MCV is lower. [17]

Low ferritin suggests iron deficiency anemia and patients should receive iron supplementation. Suspect thalassemia if there is no significant response after three months. [15][16]

Confirmatory diagnostic studies [15][16]

Interpretation of results [16][18][19]
Alpha thalassemia Beta thalassemia minor/intermedia/major
Minor Intermedia/HbH disease
MCV/MCH Normal/low Low Low
HbA2 Normal/low Normal/low High
HbF Normal Normal/high High
HbH May be present Present Absent
  • Genetic studies (PCR-based): to determine specific diagnosis and mutations
  • Bone marrow aspiration (not routinely indicated)
    • Usually performed to rule out other hematologic conditions
    • Findings in thalassemia are nonspecific (e.g., reactive hyperplasia).

Beta thalassemia minor should be strongly suspected if HbA2 is > 3.5%. [18]


References: [15][16]

Transfusion therapy [15][16][20]

This is the mainstay of management for thalassemia major and intermedia (see “Transfusion” for more information about pretransfusion testing and transfusion reactions).

  • Transfusion dependency: can fluctuate for individual patients depending on the subtype, severity, and external factors.
  • Non-transfusion-dependent patients: only require either occasional or short-term regular blood transfusions for acute needs.
  • Transfusion-dependent patients: require lifelong regular transfusions (e.g., every 2–5 weeks).
Transfusion therapy in thalassemias
Non-transfusion-dependent thalassemias (NTDT) [15] Transfusion-dependent thalassemias [16]
Indications for transfusion
  • Hb < 5 g/dL
  • Anticipated acute physiological stress
  • Declining Hb with continuous splenic enlargement
  • Frequent hemolytic crises
  • Delay in:
  • Signs of bone changes
Goals of therapy
  • Specific short-term clinical benefits (indication-dependent)
  • Maintain Hb 9–10 g/dL

Additional therapies

  • Folic acid should be considered in patients with: [20]
    • Thalassemia major or intermedia: regular supplementation
    • Thalassemia minor during periods of acute physiological stress (e.g., infections): episodic supplementation
  • Fetal hemoglobin induction: hydroxyurea may help induce fetal hemoglobin, reducing symptoms and the need for transfusions

Splenectomy [15][16]

Avoid splenectomy in patients < 5 years old due to the risk of overwhelming postsplenectomy sepsis.

All patients receiving transfusion therapy should be periodically evaluated for iron overload disease and subsequent organ damage. [15][16][18]

Iron overload can seriously affect the liver and cardiac function, as well as several endocrine glands, and is potentially lethal in the long term. Once organ damage occurs, it is often irreversible.

The objective of chelation therapy is to prevent organ damage resulting from iron overload disease and requires good adherence to treatment, continuous monitoring by specialists, and frequent dosing adjustment.

In addition to iron overload disease, patients may develop other long-term complications secondary to the disease or its treatment.

Common complications in patients with thalassemia [15][16][18]
Mechanism Management
Hepatobiliary complications Cholelithiasis
Liver disease
Hematologic complications Hypercoagulable states
Hemolytic crisis
  • Triggered by external factors (e.g., acute infections)
  • Transfusional support and adequate hydration
  • Treat the underlying cause.
  • Frequent monitoring of electrolytes and acid-base status
Extramedullary hematopoietic pseudotumors
  • Erythropoietic masses and bone deformities develop in an attempt to compensate for defective hemoglobin
  • Depending on the location, multiple presentations are possible.
  • Clinical surveillance during checkups and imaging as necessary
  • Usually an indicator for transfusion requirements
  • May require surgical management, depending on their location
Cardiovascular complications
Chronic leg ulcers
Mental health complications
  • Chronic disease and invasive treatment can negatively impact mental health (e.g., causing or exacerbating depression and/or anxiety).
  • Frequent assessment of quality of life and mental health status
  • Psychiatric referral and pharmacotherapy as needed

HSCT can have good outcomes and be considered curative, however, its use is limited due to high mortality and morbidity. Specialist evaluation and shared decision-making (involving patients and/or surrogate decision-makers) are essential and should weigh each patient's individual risks and benefits. [16]

  • Modalities
    • Compatible sibling donor (preferred): most successful alternative; mortality rate of ∼ 5%
    • Matched unrelated donor (alternative): can be considered; higher chances of rejection
  • Limitations

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