Thalassemia is a hereditary cause of microcytic, hypochromic anemia. It is a deficiency in either the alpha (α) or beta (β) globin chain resulting in hemoglobinopathy. The presentation of thalassemia depends on the number of defective chains present. The consequent hemolysis results in severe systemic symptoms rendering the patient to be transfusion dependent.

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Image: “Target cells” Target cells (Codocytes, Leptocytes or Mexican hat cells). They are red cells with a central area of intense staining surrounded by a ring of less intensely stained periphery and then a further ring of dense staining at the edge of the cell. Target cells are commonly seen in blood film of patients with liver disease, thalassaemia or sickle-cell disease, iron-deficiency anaemia and in splenectomised patients. By Prof. Osaro Erhabor. License: Public Domain

Epidemiology and Etiology


  • Worldwide prevalence
  • Mediterranean anemia, ∼10% prevalence in the region (malaria-endemic areas)
  • Carrier rate worldwide: 
    • β- thalassemia: 3%
    • α- thalassemia: 5%
  • α – presents in utero/from birth


    Image: “Thalassemia” by Lecturio.

  • β – presents in infants around 6 months of age
  • Equal incidence between the genders


  • Autosomal recessive 
  • α-thalassemia: 2 α – genes (HBA1 and HBA2) = 4 alleles (αα/αα)
    • Chromosome 16
    • Deletion error
    • 4 types of disease variations
  • β-thalassemia: 1 β-gene (HBB) = 2 alleles
    • chromosome 11 
    • Splicing mutation (β+: decreased expression) 
    • Nonsense mutation (β0: absent expression)
    •  Thalassemia minor: heterozygous, ∼50% decreased synthesis 
    • Thalassemia major: homozygous, no production of β-globulin, increase in HbA(α2δ2) and HbF(α2γ2), no HbA
α- thalassemia
Number of genes deleted/Genotype Disease Outcome


α-thalassemia minima Silent carrier

(α-/α-; trans: African)

(αα/–; cis: Asians)

α-thalassemia minor



Mild anemia

Cis: worsens with generations



HbH disease


Moderate to severe anemia


Hb Barts 

(4γ- chains)

Hydrops fetalis 

(incompatible with life)

β- thalassemia
β0/β or β+ Thalassemia minor Asymptomatic (mild)
β0/β or β++ Thalassemia intermedia Occasional transfusion
β00 or β++ Thalassemia major (Cooley anemia) Transfusion-dependent

Video Gallery

Pediatric Thalassemia by Brian Alverson, MD
Alpha Thalassemia: Etiology by Carlo Raj, MD
Beta Thalassemia: Etiology and Pathogenesis by Carlo Raj, MD


  • Defective hemoglobin formation leads to hemoglobin aggregation that damages the RBC membrane
  • Damaged RBCs undergo hemolysis that leads to: 
  • Ineffective erythropoiesis (due to lack of normal hemoglobin components) leads to
    • Anemia → high output heart failure
    • Bone marrow expansion
    • Extramedullary hematopoiesis → hepato and/or splenomegaly
  • Iron overload (from multiple need transfusions to account for damaged native RBCs)
    • Compensatory increase in GI uptake of iron
    • Endocrinopathies 

Video Gallery

Alpha Thalassemia: Pathogenesis by Carlo Raj, MD
Beta Thalassemia: Morphology and Hemoglobin Electrophoresis by Carlo Raj, MD

Clinical manifestations

Cooley Anemia and HbH Disease

  • Anemia
    • Shortness of breath
    • Fatigue
    • Weakness 
  • Hemolysis
    • Gallstones
    • Splenomegaly
    • Hepatomegaly (Cirrhosis, Spider nevi)
  • Bone Marrow Expansion
    • Frontal Bossing
    • Chipmunk Facies
    • Bone pain
    • Fragility fractures
  • Malnutrition 
  • Stunted growth (hypogonadal)


  • Cardiac failure (restrictive or high output)
  • Iron overload (secondary hemochromatosis)
    • Arthralgia
    • Bronze skin
    • Cirrhosis
    • Cardiomyopathy
    • DM
    • Hypogonadism
  • Transfusion 
    • Iron overload
    • Infections
  • Thromboembolism

Death: despite management

  • In the patient’s twenties or thirties
  • Iron overload/heart failure

Presentation based on variant

Disease Presentation
α-thalassemia minima
  • Asymptomatic
α-thalassemia minor
  • Incidental finding 
  • Mild hypochromic microcytic anemia
  • Offspring with HbH
HbH disease
  • Severe anemia (from birth)
  • Transfusion dependent
Hb Barts
  • In utero
  • High output cardiac failure: anasarca
  • Hepatosplenomegaly
  • Death (in utero) or early infancy
β- thalassemia minor
  • Incidental finding
  • Hypochromic microcytic anemia
  • Palpable spleen (rare)
β- thalassemia intermedia
  • Microcytic anemia
  • Hepatosplenomegaly
  • Occasional transfusion
β- thalassemia major

 (Cooley anemia)

  • Severe anemia ( ∼ 6 months of age)
  • Transfusion dependent

Video Gallery

Beta Thalassemia: Clinical Pathology by Carlo Raj, MD


  • Take a full medical history and family history (screen in high-risk areas).
  • Order CBC with erythrocyte indices and peripheral blood smear.
  • On CBC
    • Hb: usually < 11 g/dL or < 6 g/dL in Cooley anemia
    • MCV: microcytic (< 70 fL) in thalassemias
    • MCH: low in thalassemias
    • RDW: not very useful in thalassemias (can be normal or elevated)
  • On peripheral blood smear
    • Target cells (most common)
    • Howell-Jolly body
    • Anisocytosis
    • Inclusion bodies: seen only in HbH disease (4β aggregation) 
    • Heinz bodies
    • Basophilic stippling
  • Then, order iron studies (in any anemia) → normal (in thalassemias)
  • If iron studies normal, order a Hb electrophoresis
    • Most accurate test
    • In α-thalassemia
      • Minima: normal %
      • Minor (trait): normal % but CBC shows anemia
      • HbH – β-tetrad (i.e. Hb electrophoresis will show only a β band)
      • Hb Barts – γ-tetrad (i.e. Hb electrophoresis will show only a γ band) 
    • In β- thalassemia
      • Minor: 
        • ↓ HbA (93%)
        • ↑ HbA2>/sub> (5%)
        • ↑ HbF (2%)
      • Major: 
        • No HbA
        • ↑ HbF(90%)
        • ↑ HbA2>/sub> (10%)
  • If suspect hemolysis, order LDH – nonspecific elevation, possible hemolysis
    • If LDH elevated and suspect hemolysis, order reticulocyte count (elevated in hemoglobin H disease)
  • Other ancillary studies:
    • X-ray will show osteopenia and skull with “hair on end” appearance.
    • Echocardiogram will possibly show a reduction in LVEF.


To recall the features seen on a Peripheral Blood Smear of a Thalassemia patient, remember THAL:

  • Target cells (most common)
  • Howell-Jolly body
  • Anisocytosis
  • Low MCH, MCV, and Hb

Image: “Target cells” Target cells (Codocytes, Leptocytes, or Mexican hat cells). They are red cells with a central area of intense staining surrounded by a ring of less intensely stained periphery and then a further ring of dense staining at the edge of the cell. Target cells are commonly seen in blood films of patients with liver disease, thalassemia or sickle-cell disease, iron-deficiency anemia, and in splenectomized patients. By Prof. Osaro Erhabor. License: Public Domain

Video Gallery

Alpha Thalassemia: Clinical Pathology by Carlo Raj, MD
Alpha Thalassemia: Hemoglobin Electrophoresis by Carlo Raj, MD


This section shows treatments for Cooley anemia and HbH disease.

  • Transfusions:
    • Regular blood transfusions (Target Hb level >10 g/dL)
    • Folate if not transfused
  • Splenectomy and cholecystectomy: 
    • Splenectomies: reduce transfusion requirements
    • Post-splenectomy vaccinations 
      • Pneumococcal polyvalent
      • Haemophilus influenzae type b 
      • Pneumococcal conjugate
    • Cholecystectomy: prevents recurrent gallstones
  • Iron chelation:
    • Deferoxamine (IV)
    • Deferiprone/Deferasirox (PO)
  • Endocrine therapy:
    • Administer deficient hormones
    • Bisphosphonates: to prevent osteopenia and osteoporosis
    • Fertility agents
  • Definitive:
    • Allogeneic stem cell transplantation 
  • Genetic counseling

Differential Diagnoses

Differentials include other types of hypochromic microcytic anemia and hemolytic anemia.

  • Iron Deficiency Anemia: The most common cause of hypochromic microcytic anemia is due to a deficiency in iron and its reservoir in the body. Very important to differentiate from thalassemia as iron supplementation can worsen thalassemia due to further iron overload.
  • Anemia of Chronic Disease: second most common cause of microcytic hypochromic anemia. An imbalance in iron homeostasis secondary to infections, auto-immune disorder, or malignancy. Management of which relies on treating the underlying cause. 
  • Sideroblastic Anemia: It is microcytic anemia in which the bone marrow produces sideroblasts (ring-shaped blood cells) due to the inability of the body to place iron properly into hemoglobin. It presents with abnormal iron studies.
  • Sickle Cell Disease: hereditary hemoglobinopathy resulting in hypoxia and anemia. The difference is that it is normocytic and sickle-shaped cells are noted on peripheral smear.
  • Hemolytic Anemia: autoimmune, drug-induced, or Rh-incompatibility present as hemolysis. The difference is that there are auto-immune and the pathologic mechanism is immune-mediated destruction. They also present as normocytic anemia.
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