When should thalassemia be suspected clinically and through laboratory (lab) tests?

When to Suspect Thalassemia Clinically and Through Laboratory Tests

Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels, especially in individuals of Mediterranean, Southeast Asian, Middle Eastern, or African descent. 1 Clinical suspicion should be heightened when patients have persistent microcytic anemia that is unresponsive to iron supplementation.

Clinical Suspicion Indicators

Family History and Demographics

• Family history of thalassemia or hemoglobinopathies
• Ethnic background from high-prevalence regions:
  • Mediterranean (Italy, Greece, Cyprus)
  • Southeast Asia (particularly for alpha thalassemia)
  • Middle East
  • Africa

Clinical Presentation

• Unexplained fatigue and pallor
• Microcytic anemia unresponsive to iron therapy 2
• History of "treatment-resistant iron deficiency anemia"
• Jaundice or splenomegaly (in more severe forms)
• Bone deformities or poor growth (in thalassemia major)

Laboratory Findings Suggestive of Thalassemia

Initial Laboratory Tests

• Complete blood count (CBC) showing:
  • Microcytic (low MCV) and hypochromic (low MCH) anemia
  • Normal or elevated red blood cell (RBC) count despite anemia
  • Normal or elevated ferritin levels (key distinguishing feature from iron deficiency)

Key Diagnostic Pattern

• Low MCV with normal RDW (≤14.0%) strongly suggests thalassemia minor 3
  • This contrasts with iron deficiency anemia, which typically shows low MCV with elevated RDW (>14.0%)

Additional Laboratory Findings

• Normal or elevated serum ferritin (unlike iron deficiency)
• Normal or increased transferrin saturation
• Absence of iron-deficient erythropoiesis markers (normal erythrocyte protoporphyrin)
• Peripheral blood smear showing:
  • Microcytosis
  • Target cells
  • Basophilic stippling
  • Nucleated RBCs (in severe forms)

Confirmatory Testing

Hemoglobin Electrophoresis

• Essential for diagnosis and classification
• Findings vary by type:
  • Beta thalassemia minor: Elevated HbA2 (>3.5%) and variable HbF
  • Beta thalassemia major: Predominantly HbF with absent or reduced HbA
  • Alpha thalassemia: Normal HbA2 with variable HbH or Hb Bart's

Genetic Testing

• Definitive diagnosis requires genetic testing 1
• For alpha thalassemia: DNA analysis for common deletions in alpha-globin genes
• For beta thalassemia: Sequencing of beta-globin gene for mutations

Special Considerations

• In pregnant women with microcytic anemia, screening parents with MCV can identify potential carriers of alpha thalassemia, where MCV will be <80 fL 3
• In cases of nonimmune hydrops fetalis, alpha thalassemia should be considered, especially in Southeast Asian populations 3

Diagnostic Algorithm

1. Initial screening: CBC showing microcytic anemia with normal/elevated ferritin
2. Evaluate RDW:
   • If RDW ≤14.0% with low MCV: Suspect thalassemia
   • If RDW >14.0% with low MCV: More likely iron deficiency
3. Confirm iron status: Serum ferritin, transferrin saturation
4. Perform hemoglobin electrophoresis for pattern of hemoglobin variants
5. Genetic testing for definitive diagnosis and classification

Common Pitfalls to Avoid

• Misdiagnosing thalassemia as iron deficiency anemia, leading to unnecessary prolonged iron supplementation 2
• Failing to consider thalassemia in patients with persistent microcytic anemia despite iron therapy
• Not obtaining family history or considering ethnic background
• Relying solely on MCV without considering RDW and other parameters
• Failing to perform hemoglobin electrophoresis in suspected cases
• Not distinguishing between different forms of thalassemia, which have vastly different clinical implications and management needs 4

Early and accurate diagnosis of thalassemia is crucial for appropriate management, genetic counseling, and prevention of complications from unnecessary treatments or missed severe forms requiring intervention.