What is the appropriate workup for microcytosis (small red blood cells)?

Workup of Microcytosis

The appropriate workup for microcytosis should begin with serum ferritin, transferrin saturation, complete blood count with red cell indices, reticulocyte count, and CRP to distinguish between iron deficiency and other causes. 1

Initial Evaluation

First-line Laboratory Tests

• Complete blood count (CBC) with red cell indices
• Peripheral blood smear examination
• Serum ferritin
• Transferrin saturation (TfS)
• C-reactive protein (CRP)
• Reticulocyte count
• Red cell distribution width (RDW)

Interpretation of Initial Results

Iron Deficiency Anemia

• Serum ferritin <30 μg/L without inflammation 1
• In the presence of inflammation, serum ferritin up to 100 μg/L may still indicate iron deficiency 1
• Transferrin saturation <16% 1
• Elevated RDW 1, 2
• Low or normal reticulocyte count 1

Thalassemia Trait

• Normal or elevated serum ferritin
• Normal transferrin saturation
• Disproportionately low MCV relative to the degree of anemia
• Normal or minimally elevated RDW
• Often elevated red blood cell count 3

Second-line Testing Based on Initial Results

If Iron Deficiency Suspected

• Total iron binding capacity (TIBC)
• Serum iron level
• If ferritin is low (<30 μg/L), proceed to investigation of the cause of iron deficiency:
  • Gastrointestinal evaluation (endoscopy) for adult men and post-menopausal women 1
  • Menstrual history for pre-menopausal women
  • Nutritional assessment

If Thalassemia Suspected

• Hemoglobin electrophoresis
• HbA2 and HbF quantification
• Consider genetic testing for alpha thalassemia if beta thalassemia is ruled out 4

If Anemia of Chronic Disease Suspected

• Comprehensive metabolic panel
• Additional inflammatory markers (ESR)
• Evaluation for underlying chronic conditions 1

Other Considerations

• Lead level testing if lead toxicity is suspected
• Bone marrow examination if diagnosis remains unclear after initial workup
• Evaluation for sideroblastic anemia if other causes are excluded 1

Special Situations

Microcytosis with Inflammatory Conditions

• Serum ferritin may be falsely elevated due to inflammation
• In this context, ferritin up to 100 μg/L may still be consistent with iron deficiency 1
• RDW has high sensitivity (94%) for iron deficiency and can help differentiate when ferritin is unreliable due to inflammation 2

Microcytosis with Polycythemia

• Consider polycythemia vera, especially with JAK2 V617F mutation
• Look for secondary iron deficiency due to increased erythropoiesis 1

Common Pitfalls to Avoid

• Relying solely on MCV without considering other red cell indices
• Failing to adjust ferritin interpretation in the setting of inflammation
• Missing combined deficiency states (e.g., iron deficiency with folate deficiency) which may present with normal MCV 1
• Assuming thalassemia trait in certain ethnic groups without confirmatory testing 1
• Overlooking gastrointestinal malignancy as a cause of iron deficiency in adult men and post-menopausal women 1

Algorithm for Microcytosis Workup

1. Obtain CBC with indices, ferritin, transferrin saturation, CRP, and reticulocyte count
2. If ferritin <30 μg/L (or <100 μg/L with inflammation) and low transferrin saturation:
   • Diagnose iron deficiency anemia
   • Investigate source of blood loss or malabsorption
3. If normal/high ferritin and normal transferrin saturation:
   • Perform hemoglobin electrophoresis to evaluate for hemoglobinopathies
4. If abnormal results persist without clear diagnosis:
   • Consider less common causes (sideroblastic anemia, lead toxicity)
   • Consider hematology consultation and possible bone marrow examination

The most common causes of microcytosis are iron deficiency anemia (35.2%) and thalassemia trait (31.1%), with beta-thalassemia accounting for 18.9% of cases 4. Proper identification of the underlying cause is essential for appropriate management and prevention of complications.