How do you differentiate between various types of anemia?

Differentiating Types of Anemia

The most effective approach to differentiating types of anemia is to use a combination of morphologic classification (based on MCV) and kinetic assessment (based on reticulocyte count), followed by targeted testing for specific causes. 1

Initial Classification Framework

1. Morphologic Classification (Based on MCV)

• Microcytic Anemia (MCV < 80 fL)

  • Iron deficiency anemia
  • Thalassemia
  • Anemia of chronic disease/inflammation
  • Sideroblastic anemia 1

• Normocytic Anemia (MCV 80-100 fL)

  • Hemorrhage
  • Hemolysis
  • Bone marrow failure
  • Anemia of chronic inflammation
  • Renal insufficiency 1

• Macrocytic Anemia (MCV > 100 fL)

  • Megaloblastic: Vitamin B12 or folate deficiency
  • Non-megaloblastic: Alcoholism, myelodysplastic syndrome (MDS), medication-induced (e.g., hydroxyurea, diphenytoin) 1

2. Kinetic Classification (Based on Reticulocyte Count)

• Low Reticulocyte Index (RI < 1.0)

  • Indicates decreased RBC production
  • Suggests: Iron deficiency, vitamin B12/folate deficiency, aplastic anemia, bone marrow dysfunction 1

• Normal/High Reticulocyte Index (RI > 2.0)

  • Indicates normal/increased RBC production
  • Suggests: Blood loss or hemolysis 1

Diagnostic Algorithm

Step 1: Complete Blood Count (CBC) with Reticulocyte Count

Obtain CBC with indices and calculate reticulocyte index to classify anemia 1

Step 2: Peripheral Blood Smear Examination

Confirm RBC size, shape, and color; look for specific abnormalities 1

Step 3: Targeted Testing Based on Initial Classification

For Microcytic Anemia:

• Iron studies:

  • Serum ferritin (< 30 μg/L in non-inflammatory states, < 100 μg/L with inflammation) 1, 2
  • Transferrin saturation (< 20% suggests iron deficiency) 2
  • Total iron binding capacity (TIBC)

• Hemoglobin electrophoresis (if thalassemia suspected) 1

• Erythrocyte size-distribution width (helps distinguish iron deficiency from thalassemia) 3

For Normocytic Anemia:

• With low reticulocytes:

  • Renal function tests (creatinine, GFR < 60 mL/min/1.73m² suggests renal anemia) 1, 2
  • Inflammatory markers (CRP, ESR)
  • Bone marrow examination (if bone marrow failure suspected)

• With high reticulocytes:

  • Hemolysis workup: Coombs test, haptoglobin, LDH, indirect bilirubin 1
  • Stool guaiac test (for occult bleeding) 1

For Macrocytic Anemia:

• Vitamin B12 and folate levels 1, 2
• Liver function tests (for alcoholism)
• Bone marrow examination (if MDS suspected) 1

Key Diagnostic Tests for Specific Anemias

Iron Deficiency Anemia

• Ferritin < 30 μg/L (without inflammation)
• Ferritin < 100 μg/L (with inflammation)
• Transferrin saturation < 15%
• Increased TIBC 1, 2

Anemia of Inflammation/Chronic Disease

• Normal or elevated ferritin
• Low transferrin saturation
• Low TIBC
• Elevated inflammatory markers (CRP, ESR) 4

Hemolytic Anemia

• Elevated reticulocyte count
• Positive Coombs test (immune hemolysis)
• Low haptoglobin
• Elevated indirect bilirubin
• Elevated LDH 1

Vitamin B12/Folate Deficiency

• Macrocytic anemia
• Low vitamin B12 or folate levels
• Hypersegmented neutrophils on peripheral smear 1, 2

Thalassemia

• Microcytic anemia with normal/elevated RBC count
• Normal or slightly low ferritin
• Abnormal hemoglobin electrophoresis 1

Common Pitfalls and Caveats

1. Mixed anemias can confuse the picture

   • Combined iron and B12/folate deficiency may result in normocytic anemia 1
   • Concurrent iron deficiency and anemia of inflammation requires careful interpretation of ferritin levels 4

2. Ferritin interpretation requires context

   • As an acute-phase reactant, ferritin increases with inflammation
   • Traditional cutoffs (12 μg/L) may miss iron deficiency in inflammatory states
   • Use higher thresholds (up to 100 μg/L) when inflammation is present 1, 2

3. Reticulocyte count must be interpreted relative to degree of anemia

   • Calculate reticulocyte index to correct for anemia severity 1

4. Early blood loss may present as normocytic before becoming microcytic

   • Acute hemorrhage initially presents with normocytic anemia before iron stores are depleted 1

5. Medication effects must be considered

   • Certain drugs (hydroxyurea, diphenytoin) can cause macrocytosis
   • Proton pump inhibitors can reduce iron absorption 1, 2

By systematically applying this approach, clinicians can effectively differentiate between the various types of anemia and direct appropriate treatment to address the underlying cause.