What is the approach to differentiating anemias based on Complete Blood Count (CBC)?

Approach to Differentiating Anemias Based on CBC

The most effective approach to differentiating anemias using CBC involves a two-pronged strategy: first classifying by red cell morphology (MCV) and then by reticulocyte count to determine if the bone marrow response is appropriate. 1

Initial Classification by MCV

Microcytic Anemia (MCV < 80 fL)

• Most commonly caused by iron deficiency anemia 1
• Other causes include thalassemia, anemia of chronic disease, and sideroblastic anemia 1
• High RDW suggests iron deficiency, while normal RDW is more consistent with thalassemia 1, 2
• Follow-up testing should include serum ferritin, transferrin saturation, and CRP 1
• Serum ferritin <30 μg/L confirms iron deficiency in the absence of inflammation 1
• In inflammatory states, ferritin up to 100 μg/L may still be consistent with iron deficiency 1

Normocytic Anemia (MCV 80-100 fL)

• May be caused by hemorrhage, hemolysis, bone marrow failure, anemia of chronic inflammation, or renal insufficiency 1
• The reticulocyte count is crucial for further classification 1
• Acute blood loss may initially present with normal MCV and elevated reticulocytes 1
• Consider renal anemia when there is evidence of kidney dysfunction 1

Macrocytic Anemia (MCV > 100 fL)

• Most commonly megaloblastic, indicating vitamin B12 or folate deficiency 1
• Non-megaloblastic causes include alcoholism, medications (hydroxyurea, diphenytoin), and myelodysplastic syndrome 1, 3
• Normal B12 levels with macrocytosis should prompt folate level testing 3
• Medication effects, chronic alcohol consumption, and hypothyroidism are important considerations 3

Secondary Classification by Reticulocyte Count

Low Reticulocyte Index (RI < 1.0)

• Indicates decreased RBC production 1
• Suggests iron deficiency, vitamin B12/folate deficiency, aplastic anemia, or bone marrow dysfunction 1
• Common in cancer-related anemia and after myelosuppressive chemotherapy 1
• Reticulocyte index calculation: (Reticulocyte % × Patient's Hct) ÷ Normal Hct 4

Normal or High Reticulocyte Index (RI > 2.0)

• Indicates normal or increased RBC production 1
• Suggests blood loss or hemolysis in anemic patients 1
• Further testing for hemolysis should include Coombs test, haptoglobin, and indirect bilirubin 1
• Blood loss evaluation may require stool guaiac testing or endoscopy 1

Additional Diagnostic Tests Based on Initial Classification

For Microcytic Anemia

• Iron studies: serum iron, TIBC, transferrin saturation (<15% suggests iron deficiency) 1
• Serum ferritin: <30 ng/mL confirms iron deficiency without inflammation 1, 2
• Hemoglobin electrophoresis to evaluate for thalassemia 1
• Consider lead levels in rare cases 1

For Normocytic Anemia

• Reticulocyte count is the key follow-up test 1
• If reticulocytes are low: evaluate for renal disease, chronic inflammation, or bone marrow disorders 1
• If reticulocytes are high: evaluate for hemolysis or recent blood loss 1
• Consider direct antiglobulin test (DAT) if hemolysis is suspected 1

For Macrocytic Anemia

• Vitamin B12 and folate levels 1, 3
• Peripheral blood smear to assess for hypersegmented neutrophils (megaloblastic anemia) 5
• Liver function tests and thyroid studies 3
• Bone marrow examination if myelodysplastic syndrome is suspected 1

Common Pitfalls to Avoid

• Relying solely on MCV without considering reticulocyte count can lead to misdiagnosis 1, 4
• Inflammation can elevate ferritin, potentially masking iron deficiency 1, 2
• Mixed deficiency states (e.g., iron and B12 deficiency) can result in normocytic indices 1, 2
• Microcytosis and macrocytosis can coexist, resulting in a normal MCV but elevated RDW 1
• Recent transfusion can confound CBC interpretation 1
• Assuming all macrocytic anemias are due to B12/folate deficiency without considering medications, alcohol, or myelodysplasia 3

By systematically applying this approach of morphologic classification followed by kinetic assessment, most anemias can be accurately differentiated using CBC parameters, with targeted follow-up testing to confirm the diagnosis 1, 5.