What are the initial steps and lab tests for diagnosing and treating anemia?

Initial Diagnostic Workup for Anemia

Begin with a complete blood count (CBC) including hemoglobin, red cell indices (MCV, MCH, MCHC), white blood cell count with differential, platelet count, and absolute reticulocyte count, followed immediately by iron studies (serum ferritin and transferrin saturation) and vitamin B12 and folate levels. 1, 2

Essential First-Line Laboratory Tests

The initial evaluation must include the following tests performed simultaneously to avoid delays in diagnosis:

• Complete blood count with differential - Hemoglobin is preferred over hematocrit because it has better reproducibility across laboratories and is not affected by sample storage time or patient glucose levels 1
• Absolute reticulocyte count - This evaluates bone marrow response to anemia; a low count indicates impaired erythropoiesis while an elevated count suggests increased red cell production or hemolysis 1, 2
• Serum ferritin - The single most useful marker for iron stores, with levels <30 μg/L confirming iron deficiency in the absence of inflammation 2
• Transferrin saturation (TSAT) - Values <15-16% support iron deficiency and are less affected by inflammation than ferritin 2
• Vitamin B12 and folate levels - Essential for evaluating macrocytic anemia and should be obtained in the initial workup 1, 2

Interpretation Based on Red Cell Indices

Microcytic Anemia (MCV < 80 fL)

• Most commonly indicates iron deficiency anemia, which is the most prevalent cause of anemia globally 2, 3
• MCH is more reliable than MCHC for detecting iron deficiency because it is less dependent on storage conditions 2
• If iron studies are normal, consider hemoglobinopathies such as thalassemia trait and obtain hemoglobin electrophoresis, particularly in patients of appropriate ethnic background 2

Normocytic Anemia (MCV 80-100 fL)

• May indicate hemorrhage, hemolysis, or anemia of chronic inflammation 2
• An elevated RDW with normal MCV suggests early iron deficiency, mixed nutritional deficiencies, or other causes 2
• Low MCHC with normal MCV often accompanies iron deficiency even before MCV decreases 2

Macrocytic Anemia (MCV > 100 fL)

• Suggests vitamin B12 or folate deficiency 2, 4
• Obtain peripheral blood smear to look for megaloblastic changes such as macro-ovalocytes and hypersegmented neutrophils 4
• Consider methylmalonic acid (MMA) levels when B12 deficiency is suspected but serum B12 levels are equivocal, as MMA has greater sensitivity 4

Critical Additional Assessments

Bone Marrow Function

• Abnormalities in two or more cell lines (red cells, white cells, platelets) warrant hematology consultation 1
• Bone marrow aspiration and biopsy should be considered when initial workup is unrevealing or when additional cytopenias are present 4

Iron Deficiency Evaluation

• In adult men and postmenopausal women with confirmed iron deficiency, investigate for gastrointestinal bleeding 1, 2
• Ferritin can be falsely elevated in inflammation, chronic disease, malignancy, or liver disease, requiring clinical context for interpretation 2
• In patients with nondialysis CKD not on erythropoietic agents without significant menstrual or known iron losses, finding iron deficiency should prompt careful assessment for GI bleeding 1

Hemolysis Evaluation

• If hemolysis is suspected based on elevated reticulocyte count, measure haptoglobin, LDH, and bilirubin 2

Common Pitfalls to Avoid

• Do not rely on hematocrit alone - Hemoglobin is more reproducible and not affected by storage conditions 1
• Do not interpret ferritin in isolation - It acts as an acute-phase reactant and may be elevated despite iron deficiency in the presence of inflammation 1, 2
• Do not delay iron studies - Obtain them with the initial CBC rather than waiting for results, as iron deficiency is the most common cause of anemia 2, 3
• Do not overlook reticulocyte count - This distinguishes between production defects and increased destruction/loss 1, 2

Anemia of Chronic Disease

• If iron studies show elevated ferritin with low TSAT, consider anemia of chronic inflammation 2
• Treat by addressing the underlying condition; erythropoietin therapy may be considered in specific situations such as chronic kidney disease 2
• C-reactive protein measurement can help assess the contribution of inflammation to elevated ferritin 1