What is the appropriate workup for normocytic anemia?

Workup for Normocytic Anemia

Begin with a complete blood count (CBC) with differential, reticulocyte count, and peripheral blood smear examination—these three tests form the essential foundation for determining the mechanism and cause of normocytic anemia. 1

Initial Laboratory Assessment

The reticulocyte count (corrected for degree of anemia, reported as reticulocyte index) is the critical branching point that distinguishes production defects from compensatory responses:

• Low/normal reticulocyte index (<2.0): Indicates decreased RBC production, suggesting bone marrow dysfunction, anemia of chronic disease/inflammation, renal insufficiency, or early nutritional deficiencies 1, 2
• Elevated reticulocyte index (>2.0): Indicates appropriate marrow response, pointing toward hemolysis or acute blood loss 1, 2

Essential First-Line Tests

• CBC with red cell indices (MCV, MCH, MCHC, RDW) 1
• Peripheral blood smear review to identify morphologic abnormalities, hemolysis signs, or dysplasia 1
• Reticulocyte count corrected for anemia severity 1, 2
• Basic metabolic panel including creatinine and blood urea nitrogen to assess renal function 1, 2

Algorithmic Approach Based on Reticulocyte Count

If Reticulocyte Index is LOW (<2.0):

Order these tests to identify production defects:

• Inflammatory markers: CRP and ESR to detect anemia of chronic disease/inflammation 1
• Iron studies: Serum ferritin, iron, TIBC, and transferrin saturation—even in normocytic anemia, functional iron deficiency can occur with inflammation (ferritin up to 100 μg/L may still indicate iron deficiency in inflammatory states) 1, 3
• Renal function: Creatinine clearance calculation, as chronic kidney disease commonly causes normocytic anemia 2, 4
• Thyroid function: TSH to exclude hypothyroidism 5
• Vitamin B12 and folate levels: Early deficiency states may present as normocytic before progressing to macrocytic 1, 5

If initial workup is unrevealing, proceed to:

• Bone marrow aspiration and biopsy with iron stain to evaluate for primary marrow disorders, aplastic anemia, myelodysplastic syndrome, or infiltrative processes 1, 4

If Reticulocyte Index is HIGH (>2.0):

This indicates hemolysis or acute blood loss—order hemolysis panel:

• Indirect (unconjugated) bilirubin: Elevated in hemolysis 1, 2
• Lactate dehydrogenase (LDH): Elevated in hemolysis 1, 2
• Haptoglobin: Decreased in intravascular hemolysis 1, 2
• Direct antiglobulin test (Coombs test): Identifies immune-mediated hemolysis 1
• Free hemoglobin in serum/urine: For intravascular hemolysis 1

Additional hemolysis workup if indicated:

• Glucose-6-phosphate dehydrogenase (G6PD) level for enzyme deficiency 1
• Paroxysmal nocturnal hemoglobinuria (PNH) flow cytometry if clinically suspected 1
• Hemoglobin electrophoresis if hemoglobinopathy suspected 1

Critical History and Physical Examination Elements

Specific historical details to elicit:

• Duration and progression of symptoms (syncope, dyspnea, chest pain, fatigue severity) 1
• Medication exposures, particularly chemotherapy, immunosuppressants, antibiotics, and NSAIDs 1
• Quantified alcohol intake 5
• Evidence of blood loss (melena, hematochezia, menorrhagia) 1
• Chronic diseases (inflammatory bowel disease, rheumatologic conditions, malignancy, chronic infections) 1
• Family history of anemia or hemolytic disorders 1

Physical examination findings to document:

• Jaundice (suggests hemolysis) 1
• Splenomegaly (hemolysis, portal hypertension, infiltrative disease) 1
• Lymphadenopathy (lymphoproliferative disorders) 1
• Petechiae or purpura (bone marrow failure, consumptive processes) 1
• Neurologic abnormalities (B12 deficiency, hemolytic uremic syndrome) 1

Important Clinical Pitfalls

Anemia of chronic disease/inflammation is the most common cause of normocytic anemia and can be easily missed—it typically shows normal or elevated ferritin, low iron, low TIBC, and low transferrin saturation despite adequate iron stores 1. The presence of elevated inflammatory markers (CRP, ESR) supports this diagnosis 1.

Mixed deficiencies (e.g., combined iron and B12 deficiency) can neutralize MCV changes, presenting as normocytic when both microcytic and macrocytic processes coexist—an elevated RDW (>15%) is a critical clue to this dual pathology 1, 5.

Early nutritional deficiencies may present as normocytic before MCV changes become apparent, so checking B12, folate, and iron studies is warranted even with normal MCV 1, 5.

When to Obtain Hematology Consultation

Refer to hematology if:

• Cause remains unclear after comprehensive initial workup 1, 5
• Bone marrow examination is being considered 1, 4
• Suspected primary hematologic disorder (aplastic anemia, myelodysplasia, hemolytic anemia) 1, 2
• Refractory anemia despite treatment of identified cause 2