What are the causes and workup for normocytic anemia?

Normocytic Anemia: Causes and Workup

Primary Causes

Normocytic anemia (MCV 80-100 fL) is most commonly caused by hemorrhage, hemolysis, bone marrow failure, anemia of chronic inflammation, or renal insufficiency. 1

The key mechanistic categories include:

• Acute blood loss - hemorrhage with initially normal MCV before iron depletion develops 1, 2
• Hemolytic anemia - increased RBC destruction with compensatory reticulocytosis 1, 2
• Anemia of chronic disease/inflammation - associated with cancer, infections, inflammatory conditions (normocytic in 50-70% of cases) 3, 2
• Chronic kidney disease - develops when GFR drops below 20-30 mL/min due to inadequate erythropoietin production 1, 4
• Bone marrow failure - aplastic anemia, myelodysplastic syndrome, or marrow infiltration by malignancy 1, 2
• Medications - chemotherapy, immunosuppressants, or other myelosuppressive drugs 1, 3

Initial Diagnostic Workup

Step 1: Complete Blood Count with Indices and Peripheral Smear

• Obtain CBC with MCV, RDW, and visual review of peripheral blood smear to confirm normocytic morphology and assess for other cytopenias 1, 3
• Check white blood cell and platelet counts, as abnormalities suggest generalized bone marrow dysfunction from malignancy or vasculitis 1

Step 2: Reticulocyte Count (Corrected)

The reticulocyte index (RI) is the critical next test that distinguishes production defects from destruction/loss mechanisms. 1

• Low RI (< 1.0-2.0): Indicates decreased RBC production, suggesting iron deficiency, aplastic anemia, bone marrow dysfunction from cancer/chemotherapy, chronic kidney disease, or anemia of chronic inflammation 1, 3
• High RI (> 2.0): Indicates normal/increased production with peripheral destruction or loss, suggesting acute hemorrhage or hemolysis 1

Step 3: Targeted Testing Based on Reticulocyte Count

If Reticulocyte Count is LOW:

Iron studies (serum iron, TIBC, ferritin, transferrin saturation):

• Absolute iron deficiency: transferrin saturation < 15% and ferritin < 30 ng/mL 1
• Note: Ferritin may be falsely elevated by chronic inflammation despite true iron deficiency 1, 3
• If iron deficient, perform stool guaiac testing for occult GI bleeding 1

Renal function assessment:

• Serum creatinine and calculated GFR 3
• Anemia likely due to erythropoietin deficiency when serum creatinine ≥ 2.0 mg/dL 1
• GFR < 60 mL/min/1.73 m² with low erythropoietin level confirms renal anemia 1

Inflammatory markers:

• C-reactive protein or ESR to detect chronic inflammation 3
• Consider underlying cancer, chronic infection, or autoimmune disease 3, 2

Consider vitamin deficiencies:

• Vitamin B12 and folate levels, as deficiency can present with normocytic anemia before macrocytosis develops 5

Thyroid function:

• TSH to screen for hypothyroidism, which causes normocytic anemia mimicking erythropoietin deficiency 1

If Reticulocyte Count is HIGH:

Hemolysis workup:

• Direct Coombs test for immune-mediated hemolysis 1
• Indirect bilirubin (elevated in hemolysis) 1
• Haptoglobin (decreased in hemolysis) 1
• LDH (elevated in hemolysis) 1
• DIC panel if clinically indicated 1

Hemorrhage assessment:

• Stool guaiac for GI bleeding 1
• Endoscopy if indicated by history or positive guaiac 1
• Assess for other bleeding sources based on clinical presentation 2

Critical Clinical Examination Findings

Look specifically for these physical signs that indicate underlying causes: 1, 3

• Jaundice - suggests hemolysis
• Splenomegaly - indicates hemolysis, portal hypertension, or hematologic malignancy
• Neurologic symptoms - may indicate B12 deficiency or hemolytic uremic syndrome
• Blood in stool - GI bleeding causing blood loss anemia
• Petechiae - thrombocytopenia suggesting bone marrow failure or DIC
• Heart murmur - may indicate hemolysis or high-output cardiac state from severe anemia
• Pallor - reflects severity of anemia

Common Pitfalls to Avoid

• Do not assume normocytic anemia excludes iron deficiency - early iron deficiency or coexisting macrocytosis (from B12/folate deficiency) can mask microcytosis and present as normocytic 3
• Do not measure serum erythropoietin levels routinely - if creatinine ≥ 2.0 mg/dL with normocytic anemia, erythropoietin deficiency is presumed without needing EPO measurement 1
• Do not rely solely on hemoglobin thresholds for transfusion decisions - assess symptoms, comorbidities, and clinical context rather than arbitrary triggers 1
• Do not treat with iron supplementation without confirming deficiency - anemia of chronic disease is often mistaken for iron deficiency 6
• Do not overlook medication review - chemotherapy, immunosuppressants, and other drugs commonly cause normocytic anemia 1, 3