What is the appropriate workup for a patient with normocytic anemia?

Workup for Normocytic Anemia

The initial workup for normocytic anemia should include reticulocyte count to determine if the anemia is due to decreased production or increased destruction/loss of red blood cells, followed by targeted testing based on this classification. 1, 2, 3

Initial Assessment

• Complete blood count (CBC) with indices confirming normocytic anemia (MCV 80-100 fL)
• Peripheral blood smear examination to confirm RBC morphology and identify abnormalities
• Reticulocyte count and reticulocyte index (RI) calculation

Key Classification Step:

• Low reticulocyte index (<1.0): Indicates decreased RBC production
• High reticulocyte index (>2.0): Indicates blood loss or hemolysis

For Low Reticulocyte Index (Decreased Production)

1. Iron studies:

   • Serum ferritin
   • Total iron binding capacity (TIBC)
   • Transferrin saturation
   • Note: In inflammation, serum ferritin up to 100 μg/L may still be consistent with iron deficiency 2

2. Renal function tests:

   • BUN, creatinine (for anemia of chronic kidney disease)

3. Inflammatory markers:

   • ESR, CRP (for anemia of chronic inflammation)

4. Endocrine evaluation:

   • TSH, free T4
   • Consider testosterone in males

5. Bone marrow evaluation if other tests inconclusive or if suspicion of:

   • Myelodysplastic syndrome
   • Aplastic anemia
   • Bone marrow infiltration

For High Reticulocyte Index (Increased Destruction/Loss)

1. Hemolysis workup:

   • LDH
   • Haptoglobin
   • Direct antiglobulin test (Coombs test)
   • Bilirubin (direct and indirect)
   • Peripheral smear for schistocytes or other abnormal RBC morphology

2. Blood loss evaluation:

   • Stool guaiac test
   • Endoscopic evaluation if GI blood loss suspected
   • Menstrual history in females

3. Hemoglobinopathy screening if clinically indicated:

   • Hemoglobin electrophoresis

Special Considerations

For Suspected Immune-Mediated Hemolytic Anemia

• Direct and indirect Coombs test
• Cold agglutinin testing if indicated
• Evaluation for underlying malignancy or autoimmune disease 1

For Suspected Bone Marrow Failure

• Bone marrow aspiration and biopsy
• Cytogenetic analysis
• Flow cytometry for paroxysmal nocturnal hemoglobinuria 1

For Suspected Anemia of Chronic Disease

• Evaluate for underlying conditions: infection, inflammation, malignancy
• Iron studies may show normal or elevated ferritin with low transferrin saturation 1

Common Pitfalls to Avoid

1. Failing to calculate reticulocyte index: Reticulocyte percentage alone can be misleading without correction for degree of anemia.

2. Misdiagnosing anemia of chronic disease as iron deficiency: In inflammatory states, ferritin (an acute phase reactant) may be normal or elevated despite iron deficiency.

3. Overlooking mixed anemias: Multiple causes of anemia can coexist, particularly in elderly patients 4.

4. Premature bone marrow examination: Reserve for cases where non-invasive testing is inconclusive. In most cases of "idiopathic" normocytic anemia, bone marrow examination rarely changes management 4.

5. Missing occult blood loss: Particularly in elderly patients or those on anticoagulants or NSAIDs.

By following this systematic approach based on reticulocyte index, clinicians can efficiently narrow down the differential diagnosis of normocytic anemia and direct further testing appropriately, leading to improved patient outcomes.