A patient with macrocytic anemia, sinus tachycardia, easy fatigue, and icteric sclera, what test would you order to confirm the diagnosis?

Reticulocyte Index to Confirm Hemolytic Component

Order a reticulocyte index (option d) to confirm the diagnosis of hemolytic anemia in this patient presenting with macrocytic anemia, jaundice, and fatigue. 1, 2

Clinical Reasoning

This patient presents with a classic triad suggesting hemolytic anemia:

• Macrocytic anemia (elevated MCV)
• Icteric sclera (indicating elevated indirect bilirubin from RBC breakdown)
• Sinus tachycardia and fatigue (compensatory response to anemia)

The key diagnostic step is determining whether this represents:

1. Hemolytic process (elevated reticulocyte count indicating bone marrow response to RBC destruction)
2. Megaloblastic anemia (low/normal reticulocyte count indicating impaired RBC production)

Why Reticulocyte Index is the Correct Choice

• A low or normal reticulocyte count indicates impaired production (megaloblastic anemia from B12/folate deficiency or MDS), while an elevated count confirms hemolysis or hemorrhage. 1
• The reticulocyte index corrects for the degree of anemia and provides the most direct assessment of bone marrow response. 1, 2
• In hemolytic anemia, the reticulocyte count is typically elevated (>2-3%), whereas in B12 deficiency presenting with hemolysis-like features (pseudothrombotic microangiopathy), the reticulocyte count remains paradoxically low (<2.5%). 3

Why Other Tests Are Less Appropriate Initially

Serum Ferritin (option a) and Iron Studies (option b)

• These assess for iron deficiency, which causes microcytic (not macrocytic) anemia. 4
• In the presence of inflammation, ferritin may be falsely elevated, making it unreliable without knowing the reticulocyte status first. 4, 5

B12 Level (option c)

• While B12 deficiency causes macrocytic anemia, the presence of icteric sclera strongly suggests a hemolytic component rather than pure megaloblastic anemia. 2, 5
• Severe B12 deficiency can rarely mimic hemolysis with elevated LDH and jaundice (pseudothrombotic microangiopathy), but this presents with a LOW reticulocyte count (<2.5%), not elevated. 3
• The reticulocyte index must be checked first to differentiate true hemolysis from B12 deficiency mimicking hemolysis. 1, 3

Direct Coombs (option e)

• This test identifies autoimmune hemolytic anemia specifically, but should only be ordered after confirming hemolysis with an elevated reticulocyte count. 1
• Ordering Coombs without first establishing hemolysis is premature and may lead to unnecessary testing.

Diagnostic Algorithm

Step 1: Order reticulocyte index immediately 1, 2

Step 2: Interpret results:

• If elevated (>2-3%): Confirms hemolysis → proceed with direct Coombs, LDH, haptoglobin, indirect bilirubin to identify the cause of hemolysis 1
• If low/normal (<2%): Suggests impaired production → order B12, folate, and peripheral smear for hypersegmented neutrophils to evaluate for megaloblastic anemia 1, 2, 5

Step 3: If megaloblastic anemia is confirmed:

• Never initiate folate before excluding and treating B12 deficiency, as this can precipitate irreversible subacute combined degeneration of the spinal cord. 1, 5
• Check both serum B12 (<150 pmol/L indicates deficiency) and methylmalonic acid (>271 nmol/L confirms deficiency if B12 is borderline). 5

Critical Pitfall to Avoid

The most dangerous error would be assuming this is simple B12 deficiency and treating with folate without checking the reticulocyte count first. If this is actually hemolytic anemia, folate supplementation will not address the underlying hemolysis and may delay appropriate treatment. 1, 5 Conversely, if this is B12 deficiency with pseudohemolysis, treating with folate alone can cause irreversible neurological damage. 1, 5