What is the most appropriate test to confirm the diagnosis in a patient with macrocytic anemia, sinus tachycardia, easy fatigue, icteric sclera, and thrombocytosis?

Reticulocyte Count is the Most Appropriate Initial Test

Order a reticulocyte count (option d) to confirm the diagnosis in this patient with macrocytic anemia, icteric sclera, and fatigue. This single test will immediately differentiate between hemolytic anemia (elevated reticulocytes) and megaloblastic anemia from B12/folate deficiency (low/normal reticulocytes), which is the critical diagnostic branch point in this clinical scenario 1.

Diagnostic Reasoning

The clinical presentation combines three key features that demand immediate clarification:

• Macrocytic anemia indicates either megaloblastic processes (B12/folate deficiency) or increased reticulocyte production (hemolysis/hemorrhage) 2, 3
• Icteric sclera strongly suggests a hemolytic component with elevated indirect bilirubin, rather than pure nutritional deficiency 1
• Thrombocytosis (platelets 415,000/mm³) can occur in both hemolysis and chronic inflammation, making this finding non-specific 2

The reticulocyte count is essential because it provides direct assessment of bone marrow response and fundamentally changes the differential diagnosis 2, 1. Low or normal reticulocytes indicate inappropriate erythropoiesis from deficiencies or bone marrow disease, while elevated reticulocytes indicate increased red cell formation and exclude deficiencies, pointing instead toward hemolysis 2, 1.

Why Other Tests Are Less Appropriate Initially

Serum Ferritin and Iron Studies (Options a, b)

• These assess for iron deficiency, which causes microcytic anemia, not macrocytic 2, 1
• Ferritin may be falsely elevated in the presence of inflammation 1
• Iron studies would be appropriate after ruling out hemolysis and megaloblastic anemia 2

B12 Level (Option c)

• While B12 deficiency is a common cause of macrocytic anemia, the presence of icteric sclera suggests a hemolytic component 1
• The reticulocyte index must be checked first to differentiate true hemolysis from B12 deficiency mimicking hemolysis 1
• Treating with folate before excluding B12 deficiency can precipitate irreversible neurological damage 4, 1

Direct Coombs Test (Option e)

• This identifies autoimmune hemolytic anemia specifically, but is premature without first confirming hemolysis via reticulocyte count 1
• Direct Coombs is part of the hemolysis workup after an elevated reticulocyte count confirms increased RBC destruction 1

Diagnostic Algorithm Following Reticulocyte Count

If Reticulocyte Count is Elevated (>2.0% corrected):

• Confirms hemolysis as the primary mechanism 1, 3
• Proceed with hemolysis workup: direct Coombs, LDH, haptoglobin, indirect bilirubin 2, 1
• This explains the icteric sclera and macrocytosis (from young reticulocytes) 1, 3

If Reticulocyte Count is Low or Normal:

• Indicates megaloblastic anemia from impaired erythropoiesis 2, 1
• Then order B12, folate, and peripheral smear to evaluate for megaloblastic changes 2, 3
• The icteric sclera would be less consistent with pure megaloblastic anemia, making this scenario less likely 1

Critical Pitfall to Avoid

The most dangerous error would be assuming simple B12 deficiency and treating with folate without checking the reticulocyte count first 1. This can delay appropriate treatment for hemolytic anemia and cause irreversible neurological damage if B12 deficiency is present but masked by folate supplementation 4, 1.

The minimum workup for macrocytic anemia should include complete blood count with MCV, reticulocytes, serum ferritin, transferrin saturation, and CRP 2. In this case with icteric sclera, the reticulocyte count takes diagnostic priority to determine the mechanism of anemia before pursuing specific etiologic testing 1.