What is the initial workup for a patient with leukopenia and macrocytosis?

Initial Workup for Leukopenia with Macrocytosis

The initial workup should include a complete blood count with manual differential, peripheral blood smear review, reticulocyte count, vitamin B12 and folate levels, methylmalonic acid, liver function tests, TSH, and a comprehensive medication history, with bone marrow aspiration and biopsy reserved for cases with persistent or worsening cytopenias or when myelodysplastic syndrome is suspected. 1

Essential First-Line Laboratory Tests

The minimum diagnostic panel must include:

• Complete blood count with manual differential to examine for leukemic blasts, dysplastic changes, and establish baseline values for future comparison 2
• Peripheral blood smear review to identify megaloblastic changes (macro-ovalocytes, hypersegmented neutrophils), dysplastic features, or abnormal cells 2, 1
• Reticulocyte count to distinguish between decreased bone marrow production versus increased destruction; low or "normal" reticulocytes with cytopenias indicate inappropriate erythropoiesis or primary bone marrow disease 2

Nutritional and Metabolic Evaluation

• Vitamin B12 and folate levels are essential as macrocytosis commonly indicates B12 or folate deficiency 2, 1
• Methylmalonic acid (MMA) should be measured when B12 deficiency is suspected but serum B12 levels are equivocal, as MMA has greater sensitivity than serum B12 alone 1
• Homocysteine levels can indicate tissue deficiency of either B12 or folate with greater sensitivity than serum measurements, though MMA is more specific for B12 deficiency 1
• Thyroid-stimulating hormone (TSH) to rule out hypothyroidism as a cause of macrocytosis 1
• Liver function tests to exclude liver disease, which commonly causes macrocytosis 1

Medication History

A detailed medication review is critical, specifically looking for:

• Thiopurines (azathioprine, 6-mercaptopurine) which commonly cause macrocytosis and can lead to severe megaloblastic anemia with pancytopenia 2, 1, 3
• Hydroxyurea, methotrexate, anticonvulsants and other drugs known to cause macrocytosis 1

When to Proceed to Bone Marrow Evaluation

Bone marrow aspiration and biopsy with cytogenetic analysis should be performed when:

• The initial laboratory workup is unrevealing after excluding nutritional deficiencies, thyroid disease, liver disease, and medication causes 1
• Additional cytopenias are present beyond the isolated leukopenia 1
• Cytopenias persist or worsen on repeat CBC within 2-4 weeks 2
• Myelodysplastic syndrome (MDS) is suspected, particularly given that macrocytosis can be an early sign of bone marrow injury appearing 6-18 months before severe anemia or acute leukemia develops 4

For patients at high risk for MDS (such as those with prior chemotherapy/radiation exposure), bone marrow evaluation should include morphologic examination, cytogenetics, and consideration of flow cytometry 2, 1

Follow-Up Strategy

• Repeat CBC in 2-4 weeks if initial cytopenias are present to assess for progression 2
• For unexplained macrocytosis with leukopenia after initial workup, follow with CBC every 6 months as approximately 12% of patients develop primary bone marrow disorders (lymphomas, MDS, plasma cell disorders) with median time to first cytopenia of 18 months 5
• The probability of bone marrow biopsy establishing a diagnosis is 33% in patients without anemia but increases to 75% when anemia is present 5

Critical Pitfalls to Avoid

• Do not dismiss macrocytosis as benign without thorough evaluation, as it can precede MDS or acute leukemia by 6-18 months 4
• Do not overlook medication-induced causes, particularly azathioprine which can cause severe pancytopenia even after 22 years of therapy 3
• Do not delay bone marrow biopsy when multiple cytopenias are present or worsening, as this significantly increases diagnostic yield 5