What type of erythrocytes (red blood cells) would you expect to find in a patient with leukemia receiving chemotherapy that includes a drug antagonistic to folic acid metabolism, such as methotrexate (generic name)?

Macrocytes Would Be Expected in a Leukemia Patient Receiving a Folic Acid Antagonist

Patients receiving chemotherapy with folic acid antagonists such as methotrexate will develop macrocytes due to impaired DNA synthesis in red blood cell precursors. 1, 2

Mechanism of Macrocytosis with Folic Acid Antagonists

Methotrexate, a commonly used chemotherapeutic agent in leukemia treatment, functions as a folic acid antagonist by:

1. Inhibiting dihydrofolate reductase (DHFR), preventing the conversion of dihydrofolate to tetrahydrofolate 3
2. Reducing intracellular amounts of reduced tetrahydrofolates, which are essential for DNA synthesis 4
3. Disrupting purine and pyrimidine synthesis, leading to impaired DNA production 5

When DNA synthesis is impaired in erythroid precursors, the cells continue to produce RNA and proteins while nuclear division is delayed, resulting in:

• Larger than normal red blood cells (macrocytes)
• Nuclear-cytoplasmic asynchrony
• Megaloblastic changes in the bone marrow 6

Clinical Presentation and Laboratory Findings

In patients receiving methotrexate therapy, the following hematological findings are typically observed:

• Macrocytic red blood cells (MCV >100 fL) 6
• Elevated mean corpuscular volume (MCV) 4
• Megaloblastic changes in the bone marrow 6
• Potential development of megaloblastic anemia if therapy is prolonged 6, 3

Supporting Evidence

Studies have demonstrated that methotrexate treatment leads to folate deficiency and subsequent macrocytosis:

• Intrathecal methotrexate administration has been shown to cause megaloblastic anemia in leukemia patients 6
• Patients receiving methotrexate without folate supplementation show higher erythrocyte mean cell volumes compared to those receiving folate supplements 4
• The MTHFR gene polymorphism, which affects folate metabolism, has been associated with increased toxicity in patients receiving high-dose methotrexate 5

Clinical Management Considerations

To manage the hematologic effects of methotrexate:

1. Monitor complete blood counts regularly during therapy 1
2. Consider leucovorin (folinic acid) rescue after high-dose methotrexate to prevent severe toxicity 3
3. Be aware that supplementation with folic acid (75-200 μg/day) can affect bone marrow proliferative capacity and potentially reduce treatment efficacy 4

Common Pitfalls to Avoid

• Don't confuse macrocytosis from folate antagonists with other causes of macrocytosis (B12 deficiency, alcohol use, myelodysplastic syndrome)
• Avoid attributing megaloblastic changes to the underlying leukemia itself, as the treatment approach differs 6
• Be cautious with folic acid supplementation during methotrexate therapy, as it may reduce treatment efficacy 4

In conclusion, the expected finding in a patient with leukemia receiving a folic acid antagonist such as methotrexate would be macrocytes (option A), not microcytes, codocytes, or spherocytes.