Can upregulated erythropoietin (EPO) cause leukocytosis?

Upregulated Erythropoietin and Leukocytosis

Upregulated erythropoietin (EPO) does not directly cause leukocytosis based on current clinical evidence, though it may affect non-erythroid cell lineages in a small subset of patients. While EPO primarily stimulates red blood cell production, its effects on white blood cell counts are not consistently observed in clinical practice.

Mechanism of EPO Action and Primary Effects

Erythropoietin is a glycoprotein hormone that primarily regulates red blood cell production by:

• Stimulating erythroid progenitor cell proliferation and differentiation
• Preventing apoptosis of erythroid precursors
• Promoting hemoglobin synthesis

Evidence Regarding EPO and Leukocytosis

Clinical Observations

• The primary clinical guidelines for EPO use in various conditions do not list leukocytosis as a common side effect 1
• In myelodysplastic syndrome patients, only 1 out of 16 patients developed leukocytosis when treated with recombinant human EPO 2
• Most patients receiving EPO therapy for anemia do not develop significant changes in white blood cell counts

Potential Mechanisms for Rare Cases

In the small subset of patients who might experience changes in non-erythroid cell lines:

• EPO receptors have been identified on some non-erythroid hematopoietic progenitors 3
• EPO may have limited cross-reactivity with other hematopoietic growth factor receptors
• Individual patient factors may influence response to EPO therapy

Clinical Considerations

When to Monitor for Leukocytosis

• Patients with myeloproliferative disorders receiving EPO therapy
• Patients with known JAK2 mutations (associated with polycythemia vera) 1
• Patients receiving high doses of EPO
• Patients with concurrent inflammatory conditions

Differential Diagnosis When Leukocytosis Occurs During EPO Treatment

1. Underlying infection or inflammation
2. Progression of primary hematologic disease
3. Concurrent medication effects
4. True EPO-induced effect (rare)

Special Populations

Myelodysplastic Syndrome

In MDS patients, changes in non-erythroid cell lines were observed in a minority of cases:

• One patient developed increased white blood cell counts
• Two patients had increased platelet counts
• Three patients experienced decreased platelet counts 2

Polycythemia Vera

In patients with polycythemia vera, leukocytosis is common but is related to the underlying JAK2 mutation rather than EPO levels, which are typically suppressed in this condition 1.

Conclusion

While isolated cases of leukocytosis during EPO treatment have been reported, there is insufficient evidence to establish a direct causal relationship between upregulated erythropoietin and leukocytosis. When leukocytosis occurs during EPO therapy, clinicians should first consider other more common causes before attributing it to the EPO treatment itself.