How to manage erythrocytosis (increased red blood cell count) with normal erythropoietin (EPO) levels?

Management of Erythrocytosis with Normal Erythropoietin Levels

In patients with erythrocytosis and normal erythropoietin levels, a systematic diagnostic approach should be followed to identify the underlying cause, with phlebotomy as the primary treatment for symptomatic cases while the investigation proceeds. 1

Diagnostic Approach

When evaluating erythrocytosis with normal erythropoietin levels, consider the following algorithm:

1. Confirm true erythrocytosis:

   • Verify that the red cell mass is greater than 125% of predicted value
   • Rule out relative erythrocytosis (plasma volume contraction)

2. Evaluate for JAK2 mutation:

   • Despite normal EPO levels, JAK2 testing is essential as some polycythemia vera (PV) cases can present with normal EPO 2
   • A positive JAK2 mutation would confirm PV even with normal EPO

3. If JAK2 negative, investigate secondary causes:

   • Hypoxia-driven causes:

     • Chronic lung disease
     • Sleep apnea
     • Right-to-left cardiac shunts
     • High altitude habitation
     • Carbon monoxide exposure (including smoking)

   • Non-hypoxic causes with normal/elevated EPO:

     • Tumors: Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma 1, 3
     • Non-malignant conditions: Renal cysts, uterine leiomyomas, pheochromocytoma
     • Congenital causes: High oxygen-affinity hemoglobinopathy, Chuvash polycythemia
     • Post-renal transplant erythrocytosis

4. Consider bone marrow examination if diagnosis remains unclear after initial workup

Treatment Approach

1. Phlebotomy:

   • Primary treatment for symptomatic erythrocytosis regardless of cause
   • Target hematocrit <45% for PV
   • For secondary erythrocytosis, target hematocrit of 50-55% is often appropriate 1
   • In hypoxic conditions, avoid aggressive phlebotomy (target hematocrit ~60%)

2. Treat underlying cause:

   • For tumor-related erythrocytosis: surgical removal when possible 3
   • For hypoxia-driven causes: address the primary condition (CPAP for sleep apnea, etc.)
   • For post-renal transplant erythrocytosis: consider ACE inhibitors or angiotensin II receptor blockers 1

3. Cytoreductive therapy:

   • Reserved for confirmed PV with high thrombotic risk
   • Not indicated for secondary erythrocytosis

4. Antiplatelet therapy:

   • Low-dose aspirin for PV patients
   • Consider for secondary erythrocytosis with cardiovascular risk factors

Important Considerations

• Diagnostic pitfalls: A single normal EPO measurement does not rule out PV, as approximately 13% of PV patients may have EPO levels within the normal range 4

• Follow-up: Regular monitoring of hematocrit is essential, with frequency determined by the severity of erythrocytosis and response to treatment

• Erythropoietin fluctuation: EPO levels can fluctuate, and a single measurement may be misleading 5

• Comprehensive evaluation: Even with normal EPO, a systematic evaluation for both primary and secondary causes is necessary 6

By following this approach, the underlying cause of erythrocytosis with normal erythropoietin levels can be identified and appropriately managed, reducing the risk of complications such as thrombosis and improving patient outcomes.