What is the management approach for a patient with elevated Red Blood Cell (RBC) count, or erythrocytosis?

Management of Elevated Red Blood Cell Count (Erythrocytosis)

The first priority in managing elevated RBC count is to ensure adequate hydration to distinguish true erythrocytosis from relative erythrocytosis, followed by targeted evaluation for underlying causes and selective use of therapeutic phlebotomy only when hemoglobin exceeds 20 g/dL with hematocrit above 65% and symptoms of hyperviscosity are present. 1, 2

Initial Assessment and Diagnostic Approach

Confirm True Erythrocytosis

• Ensure adequate hydration status before proceeding with further evaluation, as dehydration can cause spurious elevation in RBC parameters (relative erythrocytosis) 1
• Assess for symptoms of hyperviscosity including headache, visual disturbances, fatigue, or poor concentration 1
• Evaluate for cardiopulmonary symptoms suggesting hypoxemia as a potential secondary cause 1

Essential Laboratory Workup

• Measure serum erythropoietin (EPO) level as the critical first step: low or low-normal EPO suggests polycythemia vera, while elevated EPO indicates secondary erythrocytosis 1, 3
• Assess iron status with serum ferritin and transferrin saturation to evaluate the full extent of erythrocytosis 1
• Perform peripheral blood smear to evaluate red cell morphology 1
• Evaluate red cell distribution width (RDW) to assess for underlying pathology 1

Important caveat: Iron deficiency can mask the full extent of erythrocytosis while still contributing to hyperviscosity symptoms 1. This is a common pitfall that must be recognized early.

Further Investigation Based on EPO Level

If EPO is low or low-normal (suggesting primary erythrocytosis):

• Screen for JAK2V617F mutation to diagnose polycythemia vera 4, 3
• Consider bone marrow biopsy if diagnosis remains unclear 3

If EPO is normal or elevated (suggesting secondary erythrocytosis):

• Investigate for hypoxemic conditions: chronic lung disease, obstructive sleep apnea, high-altitude exposure 4
• Evaluate for renal causes: cystic kidney diseases, renal cell carcinoma, renal artery stenosis, post-kidney transplant erythrocytosis 4
• Consider medication-induced causes: erythropoietin-stimulating agents overdosage, androgen therapy, SGLT2 inhibitors 4
• Screen for erythropoietin-secreting tumors 4

Management Strategy

First-Line Management: Hydration and Treat Underlying Cause

• Ensure adequate hydration as first-line therapy for all patients with erythrocytosis 1
• Treat the underlying cause of secondary erythrocytosis (e.g., supplemental oxygen for hypoxemia, CPAP for sleep apnea) 1
• Monitor hemoglobin and hematocrit periodically in patients with secondary erythrocytosis 1

Therapeutic Phlebotomy: Strict Indications Only

Phlebotomy should be performed ONLY when ALL of the following criteria are met: 2

• Hemoglobin >20 g/dL AND hematocrit >65%
• Symptoms of hyperviscosity present (headache, fatigue, poor concentration)
• Absence of dehydration or anemia

Critical warning: Avoid routine phlebotomies as they lead to iron depletion, decreased oxygen-carrying capacity, and paradoxically increase stroke risk 1, 2. This is a major pitfall in erythrocytosis management.

Phlebotomy Protocol (When Indicated)

Standard approach:

• Remove one unit of blood (400-500 mL) per session 2
• Replace with equal volume of isotonic saline (750-1000 mL) 2
• Perform weekly or fortnightly until target levels reached 2

Target hematocrit levels:

• For polycythemia vera: maintain hematocrit <45% in men (with corresponding values for women and other races) 2, 5
• For congenital heart disease with cyanosis: judicious phlebotomy to hematocrit ~60% may be reasonable to alleviate hyperviscosity symptoms 2

Alternative technique: Double red-cell phlebotomy (erythrocytapheresis) removes more RBC volume with less total blood volume loss and can be considered when standard phlebotomy is not feasible 2, 6

Management of Iron Status: A Delicate Balance

Iron deficiency in erythrocytosis increases stroke risk and should be corrected 1. However, this must be done cautiously:

• Cautious iron supplementation with close monitoring of hemoglobin levels is recommended 1
• Target serum ferritin of 50 μg/L during phlebotomy induction phase, but not lower to avoid iron deficiency 2
• Monitor for signs of iron deficiency through peripheral blood smear and iron studies 2

This represents a critical nuance: while phlebotomy-induced iron deficiency is harmful, aggressive iron repletion can worsen erythrocytosis. Close monitoring is essential.

Polycythemia Vera-Specific Management

Risk stratification determines treatment intensity: 5

Low-risk patients (<60 years old with no history of thrombosis):

• Phlebotomy to maintain hematocrit <45%
• Low-dose aspirin

High-risk patients (≥60 years old and/or history of thrombosis):

• Cytoreductive agents (hydroxyurea as first-line)
• Phlebotomy to maintain hematocrit <45%
• Low-dose aspirin

Second-line therapies (for hydroxyurea intolerance or inadequate response):

• Interferon
• Ruxolitinib

The goal is to reduce cardiovascular death and major thrombosis, which are the leading causes of morbidity and mortality in polycythemia vera 5.

Special Populations

Pregnant women with mild to moderate iron overload: phlebotomy can be paused during pregnancy in most cases 2

Patients who cannot undergo phlebotomy: iron chelation therapy (e.g., deferasirox) can be considered after careful risk-benefit assessment 2

Monitoring During Treatment

• Regular monitoring of hemoglobin, hematocrit, and iron status 2
• Assess for symptoms of hyperviscosity before each intervention 2
• Monitor renal function as chronic erythrocytosis can affect glomerular filtration rate 1
• Adjust phlebotomy schedule based on signs of iron deficiency 2