What is the management for a patient with elevated red blood cell count but normal hemoglobin and hematocrit levels?

Management of Elevated Red Blood Cell Count with Normal Hemoglobin and Hematocrit

Initial Assessment

When RBC count is elevated but hemoglobin and hematocrit remain normal, this pattern suggests either laboratory artifact, early iron deficiency with erythrocytosis, or relative polycythemia—and the first step is to confirm the finding with repeat testing after ensuring adequate hydration. 1

The key diagnostic consideration is that normal hemoglobin with elevated RBC count often indicates microcytic red cells, which can occur when iron deficiency coexists with a condition driving increased RBC production 2, 1. This creates a paradoxical situation where the bone marrow produces more cells, but each cell contains less hemoglobin 2.

Diagnostic Workup

Immediate Laboratory Tests

Order the following tests to characterize the erythrocytosis pattern 1:

• Complete blood count with red cell indices (MCV, MCH, MCHC, RDW) to assess red cell size and hemoglobin content 1, 3
• Reticulocyte count to evaluate bone marrow response 1
• Serum ferritin, transferrin saturation, and iron levels to definitively assess iron status, as MCV is unreliable for screening iron deficiency in erythrocytosis 2, 1
• C-reactive protein to evaluate for inflammatory conditions 1
• Peripheral blood smear review to assess red cell morphology 1

Interpretation of Red Cell Indices

• High RDW with normal or low MCV suggests iron deficiency coexisting with erythrocytosis 1
• Normal RDW makes coexisting iron deficiency unlikely 3
• Transferrin saturation <20% indicates functional iron deficiency requiring treatment 2, 1

Exclude Relative Polycythemia First

Before pursuing extensive workup for true erythrocytosis 1, 3:

• Assess hydration status clinically and review medications for diuretics or agents causing volume depletion 3, 4
• Increase oral fluid intake to 2-2.5 liters daily if swallowing is safe, or provide IV hydration 3
• Repeat CBC after 48-72 hours of adequate hydration to determine if the elevated RBC count persists 1, 3

Dehydration is the most common cause of relative polycythemia, resulting from plasma volume depletion while red cell mass remains constant 4. If values normalize with hydration, no further workup is needed 4.

If Erythrocytosis Persists After Hydration

Test for Primary Polycythemia

• JAK2 mutation testing (both exon 14 and exon 12) should be performed immediately, as up to 97% of polycythemia vera cases carry this mutation 1, 3
• Serum erythropoietin level to differentiate primary (low EPO) from secondary (high EPO) causes 1, 3

Evaluate for Secondary Causes

If JAK2 is negative, systematically evaluate secondary causes 1:

• Oxygen saturation and arterial blood gas to exclude hypoxia-driven polycythemia 3
• Sleep study if nocturnal hypoxemia from obstructive sleep apnea is suspected 1
• Smoking history and carbon monoxide exposure, as "smoker's polycythemia" results from chronic tissue hypoxia 1
• Medication review for testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in young adults 1
• Imaging for erythropoietin-producing tumors (renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma) if clinically indicated 1

Management Based on Diagnosis

If Iron Deficiency is Confirmed

Iron deficiency must be treated even in the presence of erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 2, 1:

• Initiate cautious oral iron supplementation with close hemoglobin monitoring 2, 1
• Monitor for rapid increases in red cell mass, which can occur with iron repletion 1
• Avoid phlebotomy, as this will worsen iron deficiency 2

If Secondary Erythrocytosis is Confirmed

Treatment focuses on the underlying condition 1:

• Smoking cessation for smoker's polycythemia 1
• CPAP therapy for obstructive sleep apnea 1
• Management of chronic lung disease if present 1
• Testosterone dose reduction or temporary discontinuation if causative 1

Therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with symptoms of hyperviscosity, after excluding dehydration 2, 1, 3. Repeated routine phlebotomies are contraindicated due to risk of iron depletion and stroke 2, 1.

If Polycythemia Vera is Confirmed

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV trial showing significantly reduced thrombotic events (2.7% vs 9.8%, P=0.007) 1:

• Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention 1
• Refer immediately to hematology for ongoing management 1
• Bone marrow biopsy is required to confirm diagnosis and assess for trilineage myeloproliferation 1

Critical Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk 1
• Never overlook iron deficiency in patients with erythrocytosis, as the combination significantly increases thrombotic complications 2, 1
• Never use standard polycythemia vera diagnostic thresholds at high altitude without adjustment, as physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation 1
• Never transfuse platelets if thrombocytopenia coexists with suspected polycythemia vera, as this may fuel thrombosis 5

When to Refer to Hematology

Immediate referral is warranted for 1:

• Positive JAK2 mutation
• Hemoglobin >20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup