Elevated RBC Count, Hemoglobin, and Hematocrit: Diagnosis and Management
The first priority is to confirm true erythrocytosis by repeating measurements and excluding dehydration, then immediately order JAK2 mutation testing alongside a complete diagnostic workup to distinguish polycythemia vera from secondary causes. 1, 2
Initial Diagnostic Confirmation
Repeat hemoglobin and hematocrit measurements to confirm persistent elevation, as a single measurement is unreliable for establishing diagnosis 1. True erythrocytosis is defined as hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women 1, 2.
Assess hydration status first by reviewing fluid intake history and recent losses, as dehydration is the most common cause of elevated hematocrit and represents relative polycythemia without true increase in red cell mass 2. If dehydration is suspected, recheck values after adequate hydration 3.
Immediate Laboratory Workup
Order the following tests immediately 1, 2:
- Complete blood count with red cell indices and manual differential to characterize the elevations and assess for thrombocytosis or leukocytosis (which suggest polycythemia vera) 1, 2
- Reticulocyte count to evaluate bone marrow response 1
- Serum ferritin and transferrin saturation to evaluate iron status, as iron deficiency can coexist with erythrocytosis and cause microcytic polycythemia 2
- Peripheral blood smear review by a qualified hematologist to identify abnormal morphology 2
- JAK2 mutation testing (exon 14 V617F) as first-line diagnostic test, found in up to 97% of polycythemia vera cases 2, 3
Diagnostic Algorithm Based on Results
If JAK2 Mutation is Positive:
This confirms polycythemia vera when combined with elevated hemoglobin/hematocrit 2, 3. The World Health Organization diagnostic criteria require both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria 2. Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal erythropoietin level, or endogenous erythroid colony formation 2.
Immediate hematology referral is required for confirmed polycythemia vera 2.
If JAK2 Mutation is Negative:
Systematically evaluate for secondary causes 2:
- Hypoxic causes: Order sleep study if nocturnal hypoxemia suspected (obstructive sleep apnea), pulmonary function tests for COPD, and assess smoking history for "smoker's polycythemia" which resolves with cessation 2
- Non-hypoxic causes: Evaluate for testosterone use (prescribed or unprescribed), erythropoietin-producing tumors (renal cell carcinoma, hepatocellular carcinoma), and measure erythropoietin levels 2
- Altitude considerations: Adjust diagnostic thresholds for altitude of residence (hemoglobin increases 0.2-4.5 g/dL depending on elevation from 1,000-4,500 meters) 1
Low or normal erythropoietin levels suggest primary polycythemia, while elevated levels indicate secondary causes 4.
Critical Thresholds Requiring Urgent Action
Hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity (headache, visual disturbances, dizziness) requires urgent therapeutic phlebotomy after excluding dehydration 1, 2. However, repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 1.
Males with hematocrit >60% and females with hematocrit >55% always have absolute polycythemia and require full diagnostic workup 5.
Management Based on Diagnosis
For Confirmed Polycythemia Vera:
- 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
- Consider cytoreductive therapy (hydroxyurea or interferon-alpha) for high-risk patients (age >60 or prior thrombosis) 1
For Secondary Erythrocytosis:
Treatment of the underlying condition is necessary 1, 2:
- Smoking cessation for smoker's polycythemia 2
- CPAP therapy for obstructive sleep apnea 1
- Management of COPD or other pulmonary disease 1
- Dose adjustment or discontinuation of testosterone if causative 1
Therapeutic phlebotomy is indicated only when hematocrit exceeds 65% with hyperviscosity symptoms, and volume replacement with equal amounts of dextrose or saline is essential to prevent hemoconcentration 1.
Special Considerations and Common Pitfalls
Do not overlook coexisting iron deficiency in patients with erythrocytosis, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1, 2. Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; serum ferritin, transferrin saturation, and iron levels are required 2.
Do not perform aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk 1.
Hemoglobin is more accurate than hematocrit for monitoring, as hematocrit can falsely increase by 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable 1.
Immediate Referral Indications
Refer immediately to hematology if 2:
- Positive JAK2 mutation
- Hemoglobin >20 g/dL with symptoms of hyperviscosity
- Unexplained splenomegaly with elevated blood counts
- Diagnosis remains unclear after initial workup