What are the causes of elevated red blood cell (RBC) and hematocrit levels?

Causes of Elevated RBC and Hematocrit

Elevated RBC and hematocrit result from either primary polycythemia (polycythemia vera), secondary polycythemia (hypoxia-driven or non-hypoxia-driven causes), or relative polycythemia (plasma volume depletion). 1

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a chronic myeloproliferative disorder caused by JAK2 mutations (present in >90-95% of cases) that results in uncontrolled red blood cell production. 1, 2

• The diagnostic threshold is hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, with hematocrit >55% in men or >49.5% in women 1
• A sustained increase of ≥2 g/dL from baseline hemoglobin should raise suspicion for early PV, even without reaching absolute diagnostic thresholds 2
• Associated features include splenomegaly, aquagenic pruritus, erythromelalgia, thrombocytosis, and leukocytosis 1, 3
• The major complication is thrombosis due to hyperviscosity, which was the leading cause of death before modern phlebotomy therapy 4, 5

Secondary Polycythemia: Hypoxia-Driven Causes

Chronic tissue hypoxia stimulates erythropoietin production, leading to compensatory erythrocytosis. 1

Pulmonary and Sleep-Related Causes

• Obstructive sleep apnea causes nocturnal hypoxemia that drives erythropoietin production, particularly in obese patients with chronic fatigue 1, 6
• Chronic obstructive pulmonary disease (COPD) and other chronic lung diseases cause persistent hypoxemia 1, 2
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport 1

Smoking and Carbon Monoxide Exposure

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which causes tissue hypoxia and stimulates erythropoietin production 1
• This is the most frequent cause of increased hematocrit in the general population 3
• Smoking cessation should be implemented before ordering extensive blood volume studies 2

High Altitude Adaptation

• Physiologic adaptation to altitude increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1,000-4,500 meters) 1
• Standard PV diagnostic thresholds should not be used at high altitude without adjustment 1

Secondary Polycythemia: Non-Hypoxia-Driven Causes

Certain conditions produce erythropoietin independently of tissue oxygen levels. 1

Malignancies

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin autonomously 1, 2

Hormonal Causes

• Testosterone therapy (prescribed or unprescribed) is a common cause of erythrocytosis, particularly in young adults 1, 2
• Dose adjustment or temporary discontinuation is necessary if hematocrit continues to rise 1

Iatrogenic Causes

• Erythropoietin therapy directly increases red blood cell production 1

Relative Polycythemia (Plasma Volume Depletion)

Reduced plasma volume with normal red cell mass causes apparent elevation in RBC and hematocrit. 1

• Dehydration is the most common cause and should always be excluded before extensive workup 1
• Diuretic use reduces plasma volume 1
• Stress polycythemia (Gaisböck syndrome) occurs in hypertensive, anxious individuals 1
• Burns cause significant plasma volume loss 1

Diagnostic Approach Algorithm

Step 1: Confirm True Elevation

• Repeat hemoglobin and hematocrit measurements, as a single measurement is unreliable 1
• Assess hydration status to exclude relative polycythemia 1
• Hemoglobin is more reliable than hematocrit for monitoring, as hematocrit can falsely increase by 2-4% with prolonged sample storage 1

Step 2: Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, and differential to assess for thrombocytosis and leukocytosis 1
• Serum ferritin and transferrin saturation to evaluate for concurrent iron deficiency, which can coexist with erythrocytosis 1
• Peripheral blood smear to assess red cell morphology 1

Step 3: Distinguish Primary from Secondary Causes

• JAK2 mutation testing (exon 14 V617F, then exon 12 if negative) is first-line for suspected PV 1, 2
• Serum erythropoietin level: low or low-normal suggests PV; elevated suggests secondary polycythemia 2
• Male patients with hematocrit >60% and female patients with hematocrit >55% always have absolute polycythemia 3

Step 4: Evaluate for Secondary Causes if JAK2 Negative

• Sleep study (polysomnography) if nocturnal hypoxemia suspected, especially in obese patients with fatigue 1, 6
• Smoking history and carbon monoxide exposure assessment 1
• Pulse oximetry or arterial blood gas to document hypoxemia 6
• Imaging for erythropoietin-producing tumors if clinically indicated 2
• Testosterone use history (prescribed or unprescribed) 1, 2

Step 5: Bone Marrow Biopsy

• Required if JAK2 mutation is positive to confirm PV diagnosis and assess for trilineage myeloproliferation 1
• Consider if diagnosis remains unclear after initial workup to exclude other myeloid neoplasms 1

Critical Management Principles

For Polycythemia Vera

• Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV trial (2.7% vs 9.8% event rate, P=0.007) 1
• Low-dose aspirin (81-100 mg daily) is the second cornerstone of therapy for thrombosis prevention 1, 2
• Refer immediately to hematology if JAK2 mutation is positive 1

For Secondary Polycythemia

• Treat the underlying condition: CPAP for obstructive sleep apnea, smoking cessation for smoker's polycythemia, management of COPD 1, 2
• In secondary erythrocytosis, a target hematocrit of 55-60% may be appropriate, as the elevated hematocrit serves a compensatory physiological role 1
• Therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with symptoms of hyperviscosity, after excluding dehydration 1

Common Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk 1
• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 1
• Don't overlook coexisting iron deficiency in patients with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera, which causes microcytic polycythemia with elevated RBC count but reduced hemoglobin 1, 7
• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; serum ferritin, transferrin saturation, and iron levels are required 1
• Don't assume "adequate sleep" rules out sleep apnea—patients with OSA are typically unaware of their sleep fragmentation and nocturnal arousals 6
• If iron deficiency is confirmed in the context of erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur 1