What are the causes and management of elevated Red Blood Cell (RBC) count, Hemoglobin (Hgb) and Hematocrit (Hct) in an adult patient with no significant past medical history?

Causes of Elevated RBC Count, Hemoglobin, and Hematocrit

The most common causes of elevated RBC, hemoglobin, and hematocrit include polycythemia vera (a JAK2-mutation-driven myeloproliferative disorder), secondary erythrocytosis from chronic hypoxia (smoking, sleep apnea, COPD, cyanotic heart disease), testosterone use, and relative polycythemia from dehydration or plasma volume depletion. 1

Initial Diagnostic Approach

Confirm true erythrocytosis by repeating measurements, as a single elevated value is unreliable—hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women defines true polycythemia. 1 Note that hemoglobin is more accurate than hematocrit because hematocrit can falsely increase by 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable. 1

Essential Laboratory Workup

Order the following tests immediately to distinguish primary from secondary causes:

• Complete blood count with red cell indices to assess RBC count, MCV, and identify concurrent cytopenias or thrombocytosis 1
• Reticulocyte count to evaluate bone marrow response 1
• Peripheral blood smear to identify abnormal morphology and rule out iron deficiency (which can coexist with erythrocytosis, causing microcytic polycythemia) 1
• Serum ferritin and transferrin saturation because iron deficiency frequently coexists with erythrocytosis, particularly in polycythemia vera, and MCV is unreliable for screening iron deficiency in this setting 1
• C-reactive protein to assess for inflammatory conditions 1

Primary Causes: Polycythemia Vera

Test for JAK2 mutations (both exon 14 and exon 12) immediately if initial workup suggests absolute erythrocytosis, as up to 97% of polycythemia vera cases carry this mutation. 1

The World Health Organization diagnostic criteria for polycythemia vera require:

• Both major criteria (elevated hemoglobin/hematocrit/RBC mass AND JAK2 mutation) plus one minor criterion, OR
• First major criterion plus two minor criteria 1

Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal serum erythropoietin level, and endogenous erythroid colony formation. 1

If JAK2 is positive, refer immediately to hematology for bone marrow biopsy to confirm diagnosis and assess for trilineage myeloproliferation. 1

Secondary Causes: Hypoxia-Driven Erythrocytosis

If JAK2 mutation is absent, systematically evaluate for secondary causes:

Chronic Hypoxic Conditions

• Smoking ("smoker's polycythemia"): Carbon monoxide exposure causes chronic tissue hypoxia, stimulating erythropoietin production—resolves with smoking cessation 1
• Obstructive sleep apnea: Nocturnal hypoxemia drives erythropoietin production—obtain sleep study if suspected 1
• Chronic obstructive pulmonary disease: Chronic hypoxemia stimulates compensatory erythrocytosis 1
• Cyanotic congenital heart disease: Right-to-left shunting causes arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport 1
• High altitude residence: Physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters)—adjust diagnostic thresholds accordingly 1

Hypoxia-Independent Causes

• Testosterone therapy: Either prescribed or unprescribed testosterone causes erythrocytosis and should be considered in any adult with unexplained erythrocytosis 1
• Erythropoietin-producing tumors: Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently 1
• Exogenous erythropoietin therapy: Direct pharmacologic stimulation of erythropoiesis 1

Rare Genetic Causes

• High-oxygen-affinity hemoglobin variants 1
• Erythropoietin receptor mutations 1
• Chuvash polycythemia (von Hippel-Lindau gene mutation) 1

Relative Polycythemia (Plasma Volume Depletion)

Assess hydration status carefully, as the following conditions cause falsely elevated hematocrit without true increase in red cell mass:

• Dehydration: Most common cause of relative polycythemia 1
• Diuretic use: Reduces plasma volume 1
• Burns: Plasma loss through damaged skin 1
• Stress polycythemia (Gaisböck syndrome): Chronic plasma volume contraction 1

Note that hematocrit values in hypovolemic anemic patients are elevated by 4-5 volume-percent compared to normovolemic values because plasma volume does not increase to achieve the normovolemic state. 2

Management Principles

When to Perform Therapeutic Phlebotomy

Therapeutic phlebotomy is indicated ONLY when hemoglobin exceeds 20 g/dL AND hematocrit exceeds 65% with associated symptoms of hyperviscosity, after excluding dehydration. 1 Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 1

When phlebotomy is performed, replace with equal volume of dextrose or saline to prevent further hemoconcentration. 1

Polycythemia Vera-Specific Management

For confirmed polycythemia vera, maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk—the CYTO-PV trial demonstrated significantly reduced thrombotic events (2.7% vs 9.8%, P=0.007) with this target. 1 Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 1

Secondary Erythrocytosis Management

Treat the underlying condition rather than performing phlebotomy:

• Smoking cessation for smoker's polycythemia 1
• CPAP therapy for obstructive sleep apnea 1
• Management of COPD or other pulmonary disease 1
• Dose adjustment or discontinuation of testosterone if causative 1

In secondary erythrocytosis, a target hematocrit of 55-60% may be appropriate, as the elevated hematocrit serves a compensatory physiological role. 1

Iron Management in Erythrocytosis

Avoid iron deficiency even in the presence of erythrocytosis, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1 If iron deficiency is confirmed, provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 1

Critical Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement—this increases hemoconcentration and stroke risk 1
• Don't use standard polycythemia vera diagnostic thresholds at high altitude without adjustment for physiologic adaptation 1
• Don't transfuse platelets if the underlying disorder is TTP or type II HIT—platelet transfusion may fuel thrombosis 3
• Don't overlook coexisting iron deficiency—serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis, as MCV is unreliable in erythrocytosis 1

Immediate Referral Indications

Refer immediately to hematology if:

• JAK2 mutation is positive 1
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 1
• Unexplained splenomegaly 1
• Diagnosis remains unclear after initial workup 1