What causes elevated hemoglobin (Hb) and hematocrit (Hct) levels?

Causes of Elevated Hemoglobin and Hematocrit

Elevated hemoglobin and hematocrit result from either true polycythemia (increased red blood cell mass) or relative polycythemia (decreased plasma volume), with the most common causes being dehydration, chronic hypoxia from smoking or lung disease, and polycythemia vera. 1

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a myeloproliferative neoplasm characterized by clonal proliferation of red blood cells, requiring specific diagnostic criteria for confirmation. 2

Diagnostic Criteria

• Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women (or hematocrit >55% in men, >49.5% in women) constitutes the first major criterion. 2, 1
• Presence of JAK2V617F mutation (found in ~95% of cases) or JAK2 exon 12 mutation is the second major criterion. 2, 1
• Diagnosis requires both major criteria plus one minor criterion (bone marrow trilineage proliferation, subnormal erythropoietin level, or endogenous erythroid colony growth). 2

Clinical Presentation

• Splenomegaly, aquagenic pruritus, and erythromelalgia are characteristic features that distinguish PV from secondary causes. 3, 4
• Thrombotic events (including unusual sites like portal vein thrombosis) may be the presenting manifestation, even with normal hemoglobin levels in masked PV. 5

A critical pitfall: Some patients with JAK2-positive PV present with normal hemoglobin and hematocrit due to blood dilution or concurrent blood loss, termed "masked PV." 5 These patients still require full evaluation if they present with unexplained thrombosis.

Secondary Polycythemia (Hypoxia-Driven)

Chronic hypoxia is the most common cause of secondary polycythemia in clinical practice, stimulating compensatory erythropoietin production. 1, 6

Pulmonary Causes

• Chronic obstructive pulmonary disease (COPD) with hypoxemia and hypocapnea indicates the lung itself as the primary problem. 6
• Hypoventilation syndromes with hypercapnea and hypoxemia indicate respiratory pump failure. 6
• Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production. 1

Smoking-Related

• "Smoker's polycythemia" results from chronic carbon monoxide exposure causing tissue hypoxia and stimulating erythropoietin production. 1
• Smoking is the most frequent cause of elevated hematocrit in clinical practice. 4
• This resolves with smoking cessation within weeks. 1

Other Hypoxia-Related Causes

• Altitude adaptation causes physiological increases in hemoglobin (e.g., +1.9 g/dL at 3,000 meters). 1
• Cyanotic congenital heart disease produces compensatory erythrocytosis to improve oxygen transport. 1
• High-oxygen-affinity hemoglobin variants are rare genetic causes. 1

Secondary Polycythemia (Hypoxia-Independent)

Certain conditions produce erythropoietin independently of tissue hypoxia, causing inappropriate red cell proliferation. 1

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin autonomously. 1
• Erythropoietin therapy or doping with erythropoietin analogs causes iatrogenic polycythemia. 1, 6
• Testosterone use (prescribed or unprescribed) stimulates erythropoietin production and should be considered in young adults. 1
• Chuvash polycythemia (von Hippel-Lindau gene mutation) and erythropoietin receptor mutations are rare genetic causes. 1

Relative Polycythemia (Plasma Volume Depletion)

Relative polycythemia occurs when plasma volume decreases while red cell mass remains normal, creating falsely elevated hemoglobin and hematocrit. 1, 7

• Dehydration is the most common cause, resulting from inadequate fluid intake, excessive losses, or diuretic use. 1, 7
• Burns cause significant plasma volume loss. 1
• Stress polycythemia (Gaisböck syndrome) represents chronic plasma volume contraction. 1

Diagnostic Approach

• Assess hydration status clinically and recheck CBC after ensuring adequate hydration to confirm persistent elevation. 1, 7
• If hematocrit normalizes with hydration, relative polycythemia is confirmed and no further workup is needed. 7

Diagnostic Algorithm

Initial Evaluation

• Confirm elevated values with repeated measurements: hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women), or hematocrit >55% (men) or >49.5% (women). 1
• Obtain complete blood count with differential, reticulocyte count, serum ferritin, transferrin saturation, and C-reactive protein. 1
• Assess hydration status and exclude relative polycythemia before proceeding with extensive workup. 1, 7

Distinguishing Primary from Secondary Causes

• Order JAK2V617F mutation testing (exon 14) as first-line, followed by JAK2 exon 12 if negative. 1, 8
• Measure serum erythropoietin level: typically low or normal in PV, elevated in secondary causes. 1

Important caveat: Erythropoietin levels can occasionally be elevated in PV, so a high EPO does not exclude the diagnosis. 9 JAK2 mutation testing and bone marrow biopsy remain definitive.

• Evaluate for secondary causes: obtain sleep study if nocturnal hypoxemia suspected, assess smoking history and carbon monoxide exposure, check for chronic lung disease. 1
• Consider imaging for erythropoietin-secreting tumors if secondary polycythemia is suspected without clear hypoxic cause. 1

Special Considerations

• High RDW with normal or low MCV suggests coexisting iron deficiency with erythrocytosis. 1
• Males with hematocrit >60% and females with hematocrit >55% always have absolute polycythemia, not relative. 4
• Hemoglobin is more accurate than hematocrit for assessment because hematocrit can increase 2-4% with storage, while hemoglobin remains stable. 1

Management Implications

When to Intervene

• Therapeutic phlebotomy is indicated only when hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity (headache, visual disturbances, dizziness). 1, 8
• For confirmed PV, maintain target hematocrit strictly below 45% to reduce thrombotic risk. 8

Critical pitfall: Repeated routine phlebotomies without clear indication risk iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1

Treatment by Etiology

• For secondary polycythemia from COPD: long-term oxygen therapy corrects hypoxemia and reduces polycythemia within weeks. 6
• For hypoventilation syndromes: non-invasive ventilation corrects hypercapnea and hypoxemia. 6
• For PV: low-dose aspirin is cornerstone therapy; cytoreductive therapy (hydroxyurea or interferon-alpha) for high-risk patients (age >60 or prior thrombosis). 8
• When phlebotomy is performed, replace with equal volume of saline or dextrose to prevent hemoconcentration. 1

Iron Management

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