What can cause an elevated hematocrit (Hct) level?

Causes of Elevated Hematocrit

Elevated hematocrit results from either true erythrocytosis (increased red blood cell mass) or relative polycythemia (decreased plasma volume), with causes ranging from primary bone marrow disorders like polycythemia vera to secondary conditions including chronic hypoxia, malignancies, and dehydration. 1

Primary Erythrocytosis (Polycythemia Vera)

Polycythemia vera is a myeloproliferative neoplasm characterized by JAK2 mutation-driven overproduction of red blood cells, occurring in up to 97% of cases. 1 This represents a clonal disorder where the bone marrow produces excessive red cells independent of physiological oxygen-sensing mechanisms.

• JAK2 V617F mutation (exon 14) is present in approximately 95% of PV cases, with JAK2 exon 12 mutations accounting for most remaining cases. 1
• Diagnosis requires either both major criteria (hemoglobin >18.5 g/dL in men or >16.5 g/dL in women AND JAK2 mutation) plus one minor criterion, OR the 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

The pathogenetic mechanism involves constitutive activation of the JAK-STAT signaling pathway, leading to erythropoietin-independent red cell production. 2 This results in markedly elevated hematocrit levels that increase thrombotic risk substantially—maintaining hematocrit strictly below 45% through phlebotomy reduces cardiovascular death and major thrombotic events from 9.8% to 2.7%. 3

Secondary Erythrocytosis: Hypoxia-Driven Causes

Chronic tissue hypoxia stimulates erythropoietin production, triggering compensatory erythrocytosis to optimize oxygen transport. 1 This represents a physiological adaptation rather than a pathological process.

Pulmonary and Cardiac Causes

• Chronic obstructive pulmonary disease (COPD) causes chronic hypoxemia, driving sustained erythropoietin production and elevated hematocrit. 1
• Obstructive sleep apnea produces nocturnal hypoxemia that stimulates erythropoietin secretion, with treatment via CPAP potentially reversing the erythrocytosis. 1, 3
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, with secondary erythrocytosis serving as a compensatory mechanism to optimize oxygen delivery. 1, 3

Smoking-Related Erythrocytosis

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which binds hemoglobin with 200-fold greater affinity than oxygen, causing tissue hypoxia that stimulates erythropoietin production. 1, 3
• This condition typically resolves with smoking cessation as carbon monoxide levels normalize. 1

High-Altitude Adaptation

• Physiologic adaptation to altitude increases hemoglobin levels progressively, ranging from +0.2 g/dL at 1,000 meters to +4.5 g/dL at 4,500 meters elevation. 1
• Standard diagnostic thresholds for polycythemia vera must be adjusted for altitude of residence to avoid misdiagnosis. 1

Secondary Erythrocytosis: Hypoxia-Independent Causes

Certain conditions produce erythropoietin independently of oxygen-sensing mechanisms, leading to inappropriate erythrocytosis.

Malignancy-Associated Erythrocytosis

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin ectopically, causing paraneoplastic erythrocytosis. 1
• Renal imaging (ultrasound or CT) should be performed to exclude renal masses, hydronephrosis, or cystic disease in unexplained erythrocytosis. 3

Medication-Induced Erythrocytosis

• Testosterone therapy (prescribed or unprescribed) commonly causes erythrocytosis through direct stimulation of erythropoiesis, requiring dose adjustment or temporary discontinuation if hematocrit continues rising. 1, 3
• Exogenous erythropoietin administration for anemia treatment can cause elevated hematocrit, with expected increases of 0.3 g/dL hemoglobin per week (1% hematocrit per week). 1

Genetic Disorders

• High-oxygen-affinity hemoglobin variants cause tissue hypoxia despite normal arterial oxygen saturation, stimulating compensatory erythrocytosis. 1
• Chuvash polycythemia (von Hippel-Lindau gene mutation) and erythropoietin receptor mutations represent rare genetic causes of primary erythrocytosis. 1

Relative Polycythemia (Plasma Volume Depletion)

Decreased plasma volume concentrates red blood cells without increasing total red cell mass, producing spuriously elevated hematocrit measurements.

• Dehydration from inadequate fluid intake, excessive sweating, or gastrointestinal losses reduces plasma volume acutely. 1
• Diuretic use chronically depletes plasma volume, particularly with aggressive dosing. 1
• Stress polycythemia (Gaisböck syndrome) occurs in hypertensive, obese individuals with chronic plasma volume contraction. 1
• Burns cause massive plasma extravasation, concentrating red cells in the intravascular space. 1

Diagnostic Approach to Elevated Hematocrit

Confirm true erythrocytosis by repeating measurements, as single values are 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 define erythrocytosis. 1

Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, and peripheral blood smear provide essential baseline data. 1
• Serum ferritin and transferrin saturation identify coexisting iron deficiency, which can mask erythrocytosis severity—iron-deficient red cells have reduced oxygen-carrying capacity despite elevated cell counts. 1, 3
• C-reactive protein (CRP) helps exclude inflammatory conditions affecting red cell parameters. 1

Distinguishing Primary from Secondary Causes

• JAK2 mutation testing (exons 14 and 12) is mandatory when erythrocytosis is confirmed, as 97% of polycythemia vera cases carry these mutations. 1
• Serum erythropoietin level differentiates primary (low/normal EPO) from secondary (elevated EPO) erythrocytosis, though sensitivity is only 70% despite >90% specificity. 1

Evaluating Secondary Causes

• Sleep study if nocturnal hypoxemia suspected based on snoring, witnessed apneas, or daytime somnolence. 1
• Pulmonary function tests and chest imaging evaluate for COPD or other chronic lung disease. 1
• Smoking history and carbon monoxide exposure assessment are essential, as smoker's polycythemia is common and reversible. 1
• Medication review specifically for testosterone, anabolic steroids, or erythropoietin use. 1
• Renal imaging excludes erythropoietin-producing renal masses or structural abnormalities. 3

Physiological Variations in Hematocrit

Normal hematocrit ranges vary significantly by sex, age, and altitude, requiring context-specific interpretation.

• Adult males and post-menopausal females typically have hemoglobin 15.5 ± 2.0 g/dL and hematocrit 47 ± 6%. 1
• Menstruating females have lower values: hemoglobin 14.0 ± 2.0 g/dL and hematocrit 41 ± 5%, due to estrogen effects and menstrual blood loss. 1
• Gender differences emerge at puberty due to testosterone's stimulatory effect on erythropoiesis and estrogen's suppressive effect. 1
• Altitude-adjusted thresholds must be applied—failure to adjust leads to overdiagnosis of polycythemia in high-altitude residents. 1

Critical Management Considerations

The approach to elevated hematocrit depends entirely on the underlying cause—polycythemia vera requires aggressive hematocrit reduction, while secondary erythrocytosis management focuses on treating the underlying condition.

When Phlebotomy is Indicated

• For polycythemia vera: maintain hematocrit strictly <45% through therapeutic phlebotomy (300-450 mL weekly or twice weekly) to reduce thrombotic risk. 3
• For secondary erythrocytosis: phlebotomy is indicated ONLY when hemoglobin >20 g/dL AND hematocrit >65% with documented hyperviscosity symptoms (headache, dizziness, poor concentration) after confirming adequate hydration and excluding iron deficiency. 1, 3

Critical Pitfalls to Avoid

• Never perform routine repeated phlebotomies in secondary erythrocytosis—this causes iron depletion, decreases oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 3
• Always exclude and correct dehydration first with oral or intravenous normal saline before considering phlebotomy, as relative polycythemia mimics true erythrocytosis. 3
• Screen for iron deficiency before phlebotomy—if transferrin saturation <20%, treat with iron supplementation rather than phlebotomy, as iron-deficient red cells cause symptoms identical to hyperviscosity but require opposite treatment. 3
• Hemoglobin is more reliable than hematocrit for monitoring, as hematocrit can falsely increase 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable. 1