What are the causes of elevated hematocrit (Hct), hemoglobin (Hgb), and red blood cell (RBC) count in adult patients?

Causes of Elevated Hematocrit, Hemoglobin, and RBC Count

Primary Polycythemia (Myeloproliferative Disorder)

Polycythemia vera is the most important primary cause and requires JAK2 mutation testing for diagnosis, as up to 97% of cases carry this mutation. 1

• JAK2 mutations (both exon 14 and exon 12) are the hallmark of polycythemia vera and should be tested when hemoglobin exceeds 18.5 g/dL in men or 16.5 g/dL in women 1
• WHO diagnostic criteria require either both major criteria (elevated hemoglobin/hematocrit/RBC mass AND presence of JAK2 mutation) plus at least one minor criterion, OR first major criterion plus at least two minor criteria 1
• Rare genetic causes include high-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia (von Hippel-Lindau gene mutation) 1

Secondary Polycythemia (Hypoxia-Driven)

Chronic hypoxemia from any source stimulates erythropoietin production and is the most common cause of secondary erythrocytosis. 1

Pulmonary and Cardiac Causes

• Chronic obstructive pulmonary disease (COPD) produces chronic tissue hypoxia that drives erythropoietin production 1
• Obstructive sleep apnea causes nocturnal hypoxemia that stimulates red cell production 1
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, and the secondary erythrocytosis is a compensatory mechanism to optimize oxygen transport 1
• High altitude residence causes physiologic adaptation with hemoglobin increases of 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 1

Smoking-Related

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which causes tissue hypoxia and stimulates erythropoietin production, and resolves with smoking cessation 1

Secondary Polycythemia (Hypoxia-Independent)

Certain malignancies and medications can produce erythropoietin independently of tissue oxygen levels. 1

Malignancy-Associated

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently, causing elevated hemoglobin levels 1

Medication-Induced

• Testosterone therapy (prescribed or unprescribed) commonly causes erythrocytosis and should be considered in the differential diagnosis, particularly in young adults 1
• Erythropoietin therapy directly increases red cell production 1

Relative Polycythemia (Plasma Volume Depletion)

Hemoconcentration from plasma volume loss creates falsely elevated hematocrit without true increase in red cell mass. 1

• Dehydration is the most common cause of relative polycythemia 1
• Diuretic use reduces plasma volume 1
• Burns cause significant plasma loss 1
• Stress polycythemia (Gaisböck syndrome) represents chronic plasma volume contraction 1
• Early borderline essential hypertension is associated with contracted plasma volume and elevated hematocrit despite normal red blood cell mass 2

Physiological Variations

Normal hemoglobin levels vary significantly by sex, age, and altitude, which must be considered before diagnosing pathologic erythrocytosis. 1

• Males typically have hemoglobin 15.5 ± 2.0 g/dL and hematocrit 47 ± 6%, while menstruating females have hemoglobin 14.0 ± 2.0 g/dL and hematocrit 41 ± 5% 1
• These gender differences emerge at puberty due to testosterone and estrogen effects 1
• Post-menopausal females have values similar to males 1

Critical Diagnostic Considerations

Iron deficiency can coexist with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin. 1

• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis 1
• Serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis 1
• Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk even in the presence of erythrocytosis 1

Thrombotic Risk

Elevated hematocrit increases thrombosis risk through enhanced blood viscosity and platelet-vessel wall interactions. 3, 4

• Men with hematocrit ≥46% have a 1.5-fold increased risk of total venous thromboembolism and a 2.4-fold increased risk of unprovoked venous thromboembolism 3
• Elevated hematocrit increases the frequency and duration of platelet-thrombus interactions, promoting arterial thrombosis 4
• For confirmed polycythemia vera, maintaining hematocrit strictly below 45% through phlebotomy significantly reduces thrombotic events 1