What causes an elevated red blood cell count?

Causes of Elevated Red Blood Cell Count

Elevated red blood cell count results from either primary bone marrow disorders (most commonly polycythemia vera with JAK2 mutations), secondary physiologic responses to hypoxia or other stimuli, or relative polycythemia from plasma volume depletion. 1

Primary Causes (Bone Marrow Disorders)

Polycythemia vera is the most important primary cause, characterized by autonomous overproduction of red blood cells. More than 95% of patients harbor a JAK2 gene mutation (exon 14 or exon 12), which distinguishes this from secondary causes. 2 Diagnosis requires elevated hemoglobin (>16.5 g/dL in men, >16.0 g/dL in women) plus JAK2 mutation, or elevated hemoglobin with at least two minor criteria including bone marrow findings. 1

Other rare genetic causes include:

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

Secondary Causes (Hypoxia-Driven)

Chronic hypoxemia triggers compensatory erythropoietin release, leading to increased red cell production. 3

Key hypoxic causes include:

• Chronic lung disease (COPD, sleep apnea) - the most common secondary cause 1, 2
• Cyanotic congenital heart disease with right-to-left shunting, where erythrocytosis represents a physiologic compensation to improve oxygen transport 3
• Chronic smoking causing "smoker's polycythemia" through carbon monoxide-induced tissue hypoxia 1
• High altitude residence - physiologic adaptation with predictable hemoglobin increases (e.g., +1.9 g/dL at 3,000 meters) 1

Secondary Causes (Hypoxia-Independent)

Inappropriate erythropoietin production occurs with certain conditions:

• Renal disorders (renal cell carcinoma, polycystic kidney disease) 1
• Hepatocellular carcinoma 1
• Other tumors (pheochromocytoma, uterine leiomyoma, meningioma) 1
• Exogenous erythropoietin therapy 1
• Testosterone therapy - a frequently overlooked cause in younger adults that requires hemoglobin monitoring, with dose adjustment needed if levels rise excessively 1, 4

Relative Polycythemia (Plasma Volume Depletion)

Reduced plasma volume creates falsely elevated red cell parameters without true increase in red cell mass:

• Dehydration 1
• Diuretic use 1, 5
• Burns 1
• Stress polycythemia (Gaisböck syndrome) 1, 5

Importantly, only 18% of patients with apparent polycythemia (elevated hematocrit with normal red cell mass) have true reduced plasma volume. 5

Diagnostic Approach

Begin with confirmation of true erythrocytosis: hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, or hematocrit >55% in men or >49.5% in women. 1

Initial workup must include:

• Complete blood count with red cell indices and reticulocyte count 1
• Serum ferritin and transferrin saturation (iron deficiency can coexist with erythrocytosis) 1
• C-reactive protein 1

Key diagnostic clues:

• High RDW with normal/low MCV suggests concurrent iron deficiency 1
• Microcytosis with elevated RBC count may indicate thalassemia minor or polycythemia vera with iron deficiency 6
• Macrocytosis can occur in COPD patients due to repeated erythropoietic stress releasing immature large red cells 7

Second-tier testing:

• JAK2 mutation testing (both exon 14 and 12) for suspected polycythemia vera 1, 2
• Erythropoietin level - low/normal suggests primary polycythemia; elevated suggests secondary cause 1
• Oxygen saturation and sleep study if nocturnal hypoxemia suspected 1
• Smoking history and carbon monoxide exposure assessment 1

Critical Management Considerations

Therapeutic phlebotomy is indicated ONLY when:

• Hemoglobin >20 g/dL AND hematocrit >65% 3, 1
• Associated symptoms of hyperviscosity (headache, fatigue) 3
• Patient is not dehydrated 3

For confirmed polycythemia vera, all patients require:

• Therapeutic phlebotomy targeting hematocrit <45% 2
• Low-dose aspirin (unless contraindicated) 2
• Cytoreductive therapy (hydroxyurea or interferon) for high-risk patients (age ≥60 or prior thrombosis) 2

Common Pitfalls to Avoid

Never perform repeated routine phlebotomies without clear indication, as this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 3, 1

Do not overlook coexisting iron deficiency - if confirmed, cautious iron supplementation with close hemoglobin monitoring is necessary, as rapid red cell mass increase can occur. 3, 1

Remember that hemoglobin is more reliable than hematocrit for assessment, as hematocrit can increase 2-4% with sample storage and is affected by hyperglycemia, while hemoglobin remains stable. 1

In cyanotic heart disease patients, most have compensated erythrocytosis requiring no intervention; aggressive phlebotomy worsens outcomes. 3