What are the possible causes of elevated red blood cell (RBC) count, hemoglobin, and hematocrit in an asymptomatic patient?

Differential Diagnosis of Elevated RBC, Hemoglobin, and Hematocrit in an Asymptomatic Patient

In an asymptomatic patient with elevated RBC count, hemoglobin, and hematocrit who is not on testosterone therapy, the most likely causes include polycythemia vera (a JAK2-driven myeloproliferative disorder), secondary erythrocytosis from chronic hypoxia (such as obstructive sleep apnea, smoking, or chronic lung disease), or relative polycythemia from plasma volume depletion.

Primary Causes (Myeloproliferative Disorders)

Polycythemia Vera

• Polycythemia vera is diagnosed when hemoglobin exceeds 18.5 g/dL in men or 16.5 g/dL in women, or hematocrit exceeds 55% in men or 49.5% in women, combined with the presence of a JAK2 mutation 1
• JAK2 mutations (exon 14 or exon 12) are present in up to 97% of polycythemia vera cases and should be tested first when primary erythrocytosis is suspected 1, 2
• The World Health Organization criteria require either both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria 1
• Minor criteria include aquagenic pruritus, splenomegaly, or erythromelalgia 1

Other Primary Causes

• High-oxygen-affinity hemoglobin variants cause familial erythrocytosis through impaired oxygen release to tissues 1
• Erythropoietin receptor mutations result in hypersensitivity to erythropoietin 1
• Chuvash polycythemia (von Hippel-Lindau gene mutation) causes inappropriate erythropoietin production 1

Secondary Causes (Hypoxia-Driven)

Chronic Hypoxic Conditions

• Obstructive sleep apnea produces nocturnal hypoxemia that drives compensatory erythropoietin production and should be evaluated with sleep study if clinically suspected 1
• Chronic obstructive pulmonary disease and other chronic lung diseases cause persistent tissue hypoxia 1
• Cyanotic congenital heart disease with right-to-left shunting results in compensatory erythrocytosis to optimize oxygen transport 2, 1
• High altitude residence causes physiologically appropriate increases in hemoglobin (ranging from +0.2 g/dL at 1,000 meters to +4.5 g/dL at 4,500 meters) 1

Smoking-Related Erythrocytosis

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which causes tissue hypoxia and stimulates erythropoietin production, and resolves with smoking cessation 1
• Carbon monoxide from smoking binds hemoglobin with higher affinity than oxygen, creating functional hypoxia despite normal oxygen saturation readings 1

Secondary Causes (Hypoxia-Independent)

Erythropoietin-Producing Tumors

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently of hypoxia 1
• These malignancies should be considered particularly if other clinical features suggest their presence 1

Iatrogenic Causes

• Erythropoietin therapy directly stimulates red blood cell production and is expected to increase hemoglobin by 0.3 g/dL per week 1
• Although the patient is not on testosterone therapy, undisclosed or unprescribed testosterone use should still be considered in the differential 1

Relative Polycythemia (Plasma Volume Depletion)

Volume Contraction States

• Dehydration causes hemoconcentration with elevated hemoglobin and hematocrit but normal red blood cell mass 1
• Diuretic use can produce chronic volume depletion 1
• Stress polycythemia (Gaisböck syndrome) occurs in hypertensive, anxious individuals with reduced plasma volume 1

Diagnostic Approach

Initial Laboratory Evaluation

• Complete blood count with red cell indices, reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation, and C-reactive protein should be obtained as the minimum workup 1
• Hemoglobin is more accurate than hematocrit for assessment because hematocrit can falsely increase by 2-4% with prolonged sample storage, while hemoglobin remains stable 1
• Peripheral blood smear review assesses red cell morphology and identifies abnormalities 1

Iron Status Assessment

• Iron deficiency can coexist with erythrocytosis, particularly in 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; serum ferritin and transferrin saturation are required 1
• High RDW with normal or low MCV suggests possible iron deficiency coexisting with erythrocytosis 1

Testing for Primary Erythrocytosis

• JAK2 mutation testing (both exon 14 and exon 12) should be performed if absolute erythrocytosis is confirmed 1
• If JAK2 is negative, secondary causes should be systematically evaluated before considering rarer genetic causes 1

Evaluation for Secondary Causes

• Sleep study should be ordered if nocturnal hypoxemia is suspected based on history of snoring, witnessed apneas, or daytime somnolence 1
• Smoking history and carbon monoxide exposure assessment are essential 1
• Imaging studies may be warranted if erythropoietin-producing tumors are suspected based on clinical context 1
• Erythropoietin levels help differentiate primary (low or normal) from secondary (elevated) causes 1

Management Considerations

When Intervention Is Required

• Therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65%, with associated symptoms of hyperviscosity (headache, increasing fatigue), and only after excluding dehydration or anemia 2, 1
• For confirmed polycythemia vera, maintenance of hematocrit strictly below 45% through phlebotomy reduces thrombotic risk, with low-dose aspirin as the second cornerstone of therapy 1

Important Caveats

• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 2, 1
• When phlebotomy is performed, it should be replaced with equal volume of dextrose or saline to prevent further hemoconcentration 1
• Iron deficiency should be avoided even in the presence of erythrocytosis, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1

Treatment of Underlying Conditions

• For secondary erythrocytosis, treatment of the underlying condition is necessary: smoking cessation for smoker's polycythemia, CPAP for obstructive sleep apnea, and management of chronic lung disease 1
• If iron deficiency is confirmed in the context of erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur 2, 1

Referral Indications

• Patients with positive JAK2 mutation, hemoglobin greater than 20 g/dL with symptoms of hyperviscosity, or unexplained splenomegaly should be referred immediately to a hematologist 1
• Evaluation by a specialist is also warranted if the diagnosis remains unclear after initial workup 1

Physiological Variations to Consider

• Adult males and post-menopausal females typically have hemoglobin of 15.5 ± 2.0 g/dL and hematocrit of 47 ± 6%, while menstruating females have hemoglobin of 14.0 ± 2.0 g/dL and hematocrit of 41 ± 5% 1
• These gender differences emerge at puberty due to testosterone and estrogen effects 1
• Anemia is not a normal consequence of aging, so age-related decline should not be assumed 1
• Athletes, particularly swimmers, may have higher baseline hemoglobin and hematocrit values compared to sedentary individuals 3