What are the differential diagnoses for a 53-year-old woman with erythrocytosis (elevated red blood cell count), hyperhemoglobinemia (elevated hemoglobin), and hyperhematocritemia (elevated hematocrit)?

Differential Diagnoses for Erythrocytosis in a 53-Year-Old Woman

Primary Assessment

This patient's values (RBC 5.91 million/μL, hemoglobin 16.6 g/dL, hematocrit 50.9%) meet WHO criteria for erythrocytosis in women and warrant immediate JAK2 mutation testing to distinguish polycythemia vera from secondary causes. 1

The hemoglobin of 16.6 g/dL exceeds the WHO diagnostic threshold of >16.5 g/dL for women, and the hematocrit of 50.9% is well above the >48-49% cutoff for female erythrocytosis. 1, 2

Differential Diagnoses

Primary Erythrocytosis

• Polycythemia Vera (PV): The most important primary diagnosis to exclude, present in >95% of cases with JAK2 V617F mutation (exon 14) or ~3% with JAK2 exon 12 mutations. 1, 3, 4
• PV diagnosis requires 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 bone marrow hypercellularity with trilineage growth, subnormal serum erythropoietin level, and endogenous erythroid colony formation. 1
• Common associated features include thrombocytosis (53%), leukocytosis (49%), splenomegaly (36%), pruritus (33%), and erythromelalgia (5.3%). 4

Secondary Erythrocytosis (Hypoxia-Driven)

• Chronic obstructive pulmonary disease (COPD): Chronic hypoxemia stimulates erythropoietin production, leading to compensatory erythrocytosis. 5, 2
• Obstructive sleep apnea: Nocturnal hypoxemia drives erythropoietin production and resolves with CPAP therapy. 5, 3
• Smoking ("smoker's polycythemia"): Carbon monoxide exposure causes tissue hypoxia and stimulates erythropoietin production, resolving with smoking cessation. 5, 3, 4
• Cyanotic congenital heart disease: Right-to-left shunting causes arterial hypoxemia with compensatory erythrocytosis to optimize oxygen transport. 5, 2
• High-altitude residence: Physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters). 5

Secondary Erythrocytosis (Hypoxia-Independent)

• Erythropoietin-producing tumors: Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently. 5
• Testosterone therapy or use: Either prescribed or unprescribed testosterone causes erythrocytosis and should be considered in the differential. 5, 3
• Post-renal transplant erythrocytosis: Can occur following kidney transplantation. 3
• Exogenous erythropoietin therapy: Direct administration of EPO causes elevated hemoglobin levels. 5

Relative Polycythemia (Apparent Erythrocytosis)

• Dehydration: Plasma volume depletion causes spurious elevation in hematocrit with normal red cell mass. 5, 2
• Diuretic use: Can cause plasma volume contraction leading to relative polycythemia. 5
• Stress polycythemia (Gaisböck syndrome): Reduction in plasma volume with normal red cell mass. 5, 2

Rare Genetic Causes

• High-oxygen-affinity hemoglobin variants: Rare genetic disorders causing elevated hemoglobin levels. 5
• Erythropoietin receptor mutations: Primary genetic causes of erythrocytosis. 5
• Chuvash polycythemia: Mutation in von Hippel-Lindau gene causing erythrocytosis. 5

Diagnostic Algorithm

Initial Laboratory Workup

• JAK2 V617F mutation testing (exon 14): Present in >95% of PV cases; if negative, proceed to JAK2 exon 12 testing to capture remaining ~3% of cases. 3, 4
• Serum erythropoietin (EPO) level: Low EPO has >90% specificity for PV, while elevated or normal EPO suggests secondary polycythemia. 3, 6, 7
• Complete blood count with differential: Assess for thrombocytosis, leukocytosis, and red cell indices. 5
• Serum ferritin and transferrin saturation: Iron deficiency can mask true polycythemia and must be excluded before dismissing the diagnosis. 5, 3
• Reticulocyte count: Evaluates bone marrow response in erythrocytosis. 5
• Peripheral blood smear: Assess red cell morphology and identify abnormalities. 5

Secondary Cause Evaluation (If JAK2 Negative and EPO Elevated/Normal)

• Smoking history and carbon monoxide exposure assessment: Evaluate for smoker's polycythemia. 5, 3
• Sleep study: If nocturnal hypoxemia from obstructive sleep apnea is suspected. 5, 3
• Pulmonary function tests and arterial blood gas: Evaluate for COPD or other chronic lung disease. 5, 3
• Echocardiography: Assess for cyanotic congenital heart disease with right-to-left shunting. 3
• Medication review: Specifically assess for testosterone use (prescribed or unprescribed). 5, 3
• Abdominal imaging (CT or ultrasound): Evaluate for EPO-producing tumors if other causes excluded. 5

Bone Marrow Biopsy Indications

• Required if JAK2 mutation is positive to confirm PV diagnosis and assess for trilineage myeloproliferation. 1
• Consider if diagnosis remains unclear after initial workup to exclude other myeloid neoplasms. 1

Critical Pitfalls to Avoid

• Do not dismiss borderline elevations: A sustained increase of ≥2 g/dL hemoglobin from baseline warrants investigation for PV, even if values remain within normal reference ranges. 3
• Iron deficiency masking: Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia with elevated RBC count but reduced hemoglobin; serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis. 5, 3
• Do not use MCV alone: Mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis. 5
• Avoid premature phlebotomy: Therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with symptoms of hyperviscosity, after excluding dehydration. 5, 2
• Do not perform repeated routine phlebotomies without diagnosis: This risks iron depletion, decreased oxygen-carrying capacity, and stroke. 5

Immediate Referral to Hematology Indicated If:

• JAK2 mutation is positive. 3
• Hemoglobin >20 g/dL with symptoms of hyperviscosity. 3
• Unexplained splenomegaly present. 3
• Diagnosis remains unclear after initial workup. 3
• Unusual thrombosis history (including splanchnic vein thrombosis). 3, 4