In an Indian adult with persistently elevated hemoglobin/hematocrit and no obvious secondary cause, how should idiopathic erythrocytosis be diagnosed and managed?

Idiopathic Erythrocytosis in the Indian Population

In Indian adults with persistently elevated hemoglobin/hematocrit and no obvious secondary cause, idiopathic erythrocytosis should be diagnosed only after systematically excluding polycythemia vera through JAK2 mutation testing (both exon 14 and exon 12) and ruling out secondary causes including altitude adaptation, smoking, sleep apnea, and chronic hypoxemia. 1, 2

Diagnostic Thresholds for Indian Population

Confirm true erythrocytosis by documenting hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, or hematocrit >55% in men or >49.5% in women on repeated measurements. 1 Single measurements are unreliable and must be confirmed with serial testing. 1

Critical consideration for altitude: If the patient resides at altitude, adjust diagnostic thresholds accordingly. For example, at 1,500 meters elevation, add 0.5 g/dL to the hemoglobin threshold; at 2,000 meters add 0.8 g/dL; at 2,500 meters add 1.3 g/dL. 1 This is particularly relevant for populations in Himalayan regions or elevated terrain.

Initial Laboratory Workup

Order the following tests immediately: 1

• Complete blood count with red cell indices, reticulocyte count, and differential
• Serum ferritin and transferrin saturation (to detect coexisting iron deficiency)
• C-reactive protein
• JAK2 V617F mutation (exon 14) testing—positive in >95% of polycythemia vera cases 2
• If JAK2 V617F negative, proceed to JAK2 exon 12 mutation testing—captures additional ~3% of polycythemia vera 2
• Serum erythropoietin level—low EPO has >90% specificity for polycythemia vera 2

Hemoglobin is more accurate than hematocrit for diagnosis because hematocrit can falsely increase by 2-4% with sample storage and is affected by hyperglycemia, while hemoglobin remains stable. 1

Systematic Exclusion of Secondary Causes

If Erythropoietin is Normal or Elevated:

Evaluate hypoxia-driven causes: 1, 2

• Smoking history: Carbon monoxide exposure causes "smoker's polycythemia" through chronic tissue hypoxia stimulating erythropoietin production 1
• Sleep study: Screen for obstructive sleep apnea causing nocturnal hypoxemia 1
• Pulmonary function tests and chest imaging: Assess for chronic obstructive pulmonary disease 1
• Arterial oxygen saturation: If <92%, indicates secondary polycythemia due to hypoxemia 2

Evaluate non-hypoxic causes: 1

• Testosterone use: Both prescribed and unprescribed testosterone can cause erythrocytosis 1
• Renal imaging: Ultrasound or CT to exclude renal cell carcinoma, hydronephrosis, or cystic disease producing erythropoietin 1
• Screen for other EPO-producing tumors: Hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 1

If Erythropoietin is Low:

This strongly suggests polycythemia vera (>90% specificity). 2 If JAK2 mutations are negative despite low EPO, proceed to bone marrow biopsy. 2

Diagnosis of Idiopathic Erythrocytosis

Idiopathic erythrocytosis is a diagnosis of exclusion reached only when: 3, 4, 5

• Absolute erythrocytosis is confirmed (elevated red cell mass)
• JAK2, CALR, and MPL mutations are all negative
• Secondary causes are systematically excluded
• Bone marrow biopsy (if performed) shows no evidence of myeloproliferative disorder

Genetic heterogeneity: Idiopathic erythrocytosis may represent undetected mutations in VHL (von Hippel-Lindau), PHD2, HIF2A, or erythropoietin receptor genes. 4, 5 Consider genetic testing for these mutations, particularly in young patients or those with family history. 6, 7

Management of Idiopathic Erythrocytosis

Phlebotomy Guidelines

Therapeutic phlebotomy is indicated ONLY when ALL of the following criteria are met: 1, 8

• Hemoglobin >20 g/dL AND hematocrit >65%
• Documented symptoms of hyperviscosity (headache, visual disturbances, poor concentration)
• Adequate hydration has been confirmed
• Iron deficiency has been excluded (transferrin saturation ≥20%)

Routine phlebotomy is contraindicated because it causes iron depletion, decreases oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 8 The elevated hematocrit in idiopathic erythrocytosis may represent a compensatory physiological response. 8

When Phlebotomy is Performed:

• Remove 300-450 mL per session 8
• Replace with equal volume of normal saline or dextrose to prevent hemoconcentration 1
• Target hematocrit 55-60% (NOT the 45% target used in polycythemia vera) 1

Aspirin Therapy

Consider low-dose aspirin (81-100 mg daily) for patients with cardiovascular risk factors or history of thrombotic events, though evidence is less robust than in polycythemia vera. 8, 5, 6

Iron Management

Monitor iron status regularly. 1, 8 If transferrin saturation <20%, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1 Rapid increases in red cell mass can occur with iron repletion. 1

Monitoring Strategy

Serial hematologic assessment every 6-12 months for asymptomatic patients with JAK2-negative erythrocytosis and hematocrit <65%. 1 Monitor for:

• Progression of hemoglobin/hematocrit levels
• Development of thrombocytosis or leukocytosis (suggesting evolution to myeloproliferative disorder)
• Iron deficiency (MCV <80 fL is strongest predictor of cerebrovascular events) 1
• Symptoms of hyperviscosity

Critical Pitfalls to Avoid

Never perform aggressive or routine phlebotomy without clear indications—this causes iatrogenic harm including iron depletion and increased stroke risk. 1, 8

Do not overlook coexisting iron deficiency, which can mask the true degree of erythrocytosis (elevated RBC count but reduced hemoglobin) and mimics hyperviscosity symptoms. 1 Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; use serum ferritin and transferrin saturation. 1

Hydration is first-line therapy for suspected hyperviscosity symptoms—not phlebotomy. Administer oral fluids or intravenous normal saline before considering any other intervention. 8

Do not apply polycythemia vera management protocols (hematocrit target <45%, routine phlebotomy) to idiopathic erythrocytosis, as the pathophysiology and thrombotic risk profile differ. 1, 8

Referral Indications

Refer immediately to hematology if: 1, 2

• JAK2 mutation is positive
• Hemoglobin >20 g/dL with symptoms of hyperviscosity
• Unexplained splenomegaly
• Development of cytopenias in other lineages
• Diagnosis remains unclear after systematic workup
• Progressive elevation despite conservative management