Workup and Treatment of Unexplained Polycythemia in Adults

Begin with serum erythropoietin (EPO) level and JAK2 V617F mutation testing immediately after confirming sustained hemoglobin/hematocrit elevation—these two tests distinguish primary polycythemia vera from secondary causes and drive all subsequent management decisions. 1, 2

Initial Diagnostic Algorithm

Step 1: Confirm True Polycythemia

Repeat complete blood count to verify sustained elevation: hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women), or hematocrit >48% (women) or >52% (men). 3, 4
Assess for relative polycythemia by evaluating clinical signs of plasma volume depletion: dehydration, diuretic use, vomiting, diarrhea, or burns. 1
Check red cell indices: low MCV suggests iron deficiency that can mask true polycythemia vera by suppressing hemoglobin despite elevated red cell mass. 1

Step 2: Order Serum EPO and JAK2 Mutation Testing Simultaneously

Low or inappropriately normal EPO has >90% specificity for polycythemia vera, but sensitivity is only 64–70%, so normal EPO does not exclude the diagnosis. 1, 2, 5
JAK2 V617F mutation is present in >95% of polycythemia vera cases, making it the single most definitive test. 1, 3, 4
Elevated EPO points toward secondary polycythemia and mandates systematic evaluation for hypoxia-driven or tumor-related causes. 1, 2

If JAK2 Positive and EPO Low/Normal: Polycythemia Vera Confirmed

Immediate Management

Therapeutic phlebotomy to maintain hematocrit <45% reduces cardiovascular death or major thrombosis from 9.8% to 2.7% (HR 3.91, P=0.007). 1, 3, 4
Low-dose aspirin 81 mg daily for all patients unless contraindicated (e.g., extreme thrombocytosis >1000 × 10⁹/L with acquired von Willebrand disease). 1, 3, 4

Risk Stratification

High-risk patients (age >60 years or prior thrombosis) require cytoreductive therapy with hydroxyurea as first-line agent. 1, 2, 3, 6
Interferon-α is preferred in young women of reproductive age, patients intolerant to hydroxyurea, or when phlebotomy requirement alone drives treatment need. 1, 6
Ruxolitinib is reserved for severe protracted pruritus or marked splenomegaly unresponsive to hydroxyurea/interferon. 3, 6

Common Pitfall

Do not assume normal EPO excludes polycythemia vera—EPO sensitivity is only 64–70%, so proceed with JAK2 testing even when EPO appears normal. 1

If EPO Elevated or JAK2 Negative: Evaluate for Secondary Polycythemia

Hypoxia-Driven Causes (Most Common)

Smoking history and carboxyhemoglobin measurement: Smoker's polycythemia is the most frequent secondary cause; carbon monoxide binds hemoglobin 200–250 times more avidly than oxygen, creating functional hypoxia. 1, 2
- Treatment: Smoking cessation alone; risk reduction begins within 1 year, returns to baseline after 5 years. 1
- Pharmacotherapy: Combination nicotine replacement (patch + short-acting NRT) or varenicline 1 mg twice daily with mandatory behavioral counseling. 1
Arterial oxygen saturation and chest imaging: Rule out chronic obstructive pulmonary disease, pulmonary fibrosis, or right-to-left cardiopulmonary shunts. 1, 2
Sleep study: Obstructive sleep apnea causes nocturnal hypoxemia-driven erythrocytosis. 1, 2
Echocardiography: If arterial O₂ saturation <92%, evaluate for cyanotic congenital heart disease with right-to-left shunting. 1

Hypoxia-Independent Causes

Abdominal ultrasound or CT: Screen for EPO-producing tumors—renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma, parathyroid carcinoma. 1, 2
Medication review: Exogenous erythropoietin, testosterone, or anabolic steroids. 1, 2
Renal function testing: Post-renal transplant erythrocytosis. 1, 2

Management of Secondary Polycythemia

General Principle

Treat the underlying condition; routine phlebotomy is contraindicated because it depletes iron, reduces oxygen-carrying capacity, and paradoxically increases stroke risk. 1

Specific Scenarios

Smoker's polycythemia: Smoking cessation is definitive treatment. 1
COPD: Optimize bronchodilators and provide supplemental oxygen when arterial O₂ saturation <92%. 1
Post-renal transplant erythrocytosis: ACE inhibitors or angiotensin-II receptor blockers effectively lower hematocrit. 1
Cyanotic congenital heart disease: Judicious phlebotomy to hematocrit ≈60% may relieve hyperviscosity symptoms, but aggressive phlebotomy increases stroke risk. 1

Phlebotomy Indications in Secondary Polycythemia (Rare)

Phlebotomy is indicated only when ALL of the following are present: 1

Hemoglobin >20 g/dL and hematocrit >65%
Documented hyperviscosity symptoms (headache, visual disturbances, confusion, bleeding)
Patient is adequately hydrated
Iron deficiency excluded (transferrin saturation ≥20%)

Technique: Remove 300–450 mL blood and replace with equal volume of normal saline to prevent hemoconcentration. 1

Critical Pitfalls to Avoid

Misinterpreting normal EPO in chronic hypoxic states: EPO may normalize after hemoglobin stabilizes at a compensatory higher level, mimicking polycythemia vera. 1, 5
Overlooking iron deficiency: Low MCV with borderline-high hematocrit plus thrombocytosis, leukocytosis, or splenomegaly should trigger immediate JAK2 testing—iron deficiency masks the hemoglobin rise that would otherwise be diagnostic. 1
Aggressive phlebotomy in secondary polycythemia: Disrupts compensatory erythropoiesis, depletes iron, and increases thrombotic risk. 1
Assuming stable hemoglobin excludes polycythemia vera: Hemoglobin stable for ≥8 years without progressive rise makes polycythemia vera very unlikely, but any sustained increase ≥2 g/dL from baseline warrants immediate workup. 1

Monitoring

Polycythemia vera: Monthly CBC during initial phlebotomy phase, then every 3 months once stable. 1
Secondary polycythemia (stable): CBC every 3–6 months with cause-specific parameters (e.g., arterial O₂ saturation for COPD, carboxyhemoglobin for smokers). 1
Secondary polycythemia (newly diagnosed): Monthly CBC for first 3 months to assess hematologic stability. 1

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