What is the diagnostic and treatment approach for a patient with elevated hemoglobin and hematocrit suggestive of polycythemia?

Diagnostic and Treatment Approach to Polycythemia

Begin with JAK2 mutation testing (V617F and exon 12) and serum erythropoietin level immediately after confirming sustained elevation of hemoglobin/hematocrit, as this single step distinguishes polycythemia vera from secondary causes with >95% sensitivity. 1, 2

Initial Confirmation and Laboratory Workup

Confirm true polycythemia by repeating hemoglobin and hematocrit measurements, as a single elevated value is unreliable. 3 Diagnostic thresholds are:

• Men: Hemoglobin >18.5 g/dL or hematocrit >52% 1, 3
• Women: Hemoglobin >16.5 g/dL or hematocrit >48-49% 1, 3

Order the following tests immediately: 1, 3

• Complete blood count with differential and red cell indices (MCV, MCH, MCHC, RDW)
• JAK2 V617F mutation (exon 14) – present in >95% of polycythemia vera cases
• JAK2 exon 12 mutation if V617F is negative – captures additional ~3% of cases
• Serum erythropoietin (EPO) level
• Serum ferritin and transferrin saturation
• Peripheral blood smear review

Critical diagnostic pearl: A sustained hemoglobin increase of ≥2 g/dL from baseline warrants immediate workup even if values remain within normal reference ranges, as this can represent early polycythemia vera. 2

Interpreting Key Laboratory Results

JAK2 Mutation and EPO Patterns

Low or inappropriately normal EPO (below reference range) has >90% specificity for polycythemia vera, though sensitivity is only 64-70%. 1 Normal EPO does not exclude polycythemia vera—proceed with JAK2 testing regardless. 1

Elevated EPO strongly suggests secondary polycythemia and triggers systematic evaluation for hypoxia-driven or tumor-related causes. 1

Important caveat: In chronic hypoxic states (e.g., COPD, smoking), EPO levels may initially be elevated but can normalize once hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera. 1 This is a common diagnostic pitfall.

Iron Status Assessment

Low MCV (<80 fL) is a strong surrogate for polycythemia vera and signals iron deficiency from either increased iron utilization by proliferating erythroid cells or prior phlebotomies. 1

Critical pitfall: Iron deficiency can mask true polycythemia vera by reducing hemoglobin/hematocrit to deceptively normal levels despite pathologically elevated red cell mass. 1 When microcytosis coexists with borderline-high hematocrit plus thrombocytosis, leukocytosis, splenomegaly, or aquagenic pruritus, immediately pursue polycythemia vera workup. 1

MCV is unreliable for screening iron deficiency in erythrocytosis—always measure serum ferritin, transferrin saturation, and iron levels. 3

WHO 2016 Diagnostic Criteria for Polycythemia Vera

Diagnosis requires EITHER: 1, 2

(A) All three major criteria:

1. Hemoglobin ≥18.5 g/dL (men) or ≥16.5 g/dL (women), OR hematocrit ≥49% (men) or ≥48% (women)
2. JAK2 mutation (V617F or exon 12)
3. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) and pleomorphic megakaryocytes

OR

(B) First two major criteria PLUS subnormal serum EPO (the sole minor criterion)

Bone marrow biopsy is required when JAK2 is positive to confirm diagnosis and assess for characteristic trilineage myeloproliferation. 3, 2

Systematic Evaluation for Secondary Polycythemia

If JAK2 is negative and EPO is elevated or normal, evaluate these causes in order: 1, 2

Hypoxia-Driven Causes (Most Common)

1. Smoking history and carboxyhemoglobin measurement – smoker's polycythemia is the most common secondary cause and resolves with cessation. 1 Carbon monoxide binds hemoglobin with 200-250× greater affinity than oxygen, creating functional hypoxia. 1

2. Sleep study for obstructive sleep apnea – nocturnal hypoxemia drives EPO production. 1, 3

3. Arterial oxygen saturation and chest imaging – screen for COPD, pulmonary fibrosis, or right-to-left cardiopulmonary shunts. 1, 3

4. High-altitude residence – physiologic adaptation increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1,000-4,500 meters). 3 Adjust diagnostic thresholds accordingly.

Hypoxia-Independent Causes

1. Abdominal ultrasound or CT – screen for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma, parathyroid carcinoma. 1, 3

2. Medication review – exogenous testosterone, anabolic steroids, or administered erythropoietin. 1, 3

3. Post-renal transplant erythrocytosis in transplant recipients. 1

4. Congenital causes – high oxygen-affinity hemoglobinopathy, EPOR mutations, Chuvash polycythemia (VHL gene mutation). 1, 3

Management Based on Diagnosis

Polycythemia Vera Management

All patients require: 4, 5

• Therapeutic phlebotomy to maintain hematocrit strictly <45% (target ~42% for women and African Americans). 1, 3 The CYTO-PV trial demonstrated that hematocrit <45% reduced cardiovascular death/major thrombosis to 2.7% vs. 9.8% with hematocrit 45-50% (HR 3.91, P=0.007). 3
• Low-dose aspirin (81-100 mg daily) for thrombosis prevention (unless contraindicated). 3, 4, 5

Risk stratification determines additional therapy: 2, 4

• Low-risk (age <60 years, no prior thrombosis): Phlebotomy + aspirin only
• High-risk (age ≥60 years OR prior thrombosis): Add cytoreductive therapy with hydroxyurea, interferon-α, or ruxolitinib

Phlebotomy technique: Remove 300-450 mL per session with hemodynamic monitoring. 3 Always replace removed volume with equal amount of isotonic fluid (normal saline or dextrose) to prevent hemoconcentration and stroke risk. 1, 3

Secondary Polycythemia Management

Treat the underlying condition: 1, 3

• Smoking cessation for smoker's polycythemia (risk reduction begins within 1 year, returns to baseline after 5 years)
• CPAP therapy for obstructive sleep apnea
• Supplemental oxygen for chronic lung disease with arterial saturation <92%
• Tumor resection for EPO-producing neoplasms
• Testosterone dose reduction or discontinuation

Phlebotomy in secondary polycythemia is CONTRAINDICATED in most cases and should only be considered when ALL of the following are met: 1, 3

1. Hemoglobin >20 g/dL AND hematocrit >65%
2. Documented hyperviscosity symptoms (headache, blurred vision, confusion, bleeding)
3. Patient is adequately hydrated
4. Iron deficiency has been excluded
5. Hematocrit remains elevated above baseline despite hydration

First-line therapy for suspected hyperviscosity is aggressive rehydration with oral fluids or IV normal saline, not phlebotomy. 3

Critical warning: Routine or repeated phlebotomies in secondary polycythemia cause iron depletion, decreased oxygen-carrying capacity, and paradoxically increase stroke risk. 1, 3 The elevated hematocrit serves a compensatory physiological role to optimize oxygen transport. 1, 3

Iron Management in Erythrocytosis

Maintain iron sufficiency even with elevated hematocrit. 1, 3 Iron-deficient red cells have reduced deformability and oxygen-carrying capacity, increasing stroke and thrombotic risk despite elevated hematocrit. 1, 3

If transferrin saturation <20%: Initiate cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 1, 3

Immediate Hematology Referral Indications

Refer immediately if: 3, 2

• JAK2 mutation is positive
• Hemoglobin >20 g/dL with hyperviscosity symptoms
• Unexplained splenomegaly
• Diagnosis remains unclear after initial workup
• Unexplained cytopenias coexist with erythrocytosis

Common Diagnostic Pitfalls to Avoid

Do not assume polycythemia vera without checking EPO levels when a patient has borderline hemoglobin and a potential secondary cause (e.g., parathyroid tumor). 1 Elevated EPO distinguishes secondary from primary polycythemia.

Do not exclude polycythemia vera based on normal EPO alone—sensitivity is only 64-70%. 1 Always perform JAK2 testing.

Do not overlook smoking as the most common cause of secondary polycythemia. 1 Carboxyhemoglobin measurement confirms ongoing exposure.

Do not perform aggressive phlebotomy in secondary polycythemia without meeting all five strict criteria listed above. 1, 3 This causes iatrogenic harm.

Do not miss iron deficiency masking polycythemia vera—microcytosis with borderline hematocrit plus thrombocytosis/leukocytosis/splenomegaly mandates immediate JAK2 testing. 1

Do not rely on hematocrit alone for monitoring—hemoglobin is more accurate and stable during sample storage. 3 Hematocrit can falsely increase 2-4% with prolonged storage and is affected by hyperglycemia. 3