What is the initial approach to managing polycythemia?

Approach to Polycythemia

Begin by confirming true polycythemia through hemoglobin/hematocrit thresholds (>95th percentile adjusted for sex and race), then systematically distinguish between primary polycythemia vera, secondary causes, and relative polycythemia using serum erythropoietin levels and bone marrow examination. 1

Initial Assessment and Confirmation

When to Suspect Polycythemia

Pursue diagnostic evaluation if any of the following are present: 1

• Hemoglobin/hematocrit exceeds the 95th percentile of normal distribution adjusted for sex and race (hemoglobin >16.5 g/dL in men or >16.0 g/dL in women) 1, 2
• Documented increase in hemoglobin/hematocrit above baseline for an individual patient, regardless of where the value lies within the reference range 1
• Borderline-high hematocrit accompanied by PV-related features: thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis (including Budd-Chiari syndrome), or erythromelalgia 1

If none of these criteria are met, repeat blood testing in 3 months is sufficient. 1

Exclude Apparent (Relative) Polycythemia First

Most causes of plasma volume depletion are clinically obvious and do not require specialized testing. 1 Look for: 1

• Severe dehydration, diarrhea, vomiting
• Diuretic use
• Capillary leak syndrome
• Severe burns

Important caveat: Gaisböck syndrome (relative polycythemia with hypertension/nephropathy) and stress polycythemia are poorly understood with little foundation—in one Mayo Clinic series of 109 consecutive measurements, no patients with relative polycythemia were identified. 1

Smoker's polycythemia is real and secondary to chronic carbon monoxide exposure; it resolves with smoking cessation. 1, 3 Carbon monoxide binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia. 3

Diagnostic Algorithm

Step 1: Measure Serum Erythropoietin (EPO)

This is the critical first test after confirming true polycythemia. 1

If EPO is LOW:

• PV is probable (specificity >90%) 1
• Proceed directly to bone marrow examination 1
• Note: Low EPO can also occur in essential thrombocythemia and rare congenital polycythemia with EPOR mutations 1

If EPO is NORMAL:

• PV remains possible (sensitivity of low EPO for PV is only <70%) 1
• Proceed to bone marrow examination 1

If EPO is HIGH:

• Evaluate for secondary polycythemia 1
• PV is unlikely to be associated with increased EPO 1
• However, rare cases of PV can present with elevated EPO, so if clinical suspicion is high, proceed with JAK2 testing 4

Step 2: Bone Marrow Examination with Cytogenetics

Bone marrow histology is the cornerstone of diagnosis. 5 An experienced hematopathologist should evaluate for: 1

• Hypercellularity
• Increased megakaryocytes with cluster formation
• Giant megakaryocytes and pleomorphism in megakaryocyte morphology
• Mild reticulin fibrosis (present in 12% of patients)
• Decreased bone marrow iron stores

Cytogenetic studies have limited diagnostic value (abnormalities in only 13-18% at diagnosis) but should still be performed. 1

Step 3: JAK2 Mutation Testing

More than 95% of PV patients have a JAK2 gene variant, which helps distinguish PV from secondary causes. 2 This test should be performed if EPO is low or normal. 3

Step 4: Specialized Testing (Only in Equivocal Cases)

These tests should be needed in no more than 10% of patients. 1 Options include: 1

• Bone marrow immunohistochemistry for thrombopoietin receptor (c-mpl): markedly decreased megakaryocyte expression supports PV diagnosis
• Peripheral blood neutrophil assay for PRV-1 expression: high expression in PV, not detectable in secondary polycythemia
• Spontaneous (endogenous) erythroid colony assays: limited availability and considerable expertise required

Critical pitfall: A negative specialized test does not exclude PV diagnosis. 1

Evaluation for Secondary Polycythemia

When EPO is Elevated, Systematically Evaluate:

Hypoxia-Driven Causes: 1, 3

• Chronic lung disease (COPD): perform chest X-ray 3
• Right-to-left cardiopulmonary shunts: evaluate with echocardiography
• High-altitude habitation
• Hypoventilation syndromes: sleep study for suspected sleep apnea 3
• High oxygen-affinity hemoglobinopathy: congenital, autosomal-dominant 3

Note: In hypoxia-driven secondary polycythemia, serum EPO is often initially elevated but may return to normal range once hemoglobin stabilizes. 1, 3

Hypoxia-Independent Causes: 1, 3

• Malignant tumors: renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, meningioma—perform abdominal ultrasound 3
• Benign tumors: uterine leiomyomas
• Congenital causes: abnormally elevated EPO set point, Chuvash polycythemia (von Hippel-Lindau gene mutations) 1
• EPOR-mediated: autosomal-dominant congenital polycythemia with activating EPOR mutations (EPO usually low in these cases) 1
• Exogenous erythropoietic drugs: EPO, androgen preparations (oral, transdermal, intramuscular)—always question patients about use 1, 3
• Post-renal transplant erythrocytosis (PRTE) 1, 3

Additional Workup for Secondary Causes: 3

• Complete blood count with differential
• Renal function tests (creatinine, BUN)
• Liver function tests (AST, ALT, bilirubin)
• Arterial blood gas analysis or pulse oximetry for hypoxemia
• Consider imaging of kidney, liver, and central nervous system if initial studies unrevealing or EPO persistently elevated 1

Critical Pitfalls to Avoid

Do not perform red cell mass (RCM) measurements in most cases. 1 RCM determination is seldom required because: 1

• Normal-range RCM does not rule out PV (misses PV patients at left extreme of Gaussian distribution)
• RCM measurement with hematocrit >60% without obvious hemoconcentration is costly redundancy (RCM almost always increased)
• Isolated hematocrit <60% without other PV features is extremely unlikely to be PV—use serum EPO instead

Do not assume low EPO always means PV. Low EPO can occur in essential thrombocythemia and rare congenital polycythemia with EPOR mutations. 1

Do not exclude PV based on normal EPO. Sensitivity of low EPO for PV is only <70%. 1

Do not dismiss PV if EPO is elevated. Rare cases of PV can present with high EPO levels—proceed with JAK2 testing if clinical suspicion is high. 4

Do not overlook smoking history. Smoker's polycythemia is real and resolves with cessation; risk reduction begins within 1 year and returns to baseline after 5 years. 1, 3

Do not aggressively phlebotomize in cyanotic heart disease or high oxygen-affinity hemoglobinopathy due to stroke risk and impaired oxygen delivery. 1