What is the appropriate workup and management for a patient with elevated hemoglobin (Hb) levels?

Workup for Elevated Hemoglobin

Begin with a complete blood count with differential to assess other cell lines, then immediately test for JAK2 V617F mutation to rule out polycythemia vera, and evaluate for secondary causes including chronic hypoxemia, smoking history, and renal disease. 1

Initial Laboratory Assessment

Essential first-line tests:

• Complete blood count with differential to evaluate for myeloproliferative disorders and assess white blood cell and platelet counts 1
• JAK2 V617F mutation testing to diagnose or exclude polycythemia vera 1
• Arterial blood gas or pulse oximetry to assess for chronic hypoxemia 1
• Renal function tests (creatinine, BUN) to evaluate for renal causes of secondary erythrocytosis 1

Additional diagnostic workup based on initial findings:

• Erythropoietin level (typically low in polycythemia vera, elevated in secondary causes) 2
• Abdominal imaging (ultrasound or CT) if renal pathology suspected, as renal tumors and cysts can produce erythropoietin 2
• Sleep study if clinical suspicion for obstructive sleep apnea exists 1

Clinical History Elements

Critical historical factors to elicit:

• Smoking history and quantification (pack-years), as smoking is a common cause of secondary erythrocytosis 1
• Symptoms of hyperviscosity: headaches, visual disturbances, dizziness, pruritus after bathing (classic for polycythemia vera) 2
• History of thrombotic events, including unusual sites such as hepatic, portal, or renal veins 2
• Respiratory symptoms suggesting chronic lung disease or sleep-disordered breathing 1
• Medication review, particularly for erythropoiesis-stimulating agents (ESAs) which must be discontinued immediately if present 1
• Family history of polycythemia or myeloproliferative disorders 2

Physical Examination Findings

Key examination elements:

• Splenomegaly (present in approximately 75% of polycythemia vera cases) 2
• Plethoric appearance, facial ruddiness 2
• Signs of chronic hypoxemia: cyanosis, clubbing 1
• Evidence of thrombosis: unilateral limb swelling, hepatomegaly (Budd-Chiari syndrome) 2

Diagnostic Algorithm Based on Hemoglobin Level

For hemoglobin >18.5 g/dL:

• This represents a medical urgency due to increased blood viscosity and thrombotic risk 1
• Initiate phlebotomy immediately (250-500 mL) to rapidly reduce hemoglobin 1
• Target hemoglobin <15 g/dL in men and <14 g/dL in women 1
• Each 400 mL unit removed decreases hemoglobin by approximately 1.5 g/dL 1

For hemoglobin 16-18.5 g/dL:

• Complete diagnostic workup as outlined above before initiating treatment 1
• Monitor for symptoms of hyperviscosity 2

Etiology-Specific Management

If polycythemia vera confirmed (JAK2 mutation positive):

• Phlebotomy to maintain hematocrit <45% 1
• Low-dose aspirin 81-100 mg daily to reduce thrombotic risk unless contraindicated 1
• Consider cytoreductive therapy (hydroxyurea) for high-risk patients 2
• Hematology referral mandatory 2

If secondary erythrocytosis identified:

• Address underlying cause: COPD management, CPAP for sleep apnea, smoking cessation 1
• Phlebotomy reserved for symptomatic patients or hemoglobin >18.5 g/dL 1
• Do not use phlebotomy in hereditary methemoglobinemia with compensatory polycythemia, as higher erythrocyte mass maintains normal tissue oxygenation 1

Critical Pitfalls to Avoid

Common errors in management:

• Failing to discontinue ESAs immediately—these agents worsen erythrocytosis and are absolutely contraindicated in elevated hemoglobin 1
• Attributing elevated hemoglobin solely to dehydration without proper workup, potentially missing polycythemia vera 2
• Delaying phlebotomy in severely elevated hemoglobin (>18.5 g/dL), which increases acute thrombotic risk 1
• Missing atypical presentations of polycythemia vera in younger patients (under 40 years) 2
• Failing to evaluate for thrombosis in unusual sites (renal vein, hepatic vein, portal vein) when polycythemia vera is diagnosed 2

The distinction between primary and secondary erythrocytosis is critical: Primary polycythemia vera requires lifelong hematologic management and carries malignant transformation risk, while secondary causes may be reversible with treatment of the underlying condition 1, 2