How do I evaluate and treat a patient with elevated hemoglobin?

Evaluation and Management of Elevated Hemoglobin

Begin by confirming true erythrocytosis with repeat hemoglobin and hematocrit measurements, then systematically distinguish between primary polycythemia vera, secondary causes, and relative polycythemia through targeted laboratory testing and clinical assessment. 1

Initial Diagnostic Confirmation

Hemoglobin is the preferred measurement over hematocrit because it remains stable during sample storage, whereas hematocrit can falsely increase by 2-4% with prolonged storage and is affected by hyperglycemia. 1

• Diagnostic thresholds for true erythrocytosis:
  • Men: Hemoglobin >18.5 g/dL or hematocrit >52% 1
  • Women: Hemoglobin >16.5 g/dL or hematocrit >48-49% 1
  • Repeat measurements are essential, as a single value is unreliable 1

Essential Initial Laboratory Workup

Order the following tests immediately to characterize the erythrocytosis and identify its cause:

• Complete blood count with red cell indices (MCV, MCH, MCHC, RDW) using an automated analyzer 1
• Reticulocyte count to assess bone marrow response 1
• Serum ferritin and transferrin saturation – iron deficiency frequently coexists with erythrocytosis and requires opposite management 1
• White blood cell differential and platelet count – thrombocytosis or leukocytosis suggests a myeloproliferative disorder 1
• Peripheral blood smear reviewed by a hematologist to identify abnormal morphology 1
• C-reactive protein (CRP) to identify inflammatory conditions 1

Critical pitfall: Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; you must check ferritin and transferrin saturation directly. 1

Distinguishing Primary from Secondary Erythrocytosis

Test for Polycythemia Vera

JAK2 mutation testing (both exon 14 V617F and exon 12) is the cornerstone first-line molecular test, detecting mutations in up to 97% of polycythemia vera cases. 1

WHO 2016 Diagnostic Criteria for Polycythemia Vera:

Diagnosis requires all three major criteria OR the first two major criteria plus one minor criterion:

Major Criteria:

1. Hemoglobin >16.5 g/dL (women) or >18.5 g/dL (men), OR hematocrit >48% (women) or >49% (men) 1
2. Presence of JAK2 mutation 1
3. Bone marrow biopsy showing hypercellularity with trilineage myeloproliferation 1

Minor Criterion:

• Subnormal serum erythropoietin level 1

Important nuance: While low erythropoietin is a WHO minor criterion, polycythemia vera can occasionally present with elevated erythropoietin levels, so a high EPO does not exclude the diagnosis if JAK2 is positive. 2

Evaluate for Secondary Causes

If JAK2 is negative, systematically evaluate secondary causes:

Hypoxia-driven causes:

• Smoking history – "smoker's polycythemia" from chronic carbon monoxide exposure stimulates erythropoietin production and resolves with cessation 1
• Sleep study if nocturnal hypoxemia suspected (obstructive sleep apnea) 1
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease 1
• Arterial oxygen saturation – levels <92% indicate hypoxemia-driven secondary polycythemia 1
• Cyanotic congenital heart disease with right-to-left shunting 1

Hypoxia-independent causes:

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease producing erythropoietin 1
• Medication review – testosterone therapy (prescribed or unprescribed) commonly causes erythrocytosis 1
• Other erythropoietin-producing tumors: hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 1

Relative polycythemia (plasma volume depletion):

• Assess hydration status, diuretic use, burns, or stress polycythemia (Gaisböck syndrome) 1

Physiological variations to consider:

• Altitude adaptation – hemoglobin increases 0.2-4.5 g/dL depending on elevation (1,000-4,500 meters); adjust diagnostic thresholds accordingly 1
• Age and sex – males and post-menopausal females typically have hemoglobin 15.5 ± 2.0 g/dL, while menstruating females have 14.0 ± 2.0 g/dL 1

Management Based on Diagnosis

Polycythemia Vera Management

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk – the CYTO-PV trial demonstrated this target reduces cardiovascular death or major thrombosis from 9.8% to 2.7% (P=0.007). 1 A slightly lower target of approximately 42% is reasonable for women and African Americans. 1

• Phlebotomy technique: Remove 300-450 mL per session with equal-volume fluid replacement to prevent hemoconcentration 1
• Add low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention 1
• Initiate cytoreductive agents (hydroxyurea, interferon-α-2a, or ruxolitinib) when phlebotomy volume becomes excessive or when thrombocytosis/leukocytosis is present 1

If bone marrow biopsy is needed: Perform when JAK2 is positive to confirm diagnosis and assess for trilineage myeloproliferation. 1

Secondary Erythrocytosis Management

Treatment of the underlying condition is the primary intervention:

• Smoking cessation for smoker's polycythemia 1
• CPAP therapy for obstructive sleep apnea 1
• Management of chronic lung disease 1
• Dose adjustment or discontinuation of testosterone if causative 1

Critical management principle: Routine therapeutic phlebotomy is contraindicated in secondary erythrocytosis because it causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1

Phlebotomy in secondary erythrocytosis is indicated ONLY when ALL of the following are present:

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

First-line therapy for suspected hyperviscosity is aggressive rehydration with oral fluids or intravenous normal saline, not phlebotomy. 1

Iron Deficiency in Erythrocytosis

Iron deficiency frequently coexists with erythrocytosis and requires opposite management – iron supplementation rather than phlebotomy. 1

• If transferrin saturation <20%, initiate cautious oral iron supplementation with close hemoglobin monitoring 1
• Iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1
• Iron deficiency can mimic hyperviscosity symptoms but requires iron supplementation, not phlebotomy 1

Hematology Referral Indications

Refer immediately to hematology if:

• JAK2 mutation is positive 1
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 1
• Unexplained splenomegaly 1
• Diagnosis remains unclear after initial workup 1
• Unexplained cytopenias occur alongside elevated red blood cell count 1

Common Pitfalls to Avoid

• Never perform routine or repeated phlebotomies in secondary erythrocytosis – this leads to iron depletion and paradoxically increases stroke risk 1
• Never perform phlebotomy without equal-volume fluid replacement – this raises hemoconcentration and stroke risk 1
• Do not overlook coexisting iron deficiency – it mimics hyperviscosity but requires iron supplementation, not phlebotomy 1
• Do not rely on MCV alone to screen for iron deficiency in erythrocytosis – check ferritin and transferrin saturation directly 1
• Do not use standard polycythemia vera diagnostic thresholds at high altitude without adjusting for physiologic adaptation 1

Monitoring Strategy

For asymptomatic individuals with JAK2-negative erythrocytosis and hematocrit <65%, serial hematologic assessment every 6-12 months is appropriate to detect progression or complications. 1