How should I evaluate and manage a patient with elevated hemoglobin?

Evaluation and Management of Elevated Hemoglobin

For a patient with elevated hemoglobin, confirm true erythrocytosis with repeat measurements, then systematically distinguish primary polycythemia vera from secondary causes through JAK2 mutation testing and evaluation of hypoxic/non-hypoxic etiologies, reserving therapeutic phlebotomy only for specific high-risk scenarios.

Initial Diagnostic Confirmation

Repeat hemoglobin and hematocrit measurements using an automated cell counter to verify true erythrocytosis, as a single measurement is unreliable 1. True erythrocytosis is defined by hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, AND hematocrit >52% in men or >48% in women 1.

• Hemoglobin is the preferred measurement over hematocrit because it remains stable during sample storage, whereas hematocrit can falsely increase by 2-4% after 8 hours of storage 1.
• Hyperglycemia can falsely elevate mean corpuscular volume (MCV) and calculated hematocrit but does not affect hemoglobin measurement 1.

Comprehensive Laboratory Workup

Order the following tests immediately to characterize the erythrocytosis 1:

• Complete blood count (CBC) with red cell indices (MCV, MCH, MCHC, RDW) to assess for concurrent cytopenias or thrombocytosis 1
• Reticulocyte count to evaluate bone marrow response 1
• Peripheral blood smear reviewed by a hematologist to identify abnormal morphology 1
• Serum ferritin and transferrin saturation to detect coexisting iron deficiency, which frequently occurs with erythrocytosis 1
• C-reactive protein (CRP) to identify inflammatory conditions 1
• White blood cell differential and platelet count, as thrombocytosis or leukocytosis suggests a myeloproliferative disorder 1

A key diagnostic pitfall: Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis; serum ferritin and transferrin saturation are required 1.

Distinguishing Primary from Secondary Polycythemia

Test for Polycythemia Vera

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

WHO 2016 diagnostic criteria for polycythemia vera require EITHER:

• Both major criteria (elevated Hb/Hct AND JAK2 mutation) plus one minor criterion, OR
• First major criterion plus two minor criteria 1

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 criteria:

• Subnormal serum erythropoietin level 1
• Bone marrow hypercellularity with trilineage growth 1
• Endogenous erythroid colony formation 1

Important caveat: Polycythemia vera can occasionally present with elevated erythropoietin levels, so a high EPO does not exclude the diagnosis 2. JAK2 mutation testing remains essential.

Evaluate for Secondary Causes

If JAK2 is negative, systematically evaluate secondary causes 1:

Hypoxia-driven causes:

• Smoking history and carbon monoxide exposure, which causes "smoker's polycythemia" through chronic tissue hypoxia 1
• Sleep study if nocturnal hypoxemia is suspected (obstructive sleep apnea) 1
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease 1
• Arterial oxygen saturation <92% indicates 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 that produce erythropoietin 1
• Medication review for testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in young adults 1
• Consider hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, or meningioma as rare erythropoietin-producing tumors 1

Relative polycythemia (plasma volume depletion):

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

Altitude Considerations

Physiologic adaptation to altitude increases hemoglobin levels, requiring adjustment of diagnostic thresholds 1:

• At 1,000 meters: +0.2 g/dL
• At 2,000 meters: +0.8 g/dL
• At 3,000 meters: +1.9 g/dL
• At 4,000 meters: +3.5 g/dL 1

Management Based on Etiology

Confirmed Polycythemia Vera

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk 1. The CYTO-PV trial demonstrated that hematocrit <45% reduced cardiovascular death or major thrombosis to 2.7% versus 9.8% with hematocrit 45-50% (HR 3.91, P=0.007) 1.

• A slightly lower target of approximately 42% is reasonable for women and African Americans due to physiological differences in baseline hematocrit 1
• Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention 1
• Remove approximately 300-450 mL of blood per phlebotomy session, with careful hemodynamic monitoring 1
• When phlebotomy is performed, replace the removed blood volume with equal fluid (dextrose or saline) to prevent hemoconcentration and reduce stroke risk 1

If JAK2 mutation is positive, perform bone marrow aspirate and biopsy to confirm diagnosis and assess for trilineage myeloproliferation 1.

Refer immediately to hematology if JAK2 mutation is positive, hemoglobin >20 g/dL with hyperviscosity symptoms, or unexplained splenomegaly 1.

Secondary Polycythemia

Treatment focuses on the underlying condition 1:

• Smoking cessation for smoker's polycythemia, which typically resolves the erythrocytosis 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 for secondary polycythemia: Routine therapeutic phlebotomy is contraindicated 1. Phlebotomy causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk 1.

Phlebotomy in secondary polycythemia is indicated ONLY when ALL of the following are present 1:

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

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

Iron Deficiency Management in Erythrocytosis

Iron deficiency frequently coexists with erythrocytosis and requires opposite management 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
• Avoid iron deficiency even in the presence of erythrocytosis 1
• Monitor for rapid increases in red cell mass with iron supplementation 1

Common Pitfalls to Avoid

• Never perform routine or repeated phlebotomies in secondary erythrocytosis, as this leads to iron depletion and increased stroke risk 1
• Never perform phlebotomy without equal-volume fluid replacement, as this increases hemoconcentration and stroke risk 1
• Do not overlook coexisting iron deficiency, which mimics hyperviscosity but requires iron supplementation, not phlebotomy 1
• Do not use standard PV diagnostic thresholds at high altitude without adjustment for physiologic adaptation 1
• Do not rely solely on MCV to screen for iron deficiency in erythrocytosis; use ferritin and transferrin saturation 1

Monitoring Strategy

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