What is the approach to a patient with elevated hemoglobin (Hb), hematocrit (Hct), and mean cell volume (MCV), potentially indicating polycythemia vera or other myeloproliferative disorders?

Approach to Elevated Hemoglobin, Hematocrit, and MCV

All patients with elevated hemoglobin (>18.5 g/dL in men, >16.5 g/dL in women) and hematocrit should undergo immediate JAK2 mutation testing to distinguish polycythemia vera from secondary causes, followed by systematic evaluation of secondary erythrocytosis if JAK2 is negative. 1, 2

Initial Diagnostic Workup

Order these tests immediately:

• Complete blood count with red cell indices, reticulocyte count, and manual differential to characterize the elevations and assess for leukocytosis or thrombocytosis that would suggest a myeloproliferative disorder 3, 2
• JAK2 V617F mutation testing as the first-line diagnostic test, present in up to 97% of polycythemia vera cases 2, 4
• Serum ferritin and transferrin saturation to evaluate iron status, as iron deficiency can coexist with erythrocytosis and cause microcytic polycythemia 3, 2
• Peripheral blood smear review by a qualified hematologist to identify abnormal morphology 3, 2
• Serum erythropoietin level to differentiate primary from secondary causes—low or inappropriately normal EPO suggests polycythemia vera, while elevated EPO suggests secondary erythrocytosis 1

Confirm true polycythemia by repeating measurements, as a single elevated value is unreliable and may reflect dehydration or laboratory variation 3

Diagnostic Criteria for Polycythemia Vera

The WHO criteria require either:

• Both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR
• First major criterion plus two minor criteria 1, 2

Major criteria:

1. Hemoglobin >18.5 g/dL in men or >16.5 g/dL in women (adjusted for altitude of residence) 1
2. Presence of JAK2 V617F or JAK2 exon 12 mutation 1

Minor criteria:

1. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) 1
2. Subnormal serum erythropoietin level 1, 4
3. Endogenous erythroid colony formation in vitro 1

If JAK2 is positive, proceed with bone marrow biopsy to confirm diagnosis and assess for trilineage myeloproliferation. 2

Evaluation for Secondary Causes (if JAK2 negative)

Systematically evaluate hypoxic causes:

• Sleep study (polysomnography) if obstructive sleep apnea is suspected based on obesity, snoring, witnessed apneas, or daytime fatigue—nocturnal hypoxemia drives erythropoietin production 3, 2, 5
• Pulmonary function tests and chest imaging for chronic obstructive pulmonary disease or other chronic lung disease 3, 2
• Smoking history—carbon monoxide exposure causes tissue hypoxia and stimulates erythropoietin production, resolving with cessation 3, 2
• Arterial blood gas or pulse oximetry to document hypoxemia 5
• Echocardiography if cyanotic congenital heart disease with right-to-left shunting is suspected 3, 2

Evaluate non-hypoxic causes:

• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or polycystic kidney disease that can produce erythropoietin 3, 2
• Medication review for testosterone use (prescribed or unprescribed), which commonly causes erythrocytosis in young adults 3, 2
• Consider other erythropoietin-producing tumors: hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma 3

Assess for relative polycythemia (plasma volume depletion):

• Review hydration status, fluid intake history, and recent losses—dehydration is the most common cause of elevated hematocrit 3, 2
• Evaluate diuretic use, which can cause plasma volume depletion without true increase in red cell mass 2

Management Based on Diagnosis

For Confirmed Polycythemia Vera:

Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk—the CYTO-PV trial demonstrated significantly reduced thrombotic events with this target (2.7% vs 9.8%, P=0.007) 1, 3, 2

Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention 1, 3, 2

Cytoreductive therapy is indicated for high-risk patients (age >60 years or prior thrombosis):

• Hydroxyurea is first-line cytoreductive therapy at any age, though use with caution in patients <40 years 1
• Interferon-alpha is an alternative first-line option and should be considered in young patients or those intolerant to hydroxyurea, as it is non-leukemogenic 1
• Busulphan may be considered in elderly patients (>70 years) 1

Indications for cytoreductive therapy in otherwise low-risk patients:

• Poor tolerance of phlebotomy or frequent phlebotomy requirement 1
• Symptomatic or progressive splenomegaly 1
• Severe disease-related symptoms 1
• Platelet count >1,500 × 10⁹/L 1
• Progressive leukocytosis 1

Aggressively manage cardiovascular risk factors and advise smoking cessation 1, 4

For Secondary Erythrocytosis:

Treat the underlying condition:

• Smoking cessation for smoker's polycythemia 3, 2
• CPAP therapy for obstructive sleep apnea 3, 2, 5
• Management of chronic lung disease 3, 2
• Dose adjustment or discontinuation of testosterone if causative 3, 2

Therapeutic phlebotomy is indicated ONLY when:

• Hemoglobin >20 g/dL AND hematocrit >65% with symptoms of hyperviscosity (headache, visual disturbances, dizziness) 3, 2
• Dehydration has been excluded 3, 2
• When performed, replace with equal volume of dextrose or saline to prevent further hemoconcentration 3

Target hematocrit of 55-60% may be appropriate in secondary erythrocytosis, as the elevated hematocrit serves a compensatory physiological role 3

Critical Thresholds and Red Flags Requiring Immediate Hematology Referral

• Positive JAK2 mutation 3, 2
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 3, 2
• Unexplained splenomegaly with elevated blood counts 2
• Diagnosis remains unclear after initial workup 3, 2

Common Pitfalls to Avoid

Never perform repeated routine phlebotomies in secondary erythrocytosis—this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk 1, 3, 2

Do not overlook coexisting iron deficiency—iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk even in the presence of erythrocytosis 3, 2

If iron deficiency is confirmed, provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur 3, 2

Do not use standard PV diagnostic thresholds at high altitude without adjustment—physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation (1,000-4,500 meters) 3

Do not assume "adequate sleep" rules out sleep apnea—patients with OSA are typically unaware of their sleep fragmentation and nocturnal arousals 5

Hemoglobin is more reliable than hematocrit for monitoring, as hematocrit can falsely increase by 2-4% with prolonged sample storage and is affected by hyperglycemia, while hemoglobin remains stable 3

Monitoring Response in Polycythemia Vera

Monitor clinicohematologic response using ELN criteria:

• Complete response: hematocrit <45% without phlebotomy, platelet count <400 × 10⁹/L, WBC count <10 × 10⁹/L, and no disease-related symptoms 1
• Partial response: hematocrit <45% without phlebotomy or response in three or more of the other criteria 1

Routine monitoring of JAK2 V617F allele burden is not indicated except in patients receiving interferon therapy, which may induce molecular responses 1

Bone marrow response monitoring is not indicated for routine clinical follow-up 1