What is the appropriate workup for a 20‑year‑old male living at high altitude with markedly elevated hemoglobin (polycythemia)?

Workup of a 20-Year-Old Male from High Altitude with Hemoglobin 20 g/dL

First, adjust the hemoglobin threshold for altitude before pursuing an extensive polycythemia vera workup, because physiologic adaptation to high altitude can increase hemoglobin by 0.2–4.5 g/dL depending on elevation, and a value of 20 g/dL may represent normal adaptation rather than pathologic erythrocytosis. 1

Initial Assessment: Altitude Adjustment

• Determine the patient's exact altitude of residence and apply the WHO-recommended altitude correction to hemoglobin thresholds before diagnosing true erythrocytosis 1, 2
• At 1,000 meters altitude, normal hemoglobin increases by +0.2 g/dL; at 1,500 meters by +0.5 g/dL; at 2,000 meters by +0.8 g/dL; at 2,500 meters by +1.3 g/dL; at 3,000 meters by +1.9 g/dL; and at 4,000 meters by +3.5 g/dL 1
• The WHO diagnostic criteria for polycythemia vera specifically state that hemoglobin thresholds must be adjusted for "altitude of residence", and failure to do so leads to overdiagnosis of polycythemia vera in high-altitude populations 1

Mandatory Initial Laboratory Panel

Order the following tests immediately to distinguish physiologic altitude adaptation from pathologic erythrocytosis: 1

• Complete blood count with red cell indices (hemoglobin, hematocrit, RBC count, MCV, MCH, MCHC, RDW) using an automated analyzer 1
• Peripheral blood smear reviewed by a hematologist to identify abnormal morphology, leukocytosis, thrombocytosis, or left shift 1, 3
• Serum ferritin and transferrin saturation to exclude iron deficiency, which frequently coexists with erythrocytosis and can mask the true red cell mass 1
• Reticulocyte count to assess bone marrow response 1
• White blood cell differential and platelet count, because polycythemia vera typically presents with leukocytosis (>10 × 10⁹/L) and thrombocytosis (>400 × 10⁹/L) in addition to erythrocytosis 1, 3

Key Diagnostic Clues from the CBC

• Polycythemia vera patients exhibit a distinct pattern: leukocytosis, thrombocytosis, and hypochromic microcytic red blood cells related to iron deficiency, which can help distinguish primary from secondary polycythemia 3
• The presence of circulating myelocytes or a left shift is abnormal and suggests a myeloproliferative disorder rather than physiologic altitude adaptation 1
• Mean corpuscular volume (MCV) < 80 fL indicates iron deficiency, which must be corrected before accurately interpreting hemoglobin levels 1

JAK2 Mutation Testing: When to Order

Do NOT reflexively order JAK2 testing in every high-altitude resident with hemoglobin 20 g/dL. The decision depends on altitude-adjusted thresholds and CBC pattern:

Indications for JAK2 Testing

• Hemoglobin remains > 18.5 g/dL in men (or > 16.5 g/dL in women) AFTER adjusting for altitude of residence 1, 4
• Presence of leukocytosis (WBC > 10 × 10⁹/L), thrombocytosis (platelets > 400 × 10⁹/L), or circulating myelocytes on peripheral smear 1, 3
• Splenomegaly, aquagenic pruritus, erythromelalgia, or unusual thrombosis (e.g., Budd-Chiari syndrome, splanchnic vein thrombosis) 1

JAK2 Testing Protocol

• Order JAK2 V617F (exon 14) mutation analysis first, which detects >90–95% of polycythemia vera cases 1, 4
• If JAK2 V617F is negative, order JAK2 exon 12 mutation analysis, which accounts for an additional 2–3% of cases 1, 4
• A positive JAK2 mutation (either V617F or exon 12) fulfills the second WHO major criterion and, when combined with elevated hemoglobin/hematocrit and at least one minor criterion, confirms polycythemia vera in >97% of patients 1, 4

Evaluation for Secondary Causes (If JAK2 Negative)

If JAK2 testing is negative or not yet indicated, systematically evaluate for secondary causes of erythrocytosis: 1

Hypoxia-Driven Causes

• Overnight pulse oximetry or polysomnography to screen for obstructive sleep apnea, which produces nocturnal hypoxemia and drives erythropoietin production 1, 5
  • High-altitude polycythemia patients can have severe oxygen desaturation during sleep (SaO₂ as low as 50–70%), which may explain excessive erythrocytosis 5
• Pulmonary function tests and chest imaging to evaluate for chronic obstructive pulmonary disease or restrictive lung disease 1
• Arterial blood gas with oxygen saturation to document baseline hypoxemia; arterial oxygen saturation < 92% indicates secondary polycythemia due to hypoxemia 1

Non-Hypoxic Causes

• Detailed smoking history, because chronic carbon monoxide exposure causes "smoker's polycythemia" that resolves with cessation 1
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or polycystic kidney disease that can produce erythropoietin 1
• Medication review for testosterone use (prescribed or unprescribed), which is a common cause of erythrocytosis in young men 1
• Serum erythropoietin level to differentiate primary from secondary causes: low or low-normal EPO suggests polycythemia vera, whereas elevated EPO indicates secondary erythrocytosis 1, 4

Iron Status: Critical Diagnostic and Therapeutic Consideration

Iron deficiency frequently coexists with erythrocytosis and requires opposite management from phlebotomy: 1

• If transferrin saturation < 20%, initiate cautious oral iron supplementation rather than phlebotomy, because iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1
• Iron deficiency can mask true erythrocytosis by lowering hemoglobin while red cell mass remains elevated; formal diagnosis of polycythemia vera requires demonstration of WHO criteria after iron replacement 1, 4
• Monitor hemoglobin closely during iron supplementation, as rapid increases in red cell mass can occur 1

When to Refer to Hematology

Immediate hematology referral is indicated if: 1

• JAK2 mutation is positive (confirms polycythemia vera requiring specialist management)
• Hemoglobin > 20 g/dL with symptoms of hyperviscosity (headache, blurred vision, confusion, bleeding) after excluding dehydration
• Unexplained splenomegaly, thrombocytosis, or leukocytosis suggesting a myeloproliferative disorder
• Diagnosis remains unclear after initial workup or if bone marrow biopsy is needed

Management Principles: Phlebotomy Thresholds

Therapeutic phlebotomy is indicated ONLY when ALL of the following criteria are met: 1

• Hemoglobin > 20 g/dL AND hematocrit > 65%
• Documented symptoms of hyperviscosity (headache, blurred vision, confusion, bleeding)
• Adequate hydration has been confirmed (rehydrate with oral or IV normal saline first)
• Iron deficiency has been excluded (transferrin saturation ≥ 20%)

Critical Contraindications

• Routine or repeated phlebotomies are explicitly contraindicated in secondary polycythemia due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 1
• When phlebotomy is performed, replace the removed blood volume with an equal amount of dextrose or saline to prevent hemoconcentration 1
• Never perform phlebotomy in patients with iron deficiency (transferrin saturation < 20%), as this worsens oxygen delivery and increases cerebrovascular risk 1

Common Pitfalls to Avoid

• Do not apply sea-level hemoglobin thresholds (Hb > 18.5 g/dL for men) to high-altitude residents without altitude adjustment, as this leads to massive overdiagnosis of polycythemia vera 1, 2
• Do not order JAK2 testing reflexively in every high-altitude resident with elevated hemoglobin, as many will have physiologic adaptation rather than pathologic erythrocytosis 3, 6
• Do not overlook coexisting iron deficiency, which mimics hyperviscosity symptoms but requires iron supplementation rather than phlebotomy 1
• Do not perform aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk 1
• Do not rely solely on mean corpuscular volume (MCV) to screen for iron deficiency in erythrocytosis; serum ferritin and transferrin saturation are required for accurate diagnosis 1

Diagnostic Algorithm Summary

1. Adjust hemoglobin threshold for patient's altitude of residence using WHO altitude correction table 1, 2
2. Order CBC with differential, peripheral smear, iron studies (ferritin, transferrin saturation), and reticulocyte count 1
3. If hemoglobin remains elevated after altitude adjustment AND CBC shows leukocytosis/thrombocytosis/left shift, order JAK2 V617F testing 1, 4, 3
4. If JAK2 V617F is negative, order JAK2 exon 12 testing 1, 4
5. If JAK2 is negative, systematically evaluate for secondary causes: sleep study, pulmonary function tests, renal imaging, smoking history, testosterone use, serum EPO level 1
6. If iron deficiency is present (transferrin saturation < 20%), initiate iron supplementation with close hemoglobin monitoring 1
7. Reserve phlebotomy for hemoglobin > 20 g/dL AND hematocrit > 65% with hyperviscosity symptoms, after excluding dehydration and iron deficiency 1
8. Refer to hematology if JAK2-positive, unexplained splenomegaly/thrombocytosis, or diagnosis unclear 1