What hemoglobin and hematocrit levels define polycythemia in adult men and women, and what are the recommended evaluation and management strategies?

Hemoglobin Thresholds Defining Polycythemia

Polycythemia is defined by hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women according to the World Health Organization (WHO) 2016 criteria, with alternative thresholds of ≥17 g/dL in men or ≥15 g/dL in women when accompanied by a sustained increase of ≥2 g/dL from baseline. 1, 2

Sex-Specific Diagnostic Thresholds

Standard Hemoglobin Criteria

• Men: Hemoglobin ≥18.5 g/dL meets the primary WHO major criterion for polycythemia vera diagnosis 1, 3
• Women: Hemoglobin ≥16.5 g/dL meets the primary WHO major criterion for polycythemia vera diagnosis 1, 3
• Hematocrit alternative: Hematocrit >99th percentile adjusted for age, sex, and altitude can substitute for hemoglobin thresholds 1

Alternative Criteria for Early/Masked Disease

• Men: Hemoglobin ≥17 g/dL plus a documented sustained rise of ≥2 g/dL from individual baseline qualifies as a major criterion 1, 2
• Women: Hemoglobin ≥15 g/dL plus a documented sustained rise of ≥2 g/dL from individual baseline qualifies as a major criterion 1, 2
• These lower thresholds capture early polycythemia vera cases that would otherwise be missed 1

WHO Diagnostic Algorithm

The WHO requires either pathway to establish diagnosis: 1, 4

Pathway 1 (Most Common)

• Both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) PLUS ≥1 minor criterion 1, 4
• This pathway captures >97% of polycythemia vera cases 4

Pathway 2 (JAK2-Negative or Borderline Cases)

• First major criterion (elevated hemoglobin/hematocrit) PLUS ≥2 minor criteria 1, 4

Major Diagnostic Criteria

1. Hemoglobin/hematocrit elevation as defined above 1
2. JAK2 mutation (V617F in >90-95% of cases, or exon 12 in additional 2-3%) 1, 4, 3
3. Bone marrow biopsy showing hypercellularity with trilineage growth and pleomorphic megakaryocytes 1, 4

Minor Diagnostic Criteria

• Serum erythropoietin below the reference range for normal 1, 4
• Bone marrow biopsy (when not used as major criterion) showing characteristic features 1
• Endogenous erythroid colony formation in vitro 1, 4

Initial Evaluation Strategy

When to Suspect Polycythemia Vera

Pursue diagnostic work-up if any of the following: 5

1. Hemoglobin/hematocrit >95th percentile adjusted for sex and race
2. Documented increase in hemoglobin/hematocrit above individual baseline, regardless of absolute value
3. Borderline-high hematocrit plus any PV-related feature:
   • Thrombocytosis (platelets ≥450 × 10⁹/L) 3
   • Leukocytosis (WBC ≥12 × 10⁹/L) 3
   • Microcytosis from iron deficiency 5
   • Splenomegaly 5, 3
   • Aquagenic pruritus 5, 3
   • Unusual thrombosis (Budd-Chiari syndrome, splanchnic vein thrombosis) 5, 3
   • Erythromelalgia 5, 3

First-Line Testing Algorithm

Step 1: JAK2 V617F mutation testing 2, 4

• Detects >90-95% of polycythemia vera cases 1, 3
• If positive and hemoglobin meets thresholds → proceed to confirm with ≥1 minor criterion 4

Step 2: If JAK2 V617F negative → JAK2 exon 12 testing 2, 4

• Captures additional 2-3% of cases 4
• If positive → requires ≥2 minor criteria when hemoglobin is below standard thresholds 4

Step 3: Serum erythropoietin level 5, 2

• Low or low-normal EPO supports primary polycythemia (specificity >90%) 5
• Normal EPO does not exclude polycythemia vera (sensitivity <70%) 5
• Elevated EPO suggests secondary polycythemia → pursue hypoxia-driven or tumor-related causes 5, 2

Step 4: Complete blood count with differential 2

• Assess for thrombocytosis (53% of cases) and leukocytosis (49% of cases) 3

Step 5: Iron studies (ferritin, transferrin saturation) 1, 2, 4

• Iron deficiency can mask true polycythemia by lowering hemoglobin while red cell mass remains elevated 1, 4
• Formal diagnosis requires demonstrating WHO criteria after iron replacement 1, 4

Step 6: Bone marrow biopsy (when indicated) 5, 4

• Required when JAK2-positive to document trilineage proliferation (minor criterion) 2
• Essential for JAK2-negative cases to establish diagnosis via ≥2 minor criteria 4

Critical Pitfalls and Caveats

Iron Deficiency Masking

• Iron deficiency lowers hemoglobin and can prevent patients from meeting diagnostic thresholds despite elevated red cell mass 1, 4
• In clinical practice, a working diagnosis of polycythemia vera should not be prevented by iron deficiency, even if formal WHO criteria are not yet met 1
• Repeat hemoglobin measurement after iron repletion to confirm diagnosis 1, 4

Red Cell Mass Measurement Limitations

• RCM measurement is rarely required in modern practice given availability of JAK2 testing and serum EPO 5
• Hematocrit >60% in the absence of obvious hemoconcentration almost always indicates elevated RCM, making measurement redundant 5
• Normal RCM does not exclude polycythemia vera, as some patients fall at the left tail of the distribution 5
• Only 35% of male polycythemia vera patients with hemoglobin >18.5 g/dL would be correctly identified by this threshold alone 6

Altitude Adjustment

• At high altitude (4000 m), normal male hemoglobin averages 17.3 g/dL (range 13-21 g/dL) and female hemoglobin averages 15.8 g/dL (range 12-19 g/dL) 2
• Physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 m) 2

Secondary Causes to Exclude

Before diagnosing polycythemia vera, systematically exclude: 2

• Hypoxia-driven: Obstructive sleep apnea, COPD, chronic lung disease, smoking (carbon monoxide exposure) 5, 2
• Tumor-related: Renal cell carcinoma, hepatocellular carcinoma, uterine leiomyoma, pheochromocytoma, meningioma 5, 2
• Medication-induced: Testosterone therapy, exogenous erythropoietin 5, 2
• Post-renal transplant erythrocytosis 5

Relative Polycythemia

• Gaisböck syndrome and stress polycythemia (contracted plasma volume) are poorly understood and rarely confirmed 5
• Clinically obvious causes of plasma volume depletion (severe dehydration, diuretics, burns) do not require RCM measurement 5
• Smoker's polycythemia resolves with smoking cessation 5

Management Priorities

All Patients with Polycythemia Vera

• Therapeutic phlebotomy to maintain hematocrit <45% reduces thrombotic risk 2, 3, 7
• Low-dose aspirin (81-100 mg daily) unless contraindicated 2, 3

High-Risk Patients (Age ≥60 or Prior Thrombosis)

• Cytoreductive therapy with hydroxyurea or interferon in addition to phlebotomy and aspirin 3
• Ruxolitinib for hydroxyurea-intolerant or resistant patients, particularly for pruritus control and splenomegaly reduction 3, 7

Thrombotic Risk

• Arterial thrombosis occurs in 16% at or before diagnosis; venous thrombosis in 7% (including unusual sites like splanchnic veins) 3
• Hematocrit control with ruxolitinib achieves 88-89% control by 3-6 months with low thrombotic risk 7

Long-Term Complications

• Median survival 14.1-27.6 years from diagnosis 3
• Progression to myelofibrosis in 12.7% and acute myeloid leukemia in 6.8% 3