What are the diagnostic criteria for polycythemia?

Diagnostic Criteria for Polycythemia

The diagnosis of polycythemia vera (PV) requires meeting specific criteria that include laboratory evidence of increased red blood cells and JAK2 mutation testing, with additional minor criteria to confirm the diagnosis when needed. 1, 2

World Health Organization (WHO) Diagnostic Criteria

The WHO criteria for diagnosing polycythemia vera have evolved over time, with the most recent updates lowering the hemoglobin thresholds to better capture cases of "masked PV." 3, 4

Major Criteria

1. Elevated red cell parameters:

   • Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, OR
   • Hematocrit >49% in men or >48% in women, OR
   • Increased red cell mass (>25% above mean normal predicted value)
   • Alternatively: A documented sustained increase in hemoglobin >2 g/dL from baseline that cannot be explained by correction of iron deficiency

2. Presence of JAK2V617F or functionally similar JAK2 mutation (e.g., exon 12 mutation)

   • JAK2V617F mutation is present in >95% of PV cases
   • JAK2 exon 12 mutations account for most remaining cases

Minor Criteria

1. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) with prominent erythroid and megakaryocytic proliferation
2. Serum erythropoietin level below the reference range for normal
3. Endogenous erythroid colony formation in vitro

Diagnostic Requirements

• Diagnosis requires either:
  • Both major criteria AND at least one minor criterion, OR
  • First major criterion AND at least two minor criteria 1

Distinguishing Primary from Secondary Polycythemia

Secondary polycythemia must be excluded when diagnosing PV:

Secondary Causes of Polycythemia

• Hypoxia-driven causes (initially elevated EPO levels):

  • Chronic pulmonary disease
  • Right-to-left cardiopulmonary shunts
  • High-altitude residence
  • Carbon monoxide poisoning
  • Smoker's polycythemia
  • Hypoventilation syndromes

• Non-hypoxia-driven causes (typically elevated EPO levels):

  • Malignant or benign tumors producing EPO
  • Congenital processes
  • Exogenous EPO administration
  • Androgen preparations 2

Diagnostic Approach

1. Initial laboratory evaluation:

   • Complete blood count with attention to hemoglobin, hematocrit, MCV, and platelet count
   • Peripheral blood smear examination
   • Serum erythropoietin level (low in PV, normal/elevated in secondary causes)
   • JAK2V617F mutation testing (sensitivity >95% for PV)
   • If JAK2V617F negative but strong clinical suspicion, test for JAK2 exon 12 mutations

2. Additional testing to exclude secondary causes:

   • Arterial oxygen saturation
   • Abdominal imaging to assess spleen size
   • Bone marrow biopsy and aspiration (shows hypercellularity with trilineage growth)

Clinical Pitfalls to Avoid

• Missing "masked PV": Patients with hemoglobin/hematocrit values below traditional thresholds but with JAK2 mutations may have worse outcomes due to delayed diagnosis and treatment 4, 5

• Overlooking JAK2-negative PV: While rare (<5% of cases), these patients require more extensive testing, including bone marrow biopsy and erythropoietin levels 6

• Confusing relative erythrocytosis with absolute erythrocytosis: Plasma volume contraction can cause elevated hemoglobin/hematocrit without true increase in red cell mass

• Neglecting to rule out secondary causes: Thorough evaluation for hypoxic and non-hypoxic causes of secondary polycythemia is essential before diagnosing PV 2

• Relying solely on hemoglobin/hematocrit without JAK2 testing: The combination of both parameters significantly increases diagnostic accuracy 1, 3

The diagnostic criteria have evolved to better capture all cases of PV, including those with lower hemoglobin/hematocrit values that were previously missed, thereby improving early detection and management of this myeloproliferative neoplasm.