What are the typical presenting hemoglobin concentrations in men and women with JAK2 exon‑12–positive polycythemia vera?

Hemoglobin Levels at Presentation in JAK2 Exon 12-Positive Polycythemia Vera

Patients with JAK2 exon 12 mutations typically present with hemoglobin levels that are often below the standard WHO diagnostic thresholds, with men frequently presenting below 18.5 g/dL and women below 16.5 g/dL, yet they still meet diagnostic criteria for polycythemia vera through alternative pathways. 1

Typical Presenting Hemoglobin Values

Men with JAK2 Exon 12 Mutations

• Hemoglobin concentrations at presentation tend to be lower than in JAK2 V617F-positive patients, often falling in the range that requires the alternative diagnostic pathway (≥17 g/dL with a sustained ≥2 g/dL increase from baseline). 1
• Approximately half of JAK2 exon 12-positive patients present with hemoglobin/hematocrit values below the standard diagnostic threshold of 18.5 g/dL for men. 1
• These patients commonly demonstrate isolated erythrocytosis with normal white blood cell and platelet counts at diagnosis, which correlates with their lower hemoglobin presentation. 1

Women with JAK2 Exon 12 Mutations

• Similar to men, women with exon 12 mutations frequently present with hemoglobin below 16.5 g/dL, the standard WHO threshold for women. 1
• The hemoglobin threshold of ≥15 g/dL with a sustained ≥2 g/dL increase from baseline captures many of these early/masked cases. 2, 3

Critical Diagnostic Considerations

Why Lower Hemoglobin Values Occur

• Iron deficiency is a major confounding factor that can mask true polycythemia vera by lowering hemoglobin while red cell mass remains elevated. 2, 3
• JAK2 exon 12-positive patients may present with increased red blood cell count with low mean corpuscular volume (56-60 fL), suggesting concurrent iron deficiency that suppresses hemoglobin levels. 1
• The polycythemic subset (those with elevated WBC and/or platelets) paradoxically tends to have lower hemoglobin and hematocrit compared to the isolated erythrocytosis subset. 1

Diagnostic Pathway for Lower Hemoglobin Presentations

• JAK2 exon 12 mutations fulfill the second major WHO criterion, allowing diagnosis even when hemoglobin thresholds are not met, provided sufficient minor criteria are present. 2
• When hemoglobin is below standard thresholds but exon 12 mutation is present, diagnosis requires ≥2 minor criteria (low erythropoietin, bone marrow hypercellularity with trilineage growth, or endogenous erythroid colony formation). 4, 2
• Bone marrow evaluation is particularly important in exon 12-positive cases, as approximately 21% (3 out of 14 PV cases in one series) lacked evidence of bone marrow hypercellularity despite meeting other criteria. 1

Comparison to JAK2 V617F-Positive Patients

• Initial hematologic parameters differ significantly between exon 12 and V617F-positive patients, with exon 12 patients presenting with lower hemoglobin/hematocrit values. 5
• Despite lower presenting hemoglobin, there is no difference in thrombotic development or myelofibrotic transformation between exon 12 and V617F-positive patients over time. 5
• The isolated erythrocytosis phenotype (normal WBC and platelets) is more common in exon 12-positive disease, occurring in approximately 64% (9 out of 14) of cases. 1

Clinical Pitfalls to Avoid

• Do not exclude polycythemia vera based solely on hemoglobin below 18.5 g/dL (men) or 16.5 g/dL (women) when JAK2 exon 12 mutation is present. 2, 1
• Always check iron studies (ferritin, transferrin saturation) before finalizing the diagnosis, as iron deficiency can artificially lower hemoglobin and mask the true red cell mass elevation. 2, 3
• Formal diagnosis after iron replacement is required when iron deficiency is present to demonstrate true WHO hemoglobin/hematocrit criteria. 4, 3
• Consider JAK2 exon 12 testing in all patients with isolated erythrocytosis who are V617F-negative, as exon 12 mutations account for an additional 2-3% of polycythemia vera cases. 2