Is iron‑deficient polycythemia vera more common in the JAK2 V617F mutation subtype?

Is Iron Deficiency More Common in JAK2 V617F-Positive Polycythemia Vera?

Iron deficiency is not inherently more common in JAK2 V617F-positive PV compared to other PV subtypes, but it is a frequent complication across all PV patients due to therapeutic phlebotomy and the underlying disease biology—the key clinical issue is that iron deficiency can mask the diagnosis of PV by lowering hemoglobin below diagnostic thresholds while the red cell count remains elevated. 1

The Diagnostic Masking Problem

Iron deficiency creates a critical diagnostic pitfall in PV regardless of mutation subtype:

• When iron deficiency coexists with PV, measured hemoglobin may fall below WHO diagnostic cut-offs (≥18.5 g/dL in men, ≥16.5 g/dL in women) even though red cell mass remains pathologically elevated. 1
• The red blood cell count stays elevated and mean corpuscular volume becomes reduced (microcytosis), creating an "unclassifiable" myeloproliferative picture. 1
• In one study of 23 cases with unclassifiable non-CML myeloproliferative disease with microcytosis, iron deficiency was the apparent cause in 15 cases (68%), and these patients showed 100% JAK2 V617F positivity (20/20), 73.9% elevated RBC counts, and 83.3% PV-compatible bone marrow findings—confirming they were masked PV cases. 1

JAK2 V617F Prevalence and Iron Status

The JAK2 V617F mutation is present in >95% of all PV patients when sensitive allele-specific PCR is used, making it the predominant mutation across the entire PV population. 2, 3

There is no evidence that JAK2 V617F-positive patients develop iron deficiency at higher rates than JAK2 exon 12-mutated patients:

• JAK2 exon 12 mutations account for only 2-4% of total PV cases and represent a rare diagnostic subset. 3, 2
• Both mutation subtypes drive the same erythropoietin-independent erythroid proliferation and require identical therapeutic phlebotomy regimens (target hematocrit <45%), which depletes iron stores over time. 3, 4
• The WHO diagnostic criteria acknowledge that iron deficiency can complicate diagnosis by requiring "failure of iron replacement therapy to increase hemoglobin to the PV range in the presence of decreased serum ferritin" as part of excluding PV when evaluating essential thrombocythemia. 5

Clinical Algorithm for Iron-Deficient Presentations

When evaluating a patient with microcytosis, thrombocytosis, and normal/borderline hemoglobin:

1. Check JAK2 V617F mutation status first, as it is present in >95% of PV cases. 3, 2
2. If JAK2 V617F is positive, assess iron studies (ferritin, serum iron, TIBC) and red blood cell count. 1
3. An elevated RBC count (>6.0 × 10¹²/L in men, >5.5 × 10¹²/L in women) with microcytosis and low ferritin strongly suggests iron-deficient PV rather than essential thrombocythemia. 1
4. Bone marrow biopsy showing panmyelosis with trilineage growth (erythroid, megakaryocytic, and granulocytic proliferation) confirms PV even when hemoglobin is not elevated. 5, 1
5. If JAK2 V617F is negative but clinical suspicion remains high, order JAK2 exon 12 mutation analysis on purified granulocyte DNA to detect the 2-4% of PV cases with this rarer mutation. 3, 2

Key Pitfall to Avoid

Do not assume that normal hemoglobin excludes PV in a patient with JAK2 V617F mutation, microcytosis, and iron deficiency—the red cell mass is likely elevated but masked by iron-restricted erythropoiesis. 1 These patients require bone marrow evaluation and should be managed as PV with phlebotomy, low-dose aspirin, and cytoreductive therapy based on risk stratification (age ≥60 years or prior thrombosis = high risk). 4, 3