Peripheral Blood Smear Findings in JAK2 Exon 12–Mutated Masked Polycythemia Vera
In JAK2 exon 12–mutated masked polycythemia vera, the peripheral blood smear typically shows an elevated red blood cell count with microcytosis (low MCV) when iron deficiency is present, often accompanied by relatively normal or only mildly elevated hemoglobin/hematocrit levels that mask the true erythrocytosis. 1, 2
Key Peripheral Blood Smear Characteristics
Red Blood Cell Findings
Elevated absolute RBC count is the hallmark finding, present in approximately 74% of masked PV cases despite normal or borderline hemoglobin levels. 2
Microcytosis (MCV < 80 fL) is frequently observed when iron deficiency coexists, which is the most common cause of the "masked" presentation—the low MCV reduces individual red cell size, preventing hemoglobin/hematocrit from reaching diagnostic thresholds even though total red cell mass is elevated. 1, 2
Hypochromic red cells may be present when iron deficiency is the masking factor, reflecting reduced hemoglobin content per cell. 2
High red cell distribution width (RDW) with normal or low MCV suggests coexisting iron deficiency with erythrocytosis, a critical clue to masked PV. 3
White Blood Cell and Platelet Findings
Lower leukocyte counts compared to JAK2 V617F–positive PV are characteristic of exon 12 mutations; approximately two-thirds of exon 12 patients present with isolated erythrocytosis without significant leukocytosis. 4, 5
Lower platelet counts are typical in exon 12–mutated PV compared to V617F–positive disease, though platelet counts may still be elevated above normal in some cases. 4, 5
Normal or only mildly elevated platelet and white blood cell counts distinguish exon 12 PV from the classic V617F phenotype, which more commonly shows thrombocytosis and leukocytosis. 4
Clinical Context and Diagnostic Pitfalls
Why the Smear Appears "Masked"
Iron deficiency is the most common masking factor, present in approximately 68% of unclassifiable myeloproliferative disease cases with microcytosis; the microcytic red cells prevent hemoglobin from reaching the WHO major criterion threshold (≥18.5 g/dL in men, ≥16.5 g/dL in women). 1, 2
Hemoglobin and hematocrit may be normal or only mildly elevated (e.g., 16 g/dL in men) despite true polycythemia, because the reduced MCV mathematically lowers these calculated values even when red cell mass is increased. 1, 2
Critical Diagnostic Clues on Smear Review
Elevated RBC count (often >5.5 × 10¹²/L) with microcytosis should immediately raise suspicion for masked PV, especially when accompanied by low serum erythropoietin. 2
Absence of significant thrombocytosis or leukocytosis in the setting of erythrocytosis favors JAK2 exon 12 mutation over V617F mutation. 4, 5
Pleomorphic megakaryocytes may be noted on smear if circulating megakaryocyte fragments are present, though bone marrow biopsy is required to fully assess megakaryocyte morphology (a WHO minor criterion). 1
Diagnostic Algorithm for Suspected Masked PV
Step 1: Recognize the Pattern
When you see elevated RBC count + microcytosis + normal/borderline hemoglobin, immediately order serum ferritin and transferrin saturation to confirm iron deficiency. 1, 3
If transferrin saturation is <20% or ferritin is low, iron deficiency is confirmed and is masking the true erythrocytosis. 1
Step 2: Molecular Testing Sequence
Order JAK2 V617F testing first; if negative, immediately proceed to JAK2 exon 12 mutation analysis, which accounts for 2–3% of PV cases and is mandatory for diagnosis. 1, 4
JAK2 exon 12 mutations fulfill the second WHO major criterion and, when combined with elevated RBC count and at least one minor criterion (e.g., low EPO), confirm PV in >97% of cases. 1
Step 3: Confirm Diagnosis After Iron Repletion
Formal PV diagnosis should be postponed until after iron replacement therapy, allowing hemoglobin/hematocrit to reach WHO diagnostic levels and confirming true erythrocytosis. 1
After iron repletion, repeat CBC to document that hemoglobin rises to meet WHO major criterion thresholds, unmasking the underlying PV. 1
Evidence Strength and Guideline Consensus
The WHO 2016 criteria explicitly recognize that iron deficiency can mask PV and require demonstration of WHO criteria after iron replacement for formal diagnosis. 1
A 2019 Turkish study demonstrated that 100% of unclassifiable myeloproliferative disease cases with microcytosis and JAK2 positivity were actually masked PV, with 83.3% showing PV-compatible bone marrow findings. 2
The 2011 European collaborative study established that JAK2 exon 12–mutated PV presents with significantly higher hemoglobin but lower platelet and leukocyte counts compared to V617F-positive disease, creating a distinct smear phenotype. 4
Common Pitfalls to Avoid
Never diagnose PV based solely on low EPO and borderline hemoglobin; this contravenes WHO criteria and risks missing secondary causes of erythrocytosis. 1
Do not overlook iron deficiency in the setting of erythrocytosis—iron-deficient red cells have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk. 1, 3
Always test for JAK2 exon 12 mutations when V617F is negative, especially in patients with isolated erythrocytosis and microcytosis; the frequency may be as high as 12% in some populations. 5
Avoid aggressive phlebotomy before correcting iron deficiency, as this further depletes iron stores and worsens tissue oxygen delivery. 1, 3