Will the findings of long‑standing polycythemia vera masked by chronic iron deficiency be evident on a peripheral blood smear?

Will Long-Standing Polycythemia Vera Masked by Chronic Iron Deficiency Show on Peripheral Blood Smear?

The peripheral blood smear in iron-deficient polycythemia vera will show microcytic red cells with anisocytosis and poikilocytosis, but will NOT show the elevated hemoglobin/hematocrit that typically defines PV—creating a diagnostic trap where the smear appears deceptively normal or even suggests simple iron deficiency. 1, 2

Key Morphologic Features You Will See

Red Cell Morphology:

• Microcytosis (low MCV) is the dominant finding, reflecting iron-depleted erythropoiesis despite the underlying myeloproliferative drive 1, 2
• Anisocytosis (variation in red cell size) and poikilocytosis (variation in red cell shape) are typically present but non-specific 3
• Hypochromia (low MCHC <32%) signals the iron deficiency that is masking the true red cell mass elevation 4
• The red blood cell COUNT may be paradoxically elevated (seen in 73.9% of masked PV cases), even when hemoglobin and hematocrit appear normal or only borderline-high 1

White Cells and Platelets:

• Leukocytosis is frequently present (approximately 50% of PV cases show elevated white count at presentation) 5
• Thrombocytosis is common (approximately 50% of PV cases) and serves as a critical clue when hemoglobin is misleadingly normal 5
• The combination of elevated RBC count + thrombocytosis + leukocytosis strongly suggests masked PV even when Hgb/Hct are not elevated 5, 1

The Diagnostic Pitfall: Why the Smear Misleads

Iron deficiency suppresses hemoglobin synthesis but does NOT suppress the JAK2-driven clonal proliferation of red cell precursors. 1, 2, 6 The result is:

• Normal or only borderline-elevated hemoglobin/hematocrit that fails to meet WHO diagnostic thresholds (Hgb >16.5 g/dL women, >18.5 g/dL men) 1, 2
• Elevated RBC count (the bone marrow is still churning out red cells, they're just smaller and iron-poor) 1
• Microcytic indices that mimic simple iron deficiency anemia 1, 2

In one study of 23 patients with unclassifiable myeloproliferative disease and microcytosis, 100% had JAK2 V617F mutations and 83.3% had PV-compatible bone marrow findings, confirming these were masked PV cases, not essential thrombocythemia or primary myelofibrosis 1.

Critical Clinical Clues Beyond the Smear

When you see microcytosis with borderline or normal Hgb/Hct, immediately look for:

• Splenomegaly (present in a substantial proportion of PV patients due to extramedullary hematopoiesis) 5, 2
• Aquagenic pruritus (low MCV is a strong surrogate marker for this PV-specific symptom) 5, 7
• Thrombocytosis and/or leukocytosis (present in ~50% of PV cases and should trigger immediate workup) 5, 1
• Low serum erythropoietin (<2.9 mU/mL, with >90% specificity for PV) 5, 4, 2
• Serum ferritin, iron, and transferrin saturation showing iron deficiency (virtually all PV patients are iron deficient at presentation or during disease course) 5, 6

What Happens When You Correct the Iron Deficiency

Iron supplementation unmasks the underlying polycythemia. 2, 8 In documented cases:

• Hemoglobin and hematocrit rise to diagnostic levels within 2-10 days of starting iron therapy 7
• The "covert erythrocytosis" becomes overt, confirming the diagnosis 2
• However, indiscriminate iron supplementation is NOT recommended because it can drive hemoglobin to dangerously high levels, increasing thrombotic risk 7

Definitive Diagnostic Algorithm When Smear Shows Microcytosis

Step	Action	Rationale
1	JAK2 V617F mutation testing	Present in >95% of PV cases; 100% positive in masked PV with microcytosis [5,1]
2	Serum EPO level	Low EPO (<2.9 mU/mL) has >90% specificity for PV [5,4]
3	Iron studies (ferritin, iron, transferrin saturation)	Quantifies iron deficiency masking the diagnosis [5,2]
4	Bone marrow biopsy	Shows hypercellularity with trilineage myeloproliferation in 83.3% of masked PV cases [1]

Common Pitfalls to Avoid

• Do not dismiss the possibility of PV solely because hemoglobin and hematocrit are normal or only mildly elevated when microcytosis is present 5, 1, 2
• Do not assume the smear showing microcytosis represents simple iron deficiency without checking for JAK2 mutation, low EPO, splenomegaly, thrombocytosis, or leukocytosis 5, 1
• Do not give iron supplementation without close hemoglobin monitoring in suspected masked PV, as rapid increases in red cell mass can occur and worsen thrombotic risk 5, 7
• In fertile-age women with menometrorrhagia, maintain high suspicion for masked PV when iron deficiency coexists with low EPO or splenomegaly, even with normal Hgb/Hct 2