In an untreated adult with iron‑deficient polycythemia vera, does the mean corpuscular volume continue to decline over a period of six or more years?

MCV Trajectory in Untreated Iron-Deficient Polycythemia Vera

Yes, mean corpuscular volume (MCV) continues to decline progressively in untreated, iron-deficient polycythemia vera (PV) patients over extended periods, as the combination of ongoing clonal erythroid hyperplasia and persistent iron deficiency creates a self-perpetuating cycle of worsening microcytosis. 1

Pathophysiology of Progressive MCV Decline

The mechanism driving continued MCV reduction in untreated PV involves several interconnected processes:

• Clonal erythroid hyperplasia in PV produces massive iron consumption that cannot be compensated by physiologic iron absorption, leading to progressive depletion of iron stores over time. 1

• Virtually all PV patients are iron deficient at presentation and/or during disease course, with this iron deficiency representing a core pathobiological feature rather than an incidental finding. 1

• Hepcidin remains insufficiently suppressed relative to the degree of iron deficiency in PV patients, suggesting fundamental dysregulation of iron metabolism that prevents recovery from iron-deficient states. 1

• The erythroferrone response to erythroid hyperplasia, which should suppress hepcidin and mobilize iron stores, is counteracted by inflammatory signaling in PV, though inflammation alone does not fully explain the persistent iron deficiency. 1

Clinical Evidence for Progressive Microcytosis

Research demonstrates clear associations between iron deficiency severity and red cell parameters in PV:

• Higher hematocrit-to-hemoglobin ratios (HHR) in PV patients correlate with lower MCV, lower mean corpuscular hemoglobin, lower ferritin levels, and higher red blood cell distribution width, indicating that progressive iron deficiency produces increasingly severe microcytosis. 2

• PV patients demonstrate significantly lower MCV relative to serum ferritin ratios compared to other myeloproliferative neoplasm suspects, reflecting the unique iron metabolism dysregulation in this disease. 3

• Iron deficiency in PV impacts the validity of hematocrit measurements because hematocrit equals red blood cell count multiplied by MCV, meaning progressive microcytosis can mask the true erythrocyte mass expansion. 3

Long-Term Natural History Without Treatment

The untreated state perpetuates and worsens microcytosis through multiple mechanisms:

• Without phlebotomy or cytoreductive therapy, the autonomous JAK2-driven erythropoiesis continues unabated, consuming iron stores at rates exceeding physiologic replacement capacity over years. 1

• Specific JAK2 mutations (V617F and exon 12) may influence iron metabolism through nuanced alterations in erythropoietin receptor signaling, potentially explaining why iron deficiency persists despite physiologic compensatory mechanisms. 1

• The combination of increased erythroferrone from erythroid hyperplasia and decreased circulating iron should theoretically suppress hepcidin and restore iron balance, but this homeostatic response fails in PV, allowing progressive iron depletion. 1

Clinical Implications Over Six-Plus Years

The progressive nature of MCV decline in untreated PV carries important consequences:

• Higher HHR (reflecting more severe microcytosis and iron deficiency) associates independently with shorter time to thrombosis and shorter overall survival in PV patients, suggesting that progressive microcytosis marks more aggressive disease biology. 2

• Iron deficiency produces non-hematological symptoms including fatigue, lethargy, and impaired concentration that diminish quality of life, and these symptoms worsen as iron deficiency becomes more severe over time. 4, 1

• Recent correlation studies show that active pruritus in PV correlates significantly with low MCV, implying that progressive microcytosis may worsen this debilitating symptom over extended periods. 5

Critical Distinction from Treated PV

The natural history differs fundamentally from treated disease:

• Phlebotomy therapy, while reducing thrombotic risk by lowering hematocrit, actively exacerbates iron deficiency and accelerates MCV decline, creating a different trajectory than untreated disease. 4, 1

• Cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients, suggesting that the iron-deficient microcytic state interacts with treatment response. 1

• Even after several months of iron deficiency in treated PV, whole blood viscosity does not increase despite progressive microcytosis, indicating that MCV decline itself does not necessarily worsen rheological parameters. 6

Monitoring Considerations

For untreated iron-deficient PV patients followed longitudinally:

• Serial MCV measurements should be interpreted alongside red blood cell count, as microcytosis can mask true erythrocyte mass when relying on hematocrit alone for disease assessment. 3

• RDW typically remains elevated (>14-16%) in iron-deficient PV and may increase further as microcytosis progresses, reflecting increasing heterogeneity in red cell size. 7, 2

• Ferritin levels below 30 μg/L confirm iron deficiency in non-inflammatory states, though levels up to 100 μg/L may still indicate deficiency when concurrent inflammation is present in PV. 7