MCV Trajectory in Iron-Deficient Polycythemia Vera Over Extended Follow-Up
In iron-deficient (masked) polycythemia vera, mean corpuscular volume typically continues to decline progressively over years as iron stores remain depleted from ongoing erythroid hyperplasia and therapeutic phlebotomy, creating a sustained downward trend in MCV that persists throughout the disease course.
Mechanisms Driving Progressive MCV Decline
The pathophysiology of worsening microcytosis in PV over extended periods involves two compounding mechanisms:
Continuous iron consumption by hyperproliferative erythropoiesis: The JAK2-mutated clone drives relentless red cell production that consumes available iron faster than it can be absorbed or mobilized, creating a chronic negative iron balance that worsens microcytosis over time. 1
Therapeutic phlebotomy exacerbates iron depletion: Phlebotomy—the cornerstone of PV management—removes approximately 200-250 mg of iron per unit of blood, further depleting already insufficient iron stores and driving MCV progressively lower with each treatment cycle. 1, 2
Dysregulated hepcidin response prevents iron recovery: Despite severe iron deficiency, hepcidin levels in PV patients remain inappropriately elevated relative to the degree of iron depletion, blocking intestinal iron absorption and preventing normalization of iron stores that would be required to reverse microcytosis. 1
Clinical Evidence for Progressive MCV Decline
In a cohort of 23 patients with masked PV followed for a median of 58.2 months (range 27-279 months), microcytosis persisted throughout follow-up despite cytoreductive therapy, demonstrating that MCV remains suppressed over multi-year observation periods in iron-deficient PV. 3
The combination of elevated red blood cell count (present in 73.9% of masked PV cases) with persistently low MCV creates a characteristic pattern where total red cell mass remains elevated but individual cells become progressively smaller as iron deficiency worsens. 3, 4
Iron deficiency is present in virtually all PV patients at presentation and/or during disease course, establishing that the substrate for progressive microcytosis exists throughout the natural history of the disease. 1
Practical Implications for Long-Term Monitoring
Key monitoring parameters over 6+ years:
Serial MCV measurements every 3-6 months will typically show either stable microcytosis (if iron stores remain depleted at a steady state) or progressive decline (if phlebotomy frequency increases or iron absorption remains blocked). 5
Red blood cell count often rises paradoxically as MCV falls, because the bone marrow compensates for smaller cells by producing more of them—this creates the diagnostic signature of masked PV with high RBC count, low MCV, and deceptively normal hemoglobin/hematocrit. 6, 3, 4
Ferritin levels typically remain suppressed (<30 μg/L in the absence of inflammation, or <100 μg/L with inflammation) throughout the disease course in patients receiving regular phlebotomy, confirming ongoing iron deficiency that sustains microcytosis. 7
Critical Pitfall to Avoid
Do not interpret stable or worsening MCV over years as evidence against PV—this pattern is actually characteristic of iron-deficient PV and reflects the pathophysiological disconnect between iron metabolism and clonal erythropoiesis. 3, 1 The downward MCV trend, when accompanied by elevated RBC count, positive JAK2 V617F mutation (present in >95% of cases), and PV-compatible bone marrow findings, confirms rather than excludes the diagnosis. 5, 3
Expected Natural History
Over a 6+ year period in untreated or phlebotomy-managed iron-deficient PV:
MCV will either remain stably low (typically 70-80 fL) or continue to decline further if phlebotomy intensity increases. 3, 4
Hemoglobin/hematocrit may remain deceptively normal or even decline despite ongoing clonal erythropoiesis, because MCV reduction counterbalances the increased RBC count. 3, 8, 2
Only with iron repletion (which is generally avoided in PV management due to thrombotic risk) would MCV be expected to rise—but this would unmask the true polycythemia by allowing hemoglobin/hematocrit to increase. 1, 2