In masked polycythemia vera, does the mean corpuscular volume (MCV) tend to decline progressively over time?

MCV Downward Trend in Masked Polycythemia Vera

Yes, in masked polycythemia vera, the mean corpuscular volume (MCV) tends to decline progressively over time as iron deficiency worsens from ongoing erythroid proliferation and therapeutic phlebotomies, creating a characteristic downward trend that can further obscure the diagnosis.

Mechanism of Progressive MCV Decline

The MCV decline in masked PV results from two compounding mechanisms that worsen over time 1:

• Increased iron utilization by the proliferating erythroid compartment continuously depletes iron stores as the clonal JAK2-mutated cells drive autonomous red cell production 1
• Repeated therapeutic phlebotomies further accelerate iron depletion, creating a vicious cycle where each phlebotomy removes iron-replete cells and forces production of increasingly microcytic cells 1

This dual process creates a progressive downward trajectory rather than a stable microcytosis, distinguishing masked PV from static causes of microcytosis like thalassemia trait 2.

Clinical Implications of Progressive Microcytosis

Diagnostic Masking Worsens Over Time

• As MCV falls progressively, the total red cell mass becomes increasingly suppressed despite ongoing clonal proliferation, causing hemoglobin and hematocrit to remain deceptively normal or only borderline elevated 1, 2
• This creates a moving target where the diagnostic window narrows over time—patients may initially have borderline-high hemoglobin that then "normalizes" as microcytosis worsens 1, 3
• The phenomenon explains why some PV patients present with completely normal hemoglobin (14.1 g/dL in one documented case) despite having hypercellular bone marrow with trilineage proliferation 3

Red Blood Cell Count Remains Elevated

• Despite falling MCV, the red blood cell count typically remains elevated (>73% of masked PV cases show elevated RBC count) because the clonal proliferation continues unabated 2, 4
• The mathematical relationship HCT = RBC × MCV means that as MCV falls, hematocrit can normalize even when RBC count stays high 4
• This dissociation between RBC count and hematocrit/hemoglobin becomes more pronounced over time as iron deficiency progresses 4

Diagnostic Approach When MCV Decline Is Suspected

Key Laboratory Pattern

When you observe a downward MCV trend in a patient with borderline or normal hemoglobin, immediately evaluate for 1, 2:

• JAK2 V617F mutation (present in >95% of PV; 100% positive in one masked PV cohort) 1, 2
• Serum erythropoietin level (typically <2.9 mU/mL in PV, with >90% specificity) 1
• Iron studies (ferritin, iron, transferrin saturation) to quantify the degree of iron deficiency 1
• Red blood cell count (often elevated despite normal hematocrit) 2, 4

Additional Supportive Findings

Look for PV-related features that persist despite masked hemoglobin 1, 2:

• Thrombocytosis or leukocytosis (present in ~50% of PV cases at diagnosis) 1
• Splenomegaly (from extramedullary hematopoiesis) 1
• Aquagenic pruritus (strongly correlated with low MCV in PV) 1
• Bone marrow hypercellularity with trilineage proliferation (83.3% of masked PV cases show PV-compatible marrow) 2

Novel Diagnostic Marker

• Erythrocyte sedimentation rate (ESR) <2 mm has 98% specificity for PV diagnosis, as the hypercoagulable state from elevated RBC count suppresses ESR even when hemoglobin appears normal 4
• The combination of elevated RBC count + ESR <2 mm + declining MCV is highly specific for masked PV 4

Critical Pitfalls to Avoid

Do Not Assume Stable Hemoglobin Excludes PV

• Hemoglobin stability over years does not rule out masked PV when progressive microcytosis is present 1, 2
• In one cohort, 3 masked PV patients developed overt hemoglobin elevation during 58-month follow-up despite cytoreductive treatment, proving the diagnosis was present all along 2

Do Not Rely on Hemoglobin/Hematocrit Alone

• The 2016 WHO criteria lowered diagnostic thresholds specifically because masked PV was being missed, leading to worse outcomes from delayed diagnosis and undertreatment 5
• Iron deficiency can completely normalize hemoglobin in true PV patients, making hemoglobin an unreliable marker when microcytosis is present 1, 2, 3

Do Not Delay JAK2 Testing

• When you observe borderline hemoglobin + declining MCV + any PV-related feature (thrombocytosis, leukocytosis, splenomegaly, unusual thrombosis), order JAK2 testing immediately rather than waiting for hemoglobin to rise 1, 2, 3
• The presence of JAK2 V617F with microcytosis and normal/borderline hemoglobin is diagnostic of masked PV and requires full PV management including thrombotic risk stratification 5, 2

Prognosis and Management Implications

• Masked PV patients have worse outcomes than overt PV, likely from missed or delayed diagnosis and lower treatment intensity 5
• The progressive nature of MCV decline means the diagnostic window may close entirely if iron deficiency becomes severe, emphasizing the need for early recognition 1, 2
• Once diagnosed, these patients require the same thrombotic risk stratification (age >60 or prior thrombosis = high risk) and cytoreductive therapy as overt PV 5