In an adult patient with unexplained microcytosis, thrombocytosis, or leukocytosis, what is the relationship between the red blood cell (RBC) count and the erythrocyte sedimentation rate (ESR) in masked polycythemia vera (PV)?

Relationship Between RBC Count and ESR in Masked Polycythemia Vera

In masked polycythemia vera, the RBC count is typically elevated (often >5.5 × 10⁹/L) while the ESR is characteristically suppressed (<2 mm/hour), creating a diagnostic signature that can identify PV even when hemoglobin and hematocrit appear deceptively normal due to concurrent iron deficiency or plasma volume expansion. 1

The Diagnostic Challenge of Masked PV

Masked PV occurs when iron deficiency or increased plasma volume conceals the true red cell mass elevation. In these cases:

• Hemoglobin and hematocrit may fall within or just above normal ranges (men 16.0–18.4 g/dL, women 15.0–16.4 g/dL) despite underlying clonal erythrocytosis, because microcytosis from iron depletion reduces the MCV component of the hematocrit calculation (HCT = RBC × MCV). 2

• Iron deficiency arises from two mechanisms: rapid consumption by the proliferating erythroid clone and therapeutic phlebotomies, both depleting iron stores and creating microcytosis (MCV <80 fL) with elevated RDW (>16–17%). 2

• Plasma volume expansion can increase by +36% in masked PV versus only +9.5% in overt PV, further diluting the measured hemoglobin and hematocrit while the absolute red cell mass remains pathologically elevated. 3

The RBC-ESR Diagnostic Signature

Elevated RBC Count

• The absolute RBC count remains elevated in masked PV (frequently >5.5 × 10⁹/L) because it directly reflects the total number of circulating erythrocytes, independent of cell size. 1, 4

• RBC count is more reliable than hematocrit when microcytosis is present, as it is not mathematically dependent on MCV and therefore not suppressed by iron-deficient small red cells. 1

• 73.9% of masked PV patients demonstrate elevated RBC counts at diagnosis despite normal hemoglobin/hematocrit, making this a critical diagnostic clue. 4

Suppressed ESR

• ESR <2 mm/hour has 98% specificity for PV diagnosis, though sensitivity is only 37%, meaning a very low ESR strongly suggests PV when present. 1

• The mechanism of ESR suppression involves the hypercoagulable state: the elevated RBC mass increases blood viscosity and alters the plasma protein milieu, preventing the normal rouleaux formation required for red cell sedimentation. 1

• ESR integrates both the elevated RBC count and the prothrombotic physiology of PV, making it a functional marker of the disease's pathophysiology rather than just a cell count. 1

Clinical Algorithm for Suspected Masked PV

When evaluating unexplained microcytosis, thrombocytosis, or leukocytosis with borderline hemoglobin:

Step 1: Identify High-Risk Features

• Microcytosis (MCV <80 fL) plus elevated RDW (>16–17%) with any of the following mandates JAK2 testing regardless of hemoglobin level: 2
  • Thrombocytosis (platelets >400 × 10⁹/L)
  • Leukocytosis (WBC >15 × 10⁹/L)
  • Splenomegaly
  • Aquagenic pruritus
  • Portal vein thrombosis or atypical thrombotic events

Step 2: Assess the RBC-ESR Pattern

• Order RBC count and ESR alongside standard CBC with indices. 1

• Elevated RBC count (>5.5 × 10⁹/L in women, >6.0 × 10⁹/L in men) combined with ESR <2 mm/hour creates a diagnostic pattern with 98% specificity for PV. 1

• This combination can substitute for hemoglobin/hematocrit in identifying masked PV when iron deficiency obscures the diagnosis. 1

Step 3: Confirm with Molecular Testing

• JAK2 V617F mutation testing is present in >95% of PV cases and provides definitive molecular confirmation. 2, 4

• 100% of masked PV patients with adequate testing demonstrate JAK2 V617F positivity in research cohorts, making this the gold standard. 4

• Serum erythropoietin <2.9 mU/mL has >90% specificity for PV and should be measured concurrently. 2

Step 4: Evaluate Iron Status

• Measure serum ferritin, iron, and transferrin saturation to quantify iron deficiency that may be masking the diagnosis. 2

• Do not delay PV diagnosis while correcting iron deficiency—the working diagnosis should be established first, with definitive confirmation following iron repletion if needed. 2

Critical Pitfalls to Avoid

• Never exclude PV based solely on normal hemoglobin/hematocrit when microcytosis and other PV-related features are present—iron deficiency can completely mask the expected hemoglobin elevation. 2, 4

• Do not rely on MCV alone to screen for iron deficiency in erythrocytosis—serum ferritin and transferrin saturation are required for accurate diagnosis. 5

• Avoid aggressive phlebotomy in suspected masked PV before confirming iron status—this worsens iron depletion, reduces oxygen-carrying capacity, and paradoxically increases stroke risk. 2, 5

• Do not overlook the diagnostic value of ESR—while often dismissed as nonspecific, ESR <2 mm/hour in the context of elevated RBC count is highly specific for PV. 1

Prognosis and Management Implications

• Masked PV patients achieve complete hematological response more frequently (79% vs 58%) and respond faster to hydroxycarbamide than overt PV, requiring fewer phlebotomies. 6

• Overall survival, thrombosis rates, and transformation probability are superimposable between masked and overt PV when appropriately diagnosed and treated. 6

• The key to favorable outcomes is early recognition—the RBC-ESR pattern provides a diagnostic window when traditional hemoglobin/hematocrit criteria fail. 1, 6