In masked polycythemia vera, what hemoglobin, hematocrit (packed cell volume), and red blood cell count values are expected in men and women?

Masked Polycythemia Vera: Expected Hemoglobin, Hematocrit, and RBC Values

In masked polycythemia vera, hemoglobin remains below the standard WHO diagnostic thresholds (men: 16.0–18.4 g/dL, women: 15.0–16.4 g/dL) while hematocrit typically ranges 48–52% in men and 47–48% in women, yet the underlying red cell mass is pathologically elevated and masked by concurrent plasma volume expansion. 1

Defining Masked PV: The Core Diagnostic Challenge

Masked PV represents a subset of true polycythemia vera where increased plasma volume conceals the elevated red cell mass, resulting in deceptively normal or borderline hemoglobin and hematocrit values that fall below standard diagnostic cutoffs. 2 This phenomenon occurs in approximately 15–35% of all PV cases, depending on whether BCSH (hematocrit-based) or WHO (hemoglobin-based) criteria are applied. 1

Expected Laboratory Values in Masked PV

Men:

• Hemoglobin: 16.0–18.4 g/dL (below the WHO threshold of 18.5 g/dL) 1
• Hematocrit: 48–52% (may be below the 52% threshold) 3, 1
• RBC count: Elevated but specific values not defined in guidelines 1

Women:

• Hemoglobin: 15.0–16.4 g/dL (below the WHO threshold of 16.5 g/dL) 1
• Hematocrit: 47–49% (may be below the 49% threshold) 3, 1
• RBC count: Elevated but specific values not defined in guidelines 1

The critical distinction is that plasma volume is increased by an average of +36.3% in masked PV compared to only +9.5% in overt PV, effectively diluting the measured hemoglobin and hematocrit despite a truly elevated red cell mass. 2

Clinical Features That Should Trigger Workup Despite Normal Hemoglobin

The diagnosis of masked PV should never be excluded based solely on borderline or normal hemoglobin/hematocrit values when the following features are present: 4, 2

• Thrombocytosis (platelet count >400 × 10⁹/L) — more common in masked PV than overt PV 1
• Leukocytosis (WBC >15 × 10⁹/L) — associated with worse survival 1
• Splenomegaly — present in substantial proportion of cases 2
• Portal vein thrombosis or other unusual thrombotic sites 2
• Aquagenic pruritus — characteristic symptom 4
• Microcytosis (MCV <80 fL) with elevated RDW (>16–17%) — indicates iron-deficient PV where iron depletion further masks the true red cell mass 4

Iron Deficiency: The Double Masking Effect

Iron deficiency creates a "double masking" phenomenon in PV by both suppressing hemoglobin production and causing microcytosis, making the diagnosis even more elusive. 4 This occurs through two mechanisms:

1. Rapid iron consumption by the proliferating erythroid clone 4
2. Therapeutic phlebotomies that deplete iron stores 4

When iron deficiency develops in masked PV, expect:

• RDW >16–17% (reflecting mixed cell populations) 4
• MCV <80 fL (microcytosis) 4
• Normal or borderline hemoglobin despite underlying clonal erythrocytosis 4

Critical diagnostic rule: The combination of microcytosis + thrombocytosis, leukocytosis, splenomegaly, or aquagenic pruritus mandates JAK2 mutation testing regardless of hemoglobin level. 4

Diagnostic Algorithm for Suspected Masked PV

Step 1: Recognize High-Risk Clinical Scenarios

Order JAK2 V617F mutation testing (detects >95% of PV) and serum erythropoietin when: 3, 4

• Borderline hemoglobin (men 16.0–18.4 g/dL, women 15.0–16.4 g/dL) plus thrombocytosis, leukocytosis, or splenomegaly 1
• Portal vein thrombosis or other unusual thrombotic sites 2
• Microcytosis (MCV <80 fL) with elevated RDW (>16%) and any myeloproliferative features 4
• Isolated splenomegaly with borderline blood counts 2

Step 2: Interpret Erythropoietin Levels

• EPO below reference range → Specificity >90% for PV; proceed with bone marrow biopsy 3
• Normal EPO → Does not exclude PV (sensitivity only 64–70%); still perform JAK2 testing 3
• Elevated EPO → Suggests secondary polycythemia; evaluate hypoxic and tumor-related causes 5

Step 3: Confirm Diagnosis with WHO Criteria

Masked PV is diagnosed when: 3

Major Criteria:

1. Hemoglobin 16.0–18.4 g/dL (men) or 15.0–16.4 g/dL (women) OR documented sustained increase >2 g/dL from baseline 3, 1
2. JAK2 V617F or JAK2 exon 12 mutation present 3

Minor Criteria (need ≥1):

1. Bone marrow hypercellularity with trilineage growth (panmyelosis) 3
2. Subnormal serum erythropoietin level 3
3. Endogenous erythroid colony formation 3

Alternative diagnostic combination: First major criterion + 2 minor criteria (for JAK2-negative cases or low mutation burden) 3

Step 4: Consider Red Cell Mass Measurement

Red cell mass measurement should be performed when: 2

• JAK2 mutation is positive but hemoglobin/hematocrit remain borderline 2
• Clinical suspicion is high (splenomegaly, thrombocytosis, portal vein thrombosis) despite normal blood counts 2
• Diagnosis remains equivocal after initial workup 3

In masked PV, red cell mass will be elevated (>125% predicted) despite normal hemoglobin/hematocrit due to compensatory plasma volume expansion. 2

Prognostic Implications of Masked PV

Masked PV patients have significantly worse overall survival compared to overt PV (P=0.011 by WHO criteria, P=0.0019 by BCSH criteria), likely due to delayed diagnosis and undertreatment. 1

Risk factors for inferior survival in masked PV: 1

• Age >65 years
• WBC count >15 × 10⁹/L

Without these risk factors, masked PV patients have the same survival as overt PV, suggesting that a fraction of patients with hemoglobin below WHO thresholds should still be treated as overt PV. 1

Critical Diagnostic Pitfalls to Avoid

1. Never exclude PV solely because hemoglobin is normal when RDW >16% and MCV <80 fL — iron deficiency can reduce apparent red cell mass while the clonal disorder persists. 4

2. Do not assume elevated RDW automatically indicates isolated iron-deficiency anemia — in the presence of thrombocytosis, leukocytosis, or splenomegaly, iron-deficient masked PV must be ruled out with JAK2 testing. 4

3. Do not wait for hemoglobin to reach standard WHO thresholds before initiating workup — the presence of myeloproliferative features (thrombocytosis, leukocytosis, splenomegaly) with borderline hemoglobin mandates immediate JAK2 testing. 2, 1

4. Recognize that the 2016 WHO criteria lowered diagnostic thresholds specifically to capture masked PV cases — hemoglobin 16.5 g/dL (men) and 16.0 g/dL (women) were adopted to prevent missed diagnoses. 6

5. In routine clinical practice, do not be prevented from making a working diagnosis of PV in the presence of iron deficiency just because WHO criteria are not met — formal diagnosis can be confirmed after iron replacement, but treatment should not be delayed. 3

Management Considerations for Masked PV

Once masked PV is confirmed, management is identical to overt PV: 1

• Maintain hematocrit strictly <45% through therapeutic phlebotomy to reduce thrombotic risk 6
• Initiate low-dose aspirin (81–100 mg daily) for thrombosis prevention 6
• Risk stratify: Age >60 years or prior thrombosis = high-risk; requires cytoreductive therapy with hydroxyurea or interferon 6
• Correct iron deficiency cautiously with close hemoglobin monitoring, as rapid red cell mass increases can occur 7