How to manage a patient with low but normal MCH, MCV, and MCHC, and elevated white blood cells, red blood cells, hemoglobin, and hematocrit, suspected of having polycythemia vera?

Management of Low-Normal Red Cell Indices with Elevated Blood Counts Suspicious for Polycythemia Vera

Immediate Diagnostic Priority

Order JAK2 V617F mutation testing immediately, as this patient's presentation—with elevated RBC, hemoglobin, hematocrit, and WBC—strongly suggests polycythemia vera, which is present in >95% of PV cases and is essential for diagnosis. 1, 2, 3, 4

The low-normal MCH, MCV, and MCHC are critical diagnostic clues that suggest concurrent iron deficiency masking the full extent of erythrocytosis—a common pitfall in PV diagnosis that can lead to underestimation of disease severity. 1

Understanding the Clinical Picture

Why Low-Normal Indices Matter

• Iron deficiency commonly coexists with PV and causes microcytic indices even in the presence of elevated RBC counts, creating a pattern of "microcytic polycythemia" where hemoglobin may be falsely lower than expected for the degree of erythrocytosis. 1

• MCV is unreliable for screening iron deficiency in erythrocytosis—you must check serum ferritin, transferrin saturation, and complete iron studies to accurately diagnose concurrent iron deficiency. 1

• The low MCHC (<32%) specifically suggests iron deficiency, which requires investigation before dismissing or delaying PV workup. 2

Elevated WBC as a Diagnostic Clue

• Leukocytosis occurs in approximately 49% of PV patients at diagnosis, typically with WBC >10 × 10⁹/L, and represents part of the trilineage myeloproliferation characteristic of this myeloproliferative neoplasm. 2, 4

• Leukocytosis >15 × 10⁹/L is a risk factor for inferior survival and increased thrombotic risk, making this finding prognostically significant. 2

Complete Initial Workup

Essential Laboratory Tests

• JAK2 V617F (exon 14) mutation testing is first-line and captures >95% of PV cases. 1, 2, 3, 4

• If JAK2 V617F is negative, proceed immediately to JAK2 exon 12 mutation testing, which identifies the remaining ~3% of PV cases. 2, 3

• Serum erythropoietin (EPO) level: Low EPO has >90% specificity for PV, though normal EPO does not exclude the diagnosis; elevated EPO suggests secondary polycythemia. 5, 1, 2, 3

• Complete iron studies: Serum ferritin, transferrin saturation, and iron levels are mandatory given the low-normal indices. 1

• Peripheral blood smear review by a qualified hematologist to assess red cell morphology and identify abnormalities. 1

• Reticulocyte count to evaluate bone marrow response. 1

Diagnostic Criteria Application

WHO Criteria for Polycythemia Vera

Diagnosis requires BOTH major criteria plus 1 minor criterion, OR the first major criterion plus 2 minor criteria: 2, 3

Major Criteria:

• Hemoglobin ≥18.5 g/dL (men) or ≥16.5 g/dL (women), OR hematocrit ≥49% (men) or ≥48% (women) 2, 3, 4
• Presence of JAK2 V617F or JAK2 exon 12 mutation 2, 3
• Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) 2, 3

Minor Criteria:

• Serum erythropoietin below normal reference range 2, 3
• Endogenous erythroid colony formation in vitro 2, 3

Critical Diagnostic Considerations

• A sustained increase of ≥2 g/dL hemoglobin from baseline warrants investigation even if values remain within normal reference ranges, making historical comparison essential. 2, 3

• Bone marrow examination is recommended when PV is suspected, particularly before initiating cytoreductive therapy, and should specifically assess for hypercellularity with trilineage growth. 2, 3

Excluding Secondary Causes

If JAK2 Mutation is Negative

Systematically evaluate for secondary polycythemia causes: 1, 3

Hypoxia-Driven Causes:

• Smoking history (causes "smoker's polycythemia" from chronic carbon monoxide exposure) 1
• Obstructive sleep apnea (nocturnal hypoxemia drives EPO production) 1
• Chronic lung disease (COPD) 1
• Cyanotic congenital heart disease 1

Hypoxia-Independent Causes:

• EPO-producing tumors (renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, meningioma) 1
• Testosterone use (prescribed or unprescribed) 1
• Post-renal transplant erythrocytosis 1

Management Strategy

If Polycythemia Vera is Confirmed

All patients with PV require two cornerstone therapies: 4

1. Therapeutic phlebotomy to maintain hematocrit strictly <45% to reduce thrombotic risk (lower target of 42% is reasonable for women). 1, 4

2. Low-dose aspirin (81-100 mg daily) for thrombosis prevention, unless contraindicated. 1, 4

Addressing Iron Deficiency in PV

• Iron deficiency should be avoided even in the presence of erythrocytosis, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1

• If iron deficiency is confirmed, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 1

• Do not perform aggressive phlebotomy in the setting of iron deficiency, as this worsens the problem and increases thrombotic risk. 1

When to Add Cytoreductive Therapy

Patients at higher risk of thrombosis require cytoreductive therapy with hydroxyurea or interferon: 4

• Age ≥60 years 4
• Prior thrombotic event 4
• Persistent PV symptoms despite phlebotomy 4
• Leukocytosis >15 × 10⁹/L 2
• Platelet count >1,500 × 10⁹/L 2

Immediate Referral Indications

Refer immediately to hematology if: 1, 3

• JAK2 mutation is positive 1, 3
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 1, 3
• Unexplained splenomegaly 1, 3
• Diagnosis remains unclear after initial workup 1, 3

Critical Pitfalls to Avoid

• Do not dismiss PV based on low-normal indices—iron deficiency masks the full extent of erythrocytosis and is common in PV. 1

• Do not wait for hemoglobin to reach diagnostic thresholds if there is sustained elevation from baseline with PV-related features (leukocytosis, thrombocytosis, unusual thrombosis). 2, 3

• Do not perform repeated routine phlebotomies without monitoring iron status—this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1

• Do not use standard PV diagnostic thresholds without considering altitude of residence—physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation. 1

• Therapeutic phlebotomy is indicated only when hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity, not for routine management of borderline elevations. 1