Can persistent mild erythrocytosis (elevated red blood cells), hyperhemoglobinemia (elevated hemoglobin), and hyperhematocritemia (elevated hematocrit) lasting for a year be a sign of polycythemia vera in an adult patient?

Can Persistent Mild Erythrocytosis Be a Sign of Polycythemia Vera?

Yes, persistent mild elevations in red blood cells, hemoglobin, and hematocrit lasting for a year can absolutely be an early sign of polycythemia vera and warrant immediate investigation with JAK2 mutation testing. 1, 2

Why This Matters Clinically

A sustained increase of ≥2 g/dL hemoglobin from baseline requires investigation for polycythemia vera, even if values remain within normal reference ranges. 3 This is critical because:

• Polycythemia vera is present in >95% of cases with a JAK2 mutation, and thrombotic events occur in 16% of patients at or before diagnosis 4
• Arterial and venous thrombosis are the most lethal complications and unfortunately often the initial manifestation of the disease 5
• Median survival from diagnosis ranges from 14.1 to 27.6 years, but early detection and treatment significantly improves outcomes 4

Diagnostic Algorithm for Persistent Erythrocytosis

Step 1: Confirm True Polycythemia

Before proceeding with extensive workup:

• Verify adequate hydration status - dehydration is the most common cause of falsely elevated hematocrit 3
• Repeat hemoglobin and hematocrit measurements - a single measurement is not reliable for establishing diagnosis 2
• Check for iron deficiency - low MCHC (<32%) suggests iron deficiency, which can mask true erythrocytosis; obtain serum ferritin, transferrin saturation, and iron studies 2, 3

Step 2: Initial Laboratory Workup

Once true erythrocytosis is confirmed:

• JAK2 V617F mutation testing (exon 14) - this is first-line and present in >95% of polycythemia vera cases 1, 3, 4
• If JAK2 V617F is negative, proceed to JAK2 exon 12 mutation testing - this captures the remaining ~3% of polycythemia vera cases 1, 3
• Serum erythropoietin (EPO) level - low EPO has >90% specificity for polycythemia vera, while elevated EPO suggests secondary polycythemia 2, 6, 3
• Complete blood count with differential - assess for thrombocytosis (present in 53%) and leukocytosis (present in 49%) 4

Step 3: Apply WHO Diagnostic Criteria

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

Major Criteria:

1. Hemoglobin ≥18.5 g/dL (men) or ≥16.5 g/dL (women), OR hematocrit ≥49% (men) or ≥48% (women) 1, 3
2. Presence of JAK2 V617F or JAK2 exon 12 mutation 1, 3

Minor Criteria:

1. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) 1, 3
2. Serum erythropoietin below normal reference range 1, 3
3. Endogenous erythroid colony formation in vitro 1, 3

Distinguishing Primary from Secondary Polycythemia

When to Suspect Secondary Causes

If JAK2 mutation is negative and EPO is elevated or normal, systematically evaluate for secondary causes: 2, 6

Hypoxia-driven causes:

• Smoking history - "smoker's polycythemia" results from chronic carbon monoxide exposure and resolves with cessation 1, 6
• Obstructive sleep apnea - produces nocturnal hypoxemia driving erythropoietin production 2, 6
• Chronic lung disease (COPD) - creates chronic tissue hypoxia 2, 6
• Cyanotic congenital heart disease - right-to-left shunting causes compensatory erythrocytosis 2, 6

Hypoxia-independent causes:

• EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyoma, pheochromocytoma, meningioma 1, 6
• Testosterone use (prescribed or unprescribed) - common in young adults 2
• Post-renal transplant erythrocytosis 1, 6

Key Diagnostic Pitfall

Beware of "normal" EPO levels in chronic hypoxic states - in hypoxia-driven secondary polycythemia, EPO levels are often initially elevated but may return to normal range once hemoglobin stabilizes at a higher compensatory level 1, 6. This can potentially mimic polycythemia vera and lead to misdiagnosis.

When to Refer to Hematology

Immediate referral is indicated if: 2

• JAK2 mutation is positive 2
• Hemoglobin >20 g/dL with symptoms of hyperviscosity (headache, visual changes, dizziness) 2
• Unexplained splenomegaly 2
• Diagnosis remains unclear after initial workup 2
• History of unusual thrombosis (splanchnic veins, cerebral veins) 4

Critical Clinical Considerations

Thrombotic Risk

• Thrombotic events are the most lethal complication and occur in 16% of patients at or before diagnosis 4, 5
• Arterial thrombosis occurs in 16% and venous thrombosis in 7% of patients, potentially involving unusual sites like splanchnic veins 4
• Risk factors include age >60 years, prior thrombosis history, JAK2 V617F mutation, and cardiovascular risk factors 7

Bleeding Risk

• Extreme thrombocytosis (≥1,000 × 10⁹/L) paradoxically increases bleeding risk due to acquired von Willebrand disease 3, 4, 7
• Screening for acquired von Willebrand syndrome is recommended before administering aspirin in patients with extreme thrombocytosis 7

Disease Progression

• About 12.7% of patients develop myelofibrosis and 6.8% develop acute myeloid leukemia 4
• Leukemic transformation rates at 20 years are estimated at <10% for polycythemia vera 7

Common Diagnostic Pitfalls to Avoid

1. Assuming normal values exclude polycythemia vera - a sustained increase from individual baseline warrants investigation even within normal reference ranges 3

2. Performing unnecessary red cell mass measurements - modern JAK2 mutation testing has largely replaced the need for red cell mass measurements in most cases 1

3. Missing coexisting iron deficiency - iron deficiency can mask true erythrocytosis by reducing hemoglobin despite elevated red cell count; check serum ferritin and transferrin saturation 2, 3

4. Overlooking smoking as a reversible cause - smoker's polycythemia is real and resolves with cessation 1, 6

5. Failing to adjust thresholds for altitude - physiologic adaptation to altitude can increase hemoglobin by 0.2-4.5 g/dL depending on elevation 2