What is the diagnosis for a 54-year-old female with leukocytosis (elevated white blood cell count), erythrocytosis (elevated red blood cell count), hyperhemoglobinemia (elevated hemoglobin), and elevated hematocrit over the past year?

Polycythemia Vera (Most Likely Diagnosis)

This 54-year-old female most likely has polycythemia vera (PV), a myeloproliferative neoplasm requiring immediate JAK2 mutation testing and hematology referral to prevent life-threatening thrombotic complications.

Why Polycythemia Vera is the Leading Diagnosis

The progressive elevation of all three cell lines over one year strongly suggests a clonal myeloproliferative process rather than a reactive condition 1, 2:

• Hemoglobin rose from 14.4 to 16.6 g/dL - now exceeds the WHO major criterion threshold of >16.5 g/dL for women, which is required for PV diagnosis 3, 1
• Hematocrit rose from 44.6% to 50.9% - exceeds the diagnostic threshold of >49.5% for women 1, 2
• Sustained increase of 2.2 g/dL from baseline - meets WHO criteria for PV even when absolute thresholds are borderline, as this represents a documented sustained increase of at least 2 g/dL that cannot be attributed to iron deficiency correction 3
• Concurrent leukocytosis (WBC 8.0→14.3) and erythrocytosis (RBC 5.2→5.91) indicate trilineage proliferation characteristic of PV 1, 4

Immediate Diagnostic Testing Required

First-Line Molecular Testing

• JAK2 V617F mutation testing (exon 14) must be ordered immediately, as this mutation is found in >90-97% of PV cases and serves as the second major WHO criterion 3, 1, 2, 4
• If JAK2 V617F is negative, JAK2 exon 12 mutation testing should follow, as this accounts for most remaining PV cases 3, 2

Supporting Laboratory Tests

• Serum erythropoietin level - will be low or low-normal in PV (distinguishing it from secondary causes where EPO is elevated) 3, 1, 2
• Complete blood count with differential - to assess for thrombocytosis (present in 53% of PV) and characterize leukocytosis 4
• Peripheral blood smear review by a qualified hematologist to identify abnormal morphology 1
• Serum ferritin and transferrin saturation - iron deficiency can coexist with PV and must be identified 1, 5

WHO 2008 Diagnostic Criteria for Polycythemia Vera

Diagnosis requires BOTH major criteria plus one minor criterion, OR the first major criterion plus two minor criteria 3:

Major Criteria

1. Hemoglobin >16.5 g/dL in women (this patient: 16.6 g/dL ✓) OR hematocrit >49% in women (this patient: 50.9% ✓) OR documented sustained increase of ≥2 g/dL from baseline (this patient: +2.2 g/dL ✓) 3
2. Presence of JAK2 V617F or JAK2 exon 12 mutation (pending testing) 3

Minor Criteria

1. Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 3
2. Serum erythropoietin level below the reference range for normal 3
3. Endogenous erythroid colony formation in vitro 3

Critical Thrombotic Risk Assessment

This patient is at significant risk for arterial and venous thrombosis, which occurs in 16% of patients at or before PV diagnosis 4:

• Arterial thrombosis (stroke, myocardial infarction) occurs in 16% at diagnosis 4
• Venous thrombosis occurs in 7% at diagnosis, including unusual sites like splanchnic veins 4
• The progressive hematocrit elevation to 50.9% increases blood viscosity and thrombotic risk 1, 4

Why Secondary Causes are Less Likely

While secondary erythrocytosis must be excluded, several features argue against reactive causes 1, 2:

• Concurrent leukocytosis and rising RBC count suggest clonal trilineage proliferation rather than isolated EPO-driven erythrocytosis 1
• Progressive elevation over one year is more consistent with a neoplastic process than physiologic adaptation 2, 6
• No mention of hypoxic conditions (smoking, sleep apnea, COPD, high altitude) that typically cause secondary polycythemia 1, 2

However, the following secondary causes should still be systematically evaluated if JAK2 is negative 1, 2:

• Obstructive sleep apnea - order polysomnography if nocturnal symptoms present 1, 2
• Smoking history - carbon monoxide exposure stimulates EPO production ("smoker's polycythemia") 1, 2
• Chronic lung disease - pulmonary function tests if respiratory symptoms present 1, 2
• Testosterone use (prescribed or unprescribed) - particularly relevant in women with virilization signs 1, 2

Immediate Management Priorities

If JAK2 Mutation is Positive (Confirming PV)

Immediate hematology referral is mandatory 1, 2:

• Therapeutic phlebotomy to maintain hematocrit strictly <45% to reduce thrombotic risk (current hematocrit 50.9% requires intervention) 1, 2, 4
• Low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention, unless contraindications exist 1, 2, 4
• Cytoreductive therapy (hydroxyurea or interferon) should be considered if patient is ≥60 years old, has prior thrombosis, or has persistent symptoms 4

Critical Thresholds Requiring Urgent Action

• Hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms (headache, visual disturbances, dizziness) requires urgent therapeutic phlebotomy after excluding dehydration 1
• This patient is not yet at this threshold but is trending toward increased risk 1

Common Diagnostic Pitfalls to Avoid

• Do not assume dehydration without clinical confirmation - relative polycythemia from plasma volume depletion can elevate hematocrit, but the concurrent leukocytosis and progressive nature over one year argue against this 1, 5
• Do not delay JAK2 testing - this is the single most important diagnostic test and should be ordered immediately, not after exhaustive secondary cause evaluation 1, 2
• Do not overlook iron deficiency - check ferritin and transferrin saturation, as iron-deficient RBCs have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk even with erythrocytosis 1, 5
• Do not perform therapeutic phlebotomy before confirming diagnosis - unless hematocrit >65% with hyperviscosity symptoms, as inappropriate phlebotomy can cause iron depletion and worsen outcomes 1, 4

Long-Term Prognosis and Complications

If PV is confirmed, this patient faces 4:

• Median survival of 14.1-27.6 years from diagnosis with appropriate management 4
• 12.7% risk of progression to myelofibrosis 4
• 6.8% risk of transformation to acute myeloid leukemia 4
• Ongoing thrombotic risk requiring lifelong antiplatelet therapy and hematocrit control 4

Next Steps Algorithm

1. Order JAK2 V617F mutation testing immediately 1, 2
2. Measure serum erythropoietin level (low/low-normal supports PV; elevated suggests secondary cause) 1, 2
3. Check iron studies (ferritin, transferrin saturation) 1, 5
4. If JAK2 positive: Immediate hematology referral for bone marrow biopsy confirmation and treatment initiation 1, 2
5. If JAK2 negative: Systematically evaluate secondary causes (sleep study, pulmonary function tests, smoking history, medication review including testosterone) 1, 2
6. Refer to hematology regardless if hemoglobin remains >16.5 g/dL or diagnosis remains unclear after initial workup 1, 2