Why would a healthy 37-year-old woman have mild erythrocytosis and lymphocytosis?

Mild Erythrocytosis and Lymphocytosis in a Healthy 37-Year-Old Woman

These laboratory findings most likely represent either physiologic variation, early polycythemia vera requiring JAK2 mutation testing, or a reactive process from smoking, chronic stress, or subclinical infection.

Understanding the Laboratory Values

The RBC count of 5.36 × 10¹²/L represents mild erythrocytosis that warrants investigation but does not automatically indicate pathology, as normal ranges vary by laboratory and individual factors 1, 2. The lymphocyte count of 4.4 × 10⁹/L constitutes mild lymphocytosis, which is commonly reactive rather than clonal in otherwise healthy individuals 3, 4.

Primary Differential Diagnosis for Erythrocytosis

Polycythemia Vera (Most Important to Exclude)

• JAK2 mutation testing is essential, as up to 97% of polycythemia vera cases carry this mutation, and diagnosis requires hemoglobin >16.5 g/dL in women plus JAK2 mutation 3.
• Polycythemia vera can present with concurrent leukocytosis affecting multiple cell lines, though the lymphocyte elevation here is modest 3, 5.
• Measure serum erythropoietin level immediately—a low level indicates primary erythrocytosis (polycythemia vera), while normal or elevated levels suggest secondary causes 1, 2, 6.

Secondary Erythrocytosis (More Common)

• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure stimulating erythropoietin production, and can coexist with stress-induced lymphocytosis 3.
• Chronic hypoxia from undiagnosed sleep apnea, high altitude exposure, or subclinical pulmonary disease drives compensatory erythrocytosis 3, 6.
• Congenital causes should be considered in young patients, particularly with family history of elevated blood counts 2, 6.

Differential Diagnosis for Lymphocytosis

Reactive Causes (Most Likely)

• Chronic stress mobilizes leukocytes including lymphocytes from the spleen and can normalize with stress management 7.
• Viral infections including HIV, hepatitis C, and Epstein-Barr virus cause lymphocytosis that may persist for weeks to months 4.
• Autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis frequently cause lymphocytosis 4.

Clonal Causes (Less Likely in Asymptomatic Patient)

• Chronic lymphocytic leukemia typically presents with absolute lymphocyte count >5.0 × 10⁹/L sustained over 3 months, often with concurrent anemia or thrombocytopenia 4.
• Lymphoma can rarely cause secondary erythrocytosis through paraneoplastic mechanisms, though this would be unusual without other symptoms 8.

Algorithmic Diagnostic Approach

Step 1: Confirm True Erythrocytosis and Lymphocytosis

• Repeat complete blood count with differential in 2-4 weeks to confirm persistence and exclude laboratory error or transient reactive process 3, 1.
• Review peripheral blood smear for dysplastic features, blast cells, rouleaux formation, or abnormal lymphocyte morphology 3, 4.

Step 2: Initial Laboratory Workup

• Serum erythropoietin level (low suggests polycythemia vera; normal/high suggests secondary causes) 1, 2, 6.
• JAK2 V617F mutation testing (positive in 97% of polycythemia vera) 3, 2.
• Comprehensive metabolic panel, liver function tests, ferritin, transferrin saturation 3, 4.
• Arterial blood gas or pulse oximetry to assess for hypoxemia 6.

Step 3: Directed Testing Based on Initial Results

If erythropoietin is low and/or JAK2 is positive:

• Immediate hematology referral for bone marrow biopsy and polycythemia vera management 3, 2.

If erythropoietin is normal/high and JAK2 is negative:

• Chest imaging to evaluate for pulmonary disease or sleep study for sleep apnea 6.
• Renal ultrasound and renal function tests to exclude renal causes of erythropoietin excess 6.
• Smoking cessation counseling if applicable 3.

For persistent lymphocytosis:

• Flow cytometry if absolute lymphocyte count remains >5.0 × 10⁹/L or if atypical lymphocytes are present on smear 4.
• Viral serologies (HIV, hepatitis panel, EBV, CMV) if clinically indicated 4.

Critical Management Considerations

Immediate Hematology Referral Indicated For:

• Positive JAK2 mutation 3.
• Hemoglobin >20 g/dL with symptoms of hyperviscosity (headache, visual disturbances, dizziness) 3.
• Splenomegaly on examination 3, 4.
• Concurrent cytopenias or dysplastic features on peripheral smear 3, 4.

Observation Appropriate For:

• Mild elevations with negative JAK2, normal erythropoietin, and identifiable secondary cause (smoking, stress) 6.
• Recheck complete blood count in 3 months; sustained monocytosis or lymphocytosis ≥3 months without clear cause warrants hematology referral 4.

Common Pitfalls to Avoid

• Failing to measure erythropoietin level before initiating workup, which is the critical branch point between primary and secondary erythrocytosis 1, 2, 6.
• Overlooking smoking history, as smoker's polycythemia is a common and reversible cause of erythrocytosis 3.
• Not distinguishing between relative and absolute lymphocytosis—confirm absolute count is elevated, not just percentage 4.
• Assuming benign etiology without follow-up—sustained elevations require documentation of stability or progression 4, 1.
• Ordering bone marrow biopsy prematurely before completing non-invasive testing including JAK2 mutation and erythropoietin level 2, 6.