What are the common causes of concurrent leukocytosis and erythrocytosis in a 54-year-old female?

Common Causes of Concurrent Leukocytosis and Erythrocytosis in a 54-Year-Old Female

The most likely diagnosis in a 54-year-old female presenting with concurrent leukocytosis and erythrocytosis is polycythemia vera (PV), a myeloproliferative neoplasm characterized by JAK2 V617F mutation in >90% of cases, which drives trilineage proliferation including both red blood cells and white blood cells. 1, 2

Primary (Clonal) Causes

Polycythemia Vera - Most Common Cause

• PV classically presents with erythrocytosis, leukocytosis, and thrombocytosis together, often with splenomegaly, representing the complete phenotype of JAK2-driven myeloproliferation 3, 4
• The JAK2 V617F mutation is present in >95% of PV cases and serves as the primary diagnostic marker 1, 5
• Bone marrow biopsy characteristically shows hypercellularity with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation 1
• Leukocytosis in PV is an adverse prognostic factor and increases thrombotic risk by 60% 5, 6
• Serum erythropoietin levels are typically low or inappropriately normal, helping differentiate from secondary causes 1, 5

Other Myeloproliferative Neoplasms (Less Likely)

• Essential thrombocythemia can present with leukocytosis but typically lacks significant erythrocytosis 1
• Primary myelofibrosis shows JAK2 V617F in nearly 50% of cases but presents with bone marrow fibrosis and atypical megakaryocytes rather than isolated erythrocytosis 1, 2

Secondary (Reactive) Causes - Less Common for Combined Presentation

Chronic Inflammatory/Autoimmune Conditions

• Adult-onset Still's disease causes marked neutrophilic leukocytosis (50% with WBC >15,000/μL) but does not cause true erythrocytosis 2
• Chronic inflammatory conditions cause persistent leukocytosis through bone marrow granulocyte hyperplasia but typically cause anemia of chronic disease, not erythrocytosis 2

Secondary Erythrocytosis with Concurrent Reactive Leukocytosis (Rare)

• Chronic hypoxic conditions (COPD, sleep apnea, high altitude) can cause secondary erythrocytosis 5, 7
• If concurrent infection or inflammation is present, reactive leukocytosis may occur simultaneously 8, 9
• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure stimulating EPO production and can cause reactive leukocytosis 5, 9
• Renal cell carcinoma or other EPO-secreting tumors can cause secondary erythrocytosis, with potential paraneoplastic leukocytosis 5

Critical Diagnostic Algorithm

Immediate Testing Required

1. JAK2 V617F mutation testing - positive in >95% of PV cases; a positive result with elevated hemoglobin strongly suggests PV 1, 5
2. Serum erythropoietin level - low or inappropriately normal in PV (specificity >90%), elevated in secondary causes 1, 5
3. Complete blood count with differential - assess for thrombocytosis (third lineage involvement) and evaluate maturity of white blood cells 1, 9

Exclusion of Secondary Causes

• Evaluate smoking history, sleep apnea symptoms, testosterone/androgen use, and chronic lung disease 5
• Renal imaging to exclude EPO-secreting renal cell carcinoma 5
• Inflammatory markers (ESR, CRP) to identify chronic inflammation 6

Confirmatory Testing

• Bone marrow biopsy with cytogenetics is mandatory to confirm PV diagnosis, fulfill WHO criteria, and assess for adverse prognostic factors 1, 5
• Characteristic findings include hypercellularity, trilineage proliferation, increased megakaryocytes, and decreased iron stores 5

Critical Pitfalls to Avoid

• Do not dismiss PV based on "normal" hemoglobin levels - plasma volume expansion in PV can mask true erythrocytosis, and a documented rise from baseline (e.g., 14 to 16.6 g/dL) warrants investigation even within reference ranges 5
• The presence of leukocytosis strengthens PV suspicion and should never be ignored as it represents part of the trilineage proliferation 1, 5
• Concurrent reactive conditions do not exclude PV - the presence of inflammation or infection does not rule out underlying myeloproliferative neoplasm if WHO criteria are met 1, 6
• Hyperleukocytosis (WBC >100,000/μL) is a medical emergency requiring immediate intervention due to risk of leukostasis, hemorrhage, and tumor lysis syndrome 2, 8