Conditions Causing Concurrent Elevation of WBC, RBC, Hemoglobin, and Hematocrit
The most likely condition causing simultaneous mild elevation of all these parameters is polycythemia vera (PV), a JAK2-driven myeloproliferative neoplasm that causes overproduction of all blood cell lines, particularly red blood cells. 1, 2
Primary Myeloproliferative Disorder: Polycythemia Vera
Polycythemia vera is the classic syndrome causing pan-elevation of blood counts and should be the primary diagnostic consideration when WBC, RBC, hemoglobin, and hematocrit are all elevated together. 1, 2
Diagnostic Criteria and Testing
JAK2 mutation testing (both exon 14 and exon 12) is the cornerstone diagnostic test, present in up to 97% of PV cases and should be ordered immediately. 1, 2
WHO diagnostic criteria require either:
- Both major criteria (elevated hemoglobin >18.5 g/dL in men or >16.5 g/dL in women AND JAK2 mutation) plus at least one minor criterion, OR
- First major criterion plus at least two minor criteria 1
In JAK2V617F-positive patients, higher allele burden correlates with elevated WBC, RBC, platelet counts, and hemoglobin levels, making this mutation central to the pathophysiology. 3
Associated Laboratory Findings
Thrombocytosis and leukocytosis commonly accompany the erythrocytosis in PV, distinguishing it from secondary causes of isolated erythrocytosis. 1, 2
Peripheral blood smear review by a qualified hematologist is essential to evaluate cell morphology and maturity across all three cell lines. 2
Secondary Causes with Multi-Lineage Elevation
While less common than PV for causing true pan-elevation, certain secondary conditions can produce concurrent increases:
Relative Polycythemia (Pseudo-polycythemia)
Dehydration causes plasma volume depletion, leading to hemoconcentration with apparent elevation of all blood cell counts while actual cell mass remains normal. 1, 4
This is distinguished from true polycythemia by repeating measurements after adequate hydration, which should normalize the values if dehydration was the cause. 4
Diuretic use, burns, and stress polycythemia (Gaisböck syndrome) can similarly cause relative polycythemia. 1
Hypoxia-Driven Secondary Polycythemia with Reactive Leukocytosis
Chronic obstructive pulmonary disease (COPD) causes hypoxemia-driven erythrocytosis through increased erythropoietin production, and the chronic inflammation can cause concurrent mild leukocytosis. 1, 2
Obstructive sleep apnea produces nocturnal hypoxemia that stimulates erythropoietin production, potentially with inflammatory leukocytosis. 1, 2
Cyanotic congenital heart disease with right-to-left shunting results in compensatory erythrocytosis to optimize oxygen transport. 1, 2
Smoking causes "smoker's polycythemia" due to chronic carbon monoxide exposure creating tissue hypoxia, plus inflammatory leukocytosis from tobacco exposure. 1, 2
Medication-Induced Elevations
Testosterone therapy (prescribed or unprescribed) commonly causes erythrocytosis and should be specifically queried in young adults, with potential for concurrent leukocytosis. 1, 2
Corticosteroid use causes leukocytosis (particularly neutrophilia) and can contribute to erythrocytosis through multiple mechanisms. 5, 6
Essential Diagnostic Workup
Immediate Laboratory Tests
Complete blood count with differential and peripheral smear to assess all cell lines, examine for left shift or immature cells, and evaluate morphology. 2
JAK2 mutation testing (exon 14 and exon 12) as the definitive test for PV. 1, 2
Serum ferritin, transferrin saturation, and iron levels to identify coexisting iron deficiency, which commonly occurs in erythrocytosis and causes microcytic polycythemia. 1, 2, 7
Erythropoietin level to differentiate primary (low/normal EPO) from secondary causes (elevated EPO). 1
C-reactive protein (CRP) as part of the minimum workup for inflammatory conditions. 1, 2
Clinical Assessment Priorities
Obtain detailed smoking history and assess carbon monoxide exposure, as this is a reversible cause that resolves with cessation. 1, 2
Screen for obstructive sleep apnea with sleep study if nocturnal symptoms or risk factors are present. 1, 2
Review all medications, particularly testosterone, corticosteroids, and erythropoietin therapy. 1, 2
Assess for symptoms suggesting hematologic malignancy: fever, weight loss, bruising, fatigue, splenomegaly, aquagenic pruritus, or erythromelalgia. 1, 5
Management Thresholds and Interventions
When to Intervene
Therapeutic phlebotomy is indicated only when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with associated symptoms of hyperviscosity, after excluding dehydration. 1, 2
For confirmed PV, maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV study. 1, 2
Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention in PV. 1, 2
Critical Pitfalls to Avoid
Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 1, 2
If WBC count exceeds 100,000/μL, initiate aggressive IV hydration immediately (2.5-3 liters/m²/day) to prevent tumor lysis syndrome and leukostasis complications. 2, 6
Iron deficiency should be avoided even in the presence of erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1
Use hemoglobin rather than hematocrit for monitoring, as hematocrit can falsely increase by 2-4% with prolonged sample storage while hemoglobin remains stable. 1, 2
When to Refer to Hematology
Immediate referral to hematology is indicated if: 1, 2
- JAK2 mutation is positive
- Hemoglobin >20 g/dL with symptoms of hyperviscosity
- Unexplained splenomegaly
- WBC count >100,000/μL
- Concurrent abnormalities in multiple cell lines suggesting primary bone marrow disorder
- Diagnosis remains unclear after initial workup