What can cause mildly elevated white blood cells (WBC), red blood cells (RBC), hemoglobin (Hb), and hematocrit (Hct) in a patient?

Causes of Mildly Elevated White Blood Cells, Red Blood Cells, Hemoglobin, and Hematocrit

The most common cause of simultaneous mild elevation in all these parameters is relative polycythemia from dehydration or plasma volume depletion, which concentrates all blood cell components without true increases in cell mass. 1, 2

Primary Diagnostic Consideration: Relative vs. Absolute Polycythemia

• Dehydration is the leading cause of this pattern, where plasma volume decreases while red cell mass remains constant, artificially elevating all measured blood components including WBC, RBC, hemoglobin, and hematocrit 1, 2
• Confirm true elevation by repeating measurements after ensuring adequate hydration, as a single measurement is unreliable for establishing diagnosis 1
• Diuretic use, burns, and stress polycythemia (Gaisböck syndrome) can also cause relative polycythemia through plasma volume depletion 1

Secondary Causes of True Erythrocytosis with Reactive Leukocytosis

When dehydration is excluded and elevations persist, consider these conditions that can elevate both red and white cell lines:

Hypoxia-Driven Conditions

• Chronic smoking causes "smoker's polycythemia" through carbon monoxide-induced tissue hypoxia, stimulating erythropoietin production while also causing chronic inflammatory leukocytosis 1
• Obstructive sleep apnea produces nocturnal hypoxemia driving erythropoietin production, often accompanied by systemic inflammation elevating WBC 1
• Chronic obstructive pulmonary disease (COPD) causes compensatory erythrocytosis from chronic hypoxemia with concurrent inflammatory leukocytosis 1
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis 1

Physiological and Environmental Factors

• High altitude residence causes normal increases in hemoglobin (ranging from +0.2 g/dL at 1,000 meters to +4.5 g/dL at 4,500 meters) as physiologic adaptation to chronic hypoxia 1
• Testosterone therapy (prescribed or unprescribed) can cause erythrocytosis and should be considered in young adults with this pattern 1

Inflammatory and Infectious States

• Acute or chronic infections can elevate WBC while simultaneously causing stress erythrocytosis or hemoconcentration from fever-related fluid losses 3
• Post-infectious states (such as post-COVID-19) show significant changes in WBC, RBC, hemoglobin, and hematocrit that can persist for months after disease onset 3

Primary Polycythemia (Polycythemia Vera)

• Polycythemia vera should be considered when hemoglobin exceeds 18.5 g/dL in men or 16.5 g/dL in women, particularly with concurrent thrombocytosis or leukocytosis 1, 4
• The combination of elevated reticulocyte count, elevated RBC count, elevated hematocrit, and elevated MCHC most strongly suggests polycythemia vera 4
• JAK2 mutation testing (exon 14 first, then exon 12 if negative) is required for diagnosis, as up to 97% of PV cases carry this mutation 1, 4
• WHO diagnostic criteria require both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR first major criterion plus two minor criteria 1, 4

Diagnostic Algorithm

Initial Assessment

• Assess hydration status clinically by reviewing fluid intake, losses, medication use (especially diuretics), and clinical signs of dehydration 2
• Repeat CBC after adequate hydration to distinguish relative from absolute polycythemia 1, 2
• Order complete blood count with red cell indices, reticulocyte count, peripheral blood smear, serum ferritin, transferrin saturation, and C-reactive protein 1

If Elevations Persist After Hydration

• Obtain detailed history focusing on smoking, sleep symptoms (snoring, daytime somnolence), testosterone use, altitude of residence, and chronic lung disease 1
• Order JAK2 mutation testing if hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women), or if accompanied by splenomegaly, aquagenic pruritus, or thrombocytosis 1, 4
• Consider sleep study if nocturnal hypoxemia suspected, and pulmonary function testing if COPD suspected 1
• Measure erythropoietin levels to differentiate primary (low EPO) from secondary causes (elevated EPO), though sensitivity is limited at <70% 1

Critical Management Considerations

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, 4
• For confirmed polycythemia vera, maintain hematocrit strictly below 45% through phlebotomy to reduce thrombotic risk, with low-dose aspirin (81-100 mg daily) as cornerstone therapy 1, 4
• Avoid repeated routine phlebotomies in secondary erythrocytosis due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 1

Treatment of Underlying Conditions

• For secondary causes, treat the underlying condition: smoking cessation for smoker's polycythemia, CPAP for obstructive sleep apnea, management of COPD, or dose adjustment/discontinuation of testosterone 1, 4
• If iron deficiency coexists with erythrocytosis (causing microcytic polycythemia), cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur 1

Common Pitfalls to Avoid

• Do not diagnose polycythemia vera based on a single elevated measurement without confirming hydration status and repeating tests 1
• Do not use standard PV diagnostic thresholds at high altitude without adjusting for physiologic adaptation (hemoglobin can increase 0.2-4.5 g/dL depending on elevation) 1
• Do not perform aggressive phlebotomy in secondary erythrocytosis, as this increases stroke risk through iron depletion and decreased oxygen-carrying capacity 1
• Do not overlook coexisting iron deficiency in patients with erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk 1

When to Refer to Hematology

• Immediate referral indicated if JAK2 mutation positive, hemoglobin >20 g/dL with hyperviscosity symptoms, unexplained splenomegaly, or diagnosis remains unclear after initial workup 1, 4
• Bone marrow biopsy is required if JAK2 mutation positive to confirm PV diagnosis and assess for trilineage myeloproliferation 1