Can hypoxia cause leukocytosis (elevated White Blood Cell (WBC) count)?

Hypoxia and Leukocytosis: Relationship and Clinical Implications

Hypoxia can induce immune system changes but does not directly cause leukocytosis in most clinical scenarios. While there are important relationships between oxygen levels and white blood cell function, true hypoxia-induced leukocytosis is not a common physiological response.

Physiological Relationship Between Hypoxia and Immune Function

Hypoxia's Effects on the Immune System

• Hypoxia is a key mediator of inflammatory and immune responses through hypoxia-inducible factors (HIFs) 1
• Hypoxia exposure in young women can induce an α-adrenergic pathway-mediated upregulation of interleukin-6, with haematological changes related to the immune system 2
• In elite female speed skaters, hypoxic exercise was associated with changes in innate immune responses (inflammation), hypoxic stress response, and platelet activity 2

Erythropoiesis vs. Leukocytosis

• The primary physiological response to hypoxia is increased erythropoietin (EPO) production by the kidneys, stimulating red blood cell production 2
• This response aims to increase oxygen-carrying capacity through increased hemoglobin mass, not through white blood cell production 2
• In hypoxia-driven secondary polycythemia, serum EPO levels are often initially increased but may return to normal once hemoglobin stabilizes at a higher level 2

Clinical Phenomenon: Pseudohypoxemia in Leukocytosis

Reverse Relationship: Leukocytosis Causing Apparent Hypoxemia

• Important clinical pitfall: Extreme leukocytosis can cause falsely low PaO2 readings on arterial blood gas analysis, known as "pseudohypoxemia" 3, 4, 5
• This occurs because the high number of metabolically active white blood cells in the sample continue to consume oxygen between collection and analysis 5
• The rate of decrease in PaO2 in blood samples is proportional to the white blood cell count 5
• This phenomenon is particularly significant when WBC counts exceed 100 × 10^9/L 6

Clinical Recognition and Management

• Discrepancy between normal oxygen saturation on pulse oximetry (SpO2) and low arterial oxygen tension (PaO2) on blood gas analysis should raise suspicion 3, 4
• Even with cooling and quick analysis of samples, there is poor correlation between SpO2 and SaO2 when WBC counts exceed 100 × 10^9/L 6
• The difference between SpO2 and SaO2 correlates with WBC count (r^2 = 0.44) 6
• Samples with WBC counts >150 × 10^9/L frequently show PaO2 <55 mm Hg despite SpO2 >94% 6

Hypoxia in Critical Care Settings

Avoiding Hyperoxia and Hypocapnia

• While hypoxemia (SpO2 <90%, corresponding to PaO2 of ~60 mmHg) is associated with poor outcomes in TBI patients, extreme hyperoxia should also be avoided 2
• Both PaO2 <110 mmHg and PaO2 >487 mmHg have been associated with increased mortality and worsened neurological outcomes 2
• Hyperventilation-induced hypocapnia may cause cerebral vasoconstriction, decreased cerebral blood flow, and impaired tissue perfusion 2

Conclusion

In summary, while hypoxia can modulate immune function through various pathways, it does not directly cause leukocytosis as a primary physiological response. Instead, the body's main adaptation to hypoxia is increased erythropoiesis. Clinicians should be aware of the reverse phenomenon where extreme leukocytosis can cause falsely low oxygen readings (pseudohypoxemia) on blood gas analysis, potentially leading to unnecessary interventions if not recognized.