At high altitudes, hemoglobin's affinity for O₂  is increased because BPG concentrations increase.

Decreases in arterial P_O2  cause the peripheral chemoreceptors to become less responsive to increases in P_CO2 .

When blood O₂ levels decline, the kidneys produce more erythropoietin, which stimulates breakdown of red blood cells in the spleen.

High-altitude conditions always result in lower-than-normal hemoglobin saturation levels because less O₂  is available to be loaded.