One important secondary effect documented in SCD patients is low oxygen
affinity[26].
Sickled
cells have a low oxygen affinity due to intracellular Hb S polymers which do not
bind oxygen[117,118] and a
significant increase (
~
33%)
[26],
in the glycolytic intermediate
2,3-diphosphoglycerate (DPG)[119]. 2,3-DPG is a potent negative allosteric
regulator of oxygen saturation. An increase in cellular 2,3-DPG is a
physiological compensatory mechanism to unload oxygen in cases of anemia[120].
In the deoxygenated state, Hb binds 2,3-DPG in a 1:1 molar ratio; 2,3-DPG binds
to the
b-subunits
of Hb to stabilize its deoxy form and
thus lowers oxygen affinity[26]. In addition, 2,3-DPG lowers the intracellular
pH, which also lowers O2 affinity via the Bohr effect[26]. This is
reported to improve oxygen delivery from the blood to the tissues[26,119].
However, this response is counterproductive in SCD since lower O2
affinity results in low O2
saturation and, consequently, can facilitate Hb S deoxygenation[26]. Thus, an
increase in 2,3-DPG can promote Hb S polymerization by lowering overall O2
affinity[26].