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One important secondary effect documented in SCD patients is low oxygen affinity[26].

Low oxygen Affinity &  2,3-Diphosphoglyceric acid(DPG)

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].