Sickle cell disease is an inherited homozygous condition where individuals have a substitution of an amino acid (valine for glutamic acid) on the β chain of the Hgb molecule. This leads to the formation of sickle cell Hgb (HgbS), which can transform into a stiff gelatinous material, distorting the normal biconcave shape of red blood cells into a crescent or sickle-shaped form when not bound to oxygen. This change in appearance increases the tendency of red blood cells to form clots, obstructing small vessels and causing acute sickle cell episodes. The symptoms of such episodes vary depending on the site of obstruction, commonly associated with intense pain. The spleen is often affected, compromising immune capabilities and increasing susceptibility to recurrent infections. In its homozygous form, this condition shortens life expectancy, but individuals with the heterozygous form are resistant to malaria. This provides a survival advantage in regions where malaria is prevalent, possibly explaining the preservation of the sickle cell mutation through evolution. The increased affinity of HgbF for O2 benefits individuals with sickle cell disease by reducing cell deformation in the sickle shape when O2 is released from Hgb to the tissues. Sickle cell disease is most prevalent among individuals of African American descent but can also be observed in Hispanic, Turkish, Asian, and other ethnic groups.

Decreased Hgb for O2 enhances O2 dissociation, resulting in reduced binding of Hgb to O2 at a given PO2 and an increase in P50. When the affinity of Hgb for O2 increases, the curve shifts to the left, leading to a decrease in P50. This inhibits O2 dissociation and delivery to tissues. Shifts to the right or left of the dissociation curve have minimal effects within the normal range of O2 partial pressures (80 to 100 mm Hg). However, at O2 partial pressures below 60 mm Hg (steep part of the curve), shifts in the oxyhemoglobin dissociation curve can significantly impact O2 transport.
Intheinheritedhomozygousconditionknownassickle cell disease, affectedindividualshaveanaminoacidsubstitution(valineforglutamicacid)ontheβ chainoftheHgbmolecule.ThiscreatesasicklecellHgb(HgbS),which,whennotboundtooxygen(deoxyhemoglobinordesaturatedHgb),cantransformintoastiffgelatinousmaterialthatdistortsthenormalbiconcaveshapeoftheredbloodcelltoacrescent,orsickle-shaped,form.Thischangeinappearancefromsphericaltoasickleshapeincreasesthetendencyoftheredbloodcelltoformthrombiorclotsthatobstructsmallvesselsandcreatesaclinicalconditionknownasacute sickle cell episode. Thesymptomsofsuchanepisodevary,dependingonthesiteoftheobstruction(e.g.,inthebrain,stroke;inthelungs,pulmonaryinfarction)andarecommonlyassociatedwithintensepain.Thespleenisacommonsiteofobstruction/infarction,andtheensuingtissuedamagecompromisestheimmunecapabilitiesofaffectedindividualsandrendersthemsusceptibletorecurrentinfections.Inthehomozygousform,thisconditionislife-shortening;however,individualswiththeheterozygousformareresistanttomalaria.Thusanindividualwithheterozygousalleleshasasurvivaladvantageinregionsoftheworldwheremalariaisprevalent,whichmayexplainwhythesicklecellmutationhasbeenpreservedthroughevolution.TheincreasedaffinityofHgbFforO2confersadvantagestoindividualswithsicklecelldiseaseinthatthecellsdonotdesaturateasmuchwhenO2isreleasedfromHgbtothetissueandthusarelesslikelytobecomedeformedinthesickleshape.SicklecelldiseaseismostprevalentamongindividualsofAfricanAmericandescent,butitisalsoobservedinHispanic,Turkish,Asian,andotherethnicgroups.
Hgb for O2 decreases, which enhances O2 dissociation. This results in decreased Hgb binding to O2 at a given PO2, which causes the P50 to increase. When the affinity of Hgb for O2 increases, the curve is shifted to the left, which causes the P50 to decrease. In this state, O2 dissociation and delivery to tissue are inhibited. Shifts to the right or left of the dissociation curve have little effect when they occur at O2 partial pressures within the normal range (80 to 100 mm Hg). However, at O2 partial pressures below 60 mm Hg (steep part of the curve), shifts in the oxyhemoglobin dissociation curve can dramatically influence O2 transport.