“Sickling” in vertebrates: Animal studies vs. sickle cell disease

Before the description of sickled cells in humans, erythrocytes of normal deer were found to deform, or sickle in vitro. Sickling required oxygenation and alkalization; human erythrocytes sickle because their abnormal sickle hemoglobin (HbS) polymerizes following deoxygenation in vivo and in vitro. HbS and some deer hemoglobins polymerize because of specific amino acid contacts between hemoglobin beta-globin chains, although different amino acid residues form the contact points of the polymer. Hemoglobin precipitation is found in other vertebrates. Most often it is a benign in vitro phenomenon. Natural selection established the balanced polymorphism accounting for the high prevalence of HbS where malaria is endemic. A similar selective advantage for “sickling” animal hemoglobins is unproven. The mean corpuscular hemoglobin concentration is about 30 to 35 g/dL. Perhaps during in vitro studies of susceptible animal hemoglobins, minor changes in buffer pH, osmolality and the ligand state of the molecule increases mean cell hemoglobin concentration beyond its solubility limit allowing precipitation.