Oxidative denaturation in congenital hemolytic anemias: the unstable hemoglobins.

The unstable Hbs vary in their degree of instability and in their clinical manifestations, with some causing a hemolytic anemia in the heterozygote. The molecular abnormalities result in increased flexibility or conformational distortion that alters the environment of the heme groups. As a result, oxidation to methemoglobin is enhanced and, more importantly, there is also rapid conversion of methemoglobin to hemichrome and sometimes heme loss, with resultant denaturation and precipitation as Heinz bodies. Methemoglobin formation and recycling are accompanied by release of superoxide. Distortion and decreased deformability of the cells due to the presence of Heinz bodies, leading to trapping in the microcirculation, is one likely contributor to red cell destruction; membrane damage caused by excess oxidants released from the unstable Hb is another. However, a prime factor could be hemichrome binding to the cytoplasmic domain of band 3, leading to clustering of band 3 in the membrane and aggregation of the hemichrome as Heinz bodies. This could result in immunologic recognition of the redistributed band 3 by autologous senescent antibodies, leading to removal of the cells from circulation. Hemolytic crises are often precipitated by the administration of redox-active drugs or by infections. One mechanism for this is the enhanced intracellular oxidation of Hb due either to reaction with the drug or with oxidants generated by phagocytic cells in combating the infectious agent. Another factor in infections is pyrexia, since even a small elevation in temperature can cause a marked increase in the rate of conversion of methemoglobin to hemichrome.