Hemoglobinopathies

Sickle cell disease is the most prevalent genetically based disease in the United States. Approximately 1 in 12 Americans of African descent are carriers, having one allele coding for HbS and one gene for HbA. About 1 in 375 Americans of African descent are homozygous for HbS and have the active disease. High occurrence of the HbS allele also occurs in people who live, or whose ancestors lived, in certain parts of Asia, the Mediterranean, and the Middle East.

The alpha chain gene is found on chromosome 11. Each gene is made up of a very long strand of nucleotides. In sickle cell disease, there is a change in only one nucleotide in the sequence that codes for the beta chain: A thymine is substituted for an adenine.

Genes code for proteins. Because of that change in one nucleotide, a slightly different protein is produced. HbS differs from HbA by only one amino acid: Glutamic acid in HbA is replaced by valine in the sixth position on the beta chain. The substitution does not affect the hemoglobin molecule's ability to bind with oxygen. HbS can carry oxygen just as effectively as HbA. However, glutamic acid is a hydrophilic ("water-loving") amino acid, whereas valine is hydrophobic ("water-hating"). The valine occurs on the outside of the beta chain. The hydrophobic portions of HbS molecules are attracted to each other. When the concentration of oxygen is low, as it is deep in the body's tissues, HbS molecules will attach to each other. Since a single red blood cell contains about 250 million hemoglobin molecules, this can result in very long chains, or polymers.

The polymerization that occurs distorts the red blood cell into a curved, sickle shape. Whereas normal erythrocytes travel smoothly through the blood vessels, these unusually elongated and pointed erythrocytes move much more slowly and can block smaller blood vessels. Both the slow movement and the blockages further reduce the amount of oxygen in the blood, promoting even more polymerization and sickling.

The decreased amount of oxygen in the blood also damages local tissues and will cause permanent damage if it lasts long enough. The lack of oxygen is very painful. This progressive cycle of worsening symptoms, called a vaso-occlusive crisis, can last for more than a week.

People with sickle cell disease often develop other health problems. For example, the crescent shaped erythrocytes have shorter life spans than normally shaped cells do. A healthy red blood cell lives about 120 days, while a sickle cell lives only for 10 to 30 days. The body is unable to replace the red blood cells quickly enough, resulting in anemia.

Situations that cause the body to use up oxygen, such as exercise, can precipitate a vaso-occlusive crisis. Also, because dehydration causes the hemoglobin molecules to be packed more tightly together within the erythrocyte, insufficient fluid intake can also cause red blood cells to sickle.