April 2001

From University of North Carolina at Chapel Hill

In possible boon to sickle cell victims, basic scientists find reason cells stick

CHAPEL HILL - Despite recent advances in treating sickle cell disease, an inherited illness chiefly affecting black people in the United States, patients still suffer periodic painful episodes known as crises.

Those debilitating events result from misshapen red blood cells sticking to and clogging up blood vessels like twigs in a pipe and blocking oxygen supply to various tissues. Organ damage and shortened life spans often result.

Now, researchers at the University of North Carolina at Chapel Hill have discovered a protein on the surface of sickled red cells that causes them to stick to another protein that is part of blood vessel walls. Their work, so far confined to the test tube, offers new hope that treatments for sickle cell disease will improve, they say.

A report on the experiments, funded by the National Institutes of Health, appears in the April 1 issue of the journal Blood. Authors, all at the UNC School of Medicine, are Dr. Julia E. Brittain, postdoctoral fellow in pharmacology; medical student Kathryn J. Milnar; technician Christopher S. Anderson; Dr. Eugene P. Orringer, professor of medicine; and Dr. Leslie V. Parise, professor of pharmacology.

"We had previously found that sickle red blood cells in these patients are, in a sense, 'stickier' than normal red blood cells," Parise said. "In our new work, we have identified integrin-associated protein, or IAP, on sickled cells as a receptor for thrombospondin, a blood vessel wall protein. IAP now becomes a potential new therapeutic target for preventing the cells from adhering to the vessels."

The findings are possibly good news for sickle cell patients because the team may have identified the mechanism, or one of the mechanisms, that causes the painful crises, she said. Understanding what's involved in such an important process could be the key to controlling it.

Brittain said the team's experiments used a system that mimics blood flow and shear conditions inside blood vessels, as well as other characteristics such as temperature and pressure.

An antibody against human IAP succeeded in keeping the affected red blood cells from sticking to thrombospondin in the blood flow system, she said. From that they concluded that IAP may cause part of the impaired blood flow.

Thrombospondin also is elevated in blood plasma of sickle cell disease patients, Parise said. That might be important in causing the crises if the circulating thromobospondin acts like a glue. Blood vessel walls damaged by the illness might boost clogging as the two proteins interact more readily because of the damage.

"The next step will be to test our results in a mouse model of sickle cell disease and evaluate potential blockers there," Brittain said. "We are still years away from taking this into the clinic, but we are one step closer than we were a year ago."

About 150 in every 100,000 U.S. black children suffer from sickle cell disease, also known as sickle cell anemia, according to the American Medical Association. About one in 12 blacks has sickle cell trait, which means they carry a gene that produces a defective kind of hemoglobin, the complex protein that carries oxygen to tissues throughout the body.

If a person inherits the gene from a parent, he or she is a carrier like the parent but usually is symptom free. When two carriers have a child, there's a 25 percent chance the child will have sickle cell disease, 50 percent chance the child will be a carrier and a 25 percent chance he or she will have neither.

Until about 1960, most infants born with the illness died in childhood, but today with improved treatments many survive into adulthood. A relatively simple blood test can show who carries the sickle cell gene, and doctors advise that couples who both carry it should undergo genetic counseling before starting a family.












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