NIH Clinical Center

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Media Notice
November 25, 2002

Contact: Dianne Needham, Warren Grant Magnuson Clinical Center Communications Office, (301) 496-2563

Unraveling the Pain of Sickle Cell Anemia

People with sickle cell anemia suffer episodes of excruciating pain caused by blockage of blood vessels by sickled red blood cells. This blockage may be exacerbated by the over abundance of hemoglobin in the blood from faulty red blood cells, report researchers from the Warren Grant Magnuson Clinical Center at the National Institutes of Health (NIH). A study published in Nature Medicine (November 11 online; December 1 print) explains the link between freely circulating hemoglobin and the pain associated with sickle cell anemia.

In individuals with sickle cell anemia normally disc-shaped red blood cells become crescent shaped because of an inherited abnormal type of hemoglobin called hemoglobin S. Hemoglobin is a vital protein that carries oxygen from the lungs to the body tissues. For those who have inherited this mutation the red blood cells don't work properly, break down and release large amounts of hemoglobin directly into the blood stream.

Lead researcher Dr. Mark Gladwin and his colleagues at the NIH Clinical Center have discovered that the chronic release of hemoglobin into the blood stream overwhelms the systems in place to remove it. "This excess cell-free hemoglobin reacts with the gas nitric oxide, a short-lived gas produced by cells lining the blood vessels, 1,000 times more rapidly than it would if the hemoglobin was in a red blood cell," Dr. Gladwin said. "Nitric oxide has an important role in regulating blood flow responses, and when unavailable (due to excess removal by the freely circulating hemoglobin) can cause vessels to constrict unnecessarily."

This study demonstrates that the cell-free hemoglobin rapidly destroys the nitric oxide, according to Dr. Gladwin. Destruction of the nitric oxide leads to constricted blood vessels, high blood pressure in the lungs and the restricted flow of oxygen and nutrients to vital tissues and organs. "This could contribute to the episodes of severe pain, known as crises, endured by sickle cell patients," he explained.

Nitric oxide inhalation therapy and a set of highly sensitive assays were used by the scientists in this study to show that nitric oxide scavenging by the cell-free hemoglobin may play a major role in sickle cell disease. They also show that the increase in cell-free hemoglobin increases a soluble vascular cell adhesion molecule which can trap red blood cells and initiate a vicious cycle.

"The patients in our study were given inhaled nitric oxide gas. We were able to show that this therapy inactivated the cell-free hemoglobin, a mechanism that might reduce the severity or duration of pain crisis," Dr. Gladwin said.

The research team, that includes investigators from the National Institute of Diabetes, Digestive, and Kidney Diseases, NIH; the National Heart, Lung, and Blood Institute, NIH; and the Medical College of Wisconsin, believe that these findings hold great promise both for sickle cell research and for better understanding of the complications of other diseases in which red blood cells breakdown, such as malaria and cardio-pulmonary bypass.

The full Nature Medicine article is available at

The Warren Grant Magnuson Clinical Center is the research hospital of the National Institutes of Health. Through clinical research, physicians and scientists translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. NIH is an agency of the U.S. Department of Health and Human Services.

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