Study Links Pain of Sickle Cell Disease to Excess Hemoglobin

By WARREN E. LEARY

ASHINGTON, Nov. 10 — The painful episodes suffered by people with sickle cell disease appear to be caused by excess hemoglobin in the blood from damaged red blood cells, researchers reported today.

Studies found that the hemoglobin rapidly destroyed nitric oxide, a gas known to relax blood vessels and contribute to good circulation, said the report, published in Monday's issue of the journal Nature Medicine.

The destruction of nitric oxide begins a cascade of events leading to constricted blood vessels, high blood pressure in the lungs and the restricted flow of oxygen and nutrients to vital tissues and organs. This causes the episodes of intense pain, known as crises, experienced by sickle cell patients, said the researchers, most of them from the National Institutes of Health.

The scientists said the findings pointed to new approaches that might cancel the hemoglobin effect and relieve some of the suffering, which some patients say is more agonizing than the pain of childbirth or terminal cancer.

"We think this is an important mechanism leading to the painful symptoms of sickle cell disease and, perhaps, other conditions that involve damaged red cells," said the lead researcher, Dr. Mark T. Gladwin of the National Institute of Diabetes, Digestive and Kidney Diseases. "But more work is needed to prove it."

Dr. Robert P. Hebbel of the University of Minnesota, a sickle cell blood researcher not connected with the study, said the work — once confirmed — might help explain some of the pathology of the disease.

"This is an important observation, one that resonates as making sense," Dr. Hebbel said.

Dr. Jack R. Lancaster Jr. of the University of Alabama at Birmingham, another prominent researcher in the field, called the study "a beautiful piece of analysis" that has direct therapeutic implications.

Sickle cell disease is a family of inherited blood disorders caused by a flaw in the gene that makes hemoglobin, the component of red blood cells that carries oxygen. When low on oxygen, this flawed hemoglobin causes blood cells to stiffen and contort into jagged sickle shapes. These distorted cells block small blood vessels and cause vascular inflammation and other changes that interfere with blood flow.

The disease afflicts millions worldwide, primarily those with ancestors from Africa, the Mediterranean and India. In this country, an estimated 80,000 people, mostly African-Americans, have the disease.

Dr. Gladwin said the new work connected several facts already known about the disease, including that the distortion of red blood cells into sickle shapes destabilizes their membranes and prematurely destroys 10 percent of a patient's total red cells each day, causing anemia. Rates of red cell disruption rise even higher during crises, he said.

This cell destruction dumps cellular hemoglobin into the bloodstream, a phenomenon that took on new importance as researchers started paying more attention to the role of nitric oxide in the body. It has been known for decades that hemoglobin is a potent scavenger of nitric oxide and a constrictor of blood vessels, experts said. Laboratory work more than a decade ago showed that free hemoglobin in solutions destroyed nitric oxide 1,000 times as fast as hemoglobin confined in blood cells.

Nitric oxide, a short-lived gas produced by cells lining the blood vessels, is now known to be a primary regulator of blood flow, Dr. Gladwin said. Among other things, it prevents the aggregation of platelet cells that promote clotting, and it protects cell membranes. The gas is also a major part of the system to protect the body from excess hemoglobin.

In the latest study, the researchers tested blood from 27 sickle cell patients and 28 normal volunteers and found that plasma from the patients rapidly inactivated nitric oxide. When free hemoglobin was removed in the laboratory, the plasma consumption of nitric oxide fell to nearly normal levels, the researchers found. They concluded that excess hemoglobin in the blood of sickle cell patients quickly overwhelmed the body's system for neutralizing it.

Dr. Gladwin said the findings would prompt study of new treatment approaches, including having patients breathe higher doses of nitric oxide to try to neutralize the excess hemoglobin in their blood. Other treatment possibilities include giving patients supplemental supplies of haptoglobin, a naturally occurring substance that clears hemoglobin from the body, he said.