2007-10-09

DURHAM, N.C., Oct. 9 -- The oxygen-transporting efficacy of stored blood begins to decay almost immediately but adding nitric oxide may keep it fresh, two groups of researchers here said.

Because stored red blood cells become deficient in nitric oxide, which limits their ability to get oxygen to tissues that need it, transfusions of banked blood may do more harm than good, the Duke researchers here reported online in the Proceedings of the National Academy of Sciences.

But adding nitric oxide - at least in animals -- restores the cells' ability to dilate blood vessels and oxygenate tissue, according to Jonathan Stamler, M.D., and colleagues.

The finding opens to the door to possible interventions that would improve the efficacy of transfusions, they said. "Blood can be life saving, only it is not helping the way we had hoped and in many cases it may be making things worse," added Dr. Stamler.

"In principle," he added, "we now have a solution to the nitric oxide problem -- we can put it back -- but it needs to be proven in a clinical trial."

In a second paper in the journal, Tim McMahon, M.D., Ph.D., and Duke colleagues, reported on exactly how quickly the deterioration of banked blood occurs.

"We saw clear indications of nitric oxide depletion within the first three hours," Dr. McMahon said.

That implies that even so-called fresh blood may already have what he called "adverse biological characteristics."

The two research groups are independent but related, a Duke spokesman said. Dr. McMahon is a former student of Dr. Stamler who now has his own lab at Duke.

Dr. Stamler and colleagues, suspecting that a deficiency in nitric oxide was responsible for higher rates of death and ischemia among transfusion recipients, focused their attention on a molecule called S-nitrohemoglobin. S-nitrohemoglobin is a derivative of hemoglobin that carries nitric oxide.

In vitro studies showed that levels of S-nitrohemoglobin declined rapidly in stored red blood cells, Dr. Stamler and colleagues said, with a 70% drop in the first day -- a difference from fresh blood that was significant at P<0.05.

By day 21, the molecule was below the level of detectability. In the U.S., red blood cells can be stored up to 42 days.

But treating red blood cells with a solution of aqueous nitric oxide resulted in a 10-fold increase in S-nitrohemoglobin compared with untreated samples and the levels of S-nitrohemoglobin were not significantly different from fresh blood.

In conditions with normal oxygen availability, use of stored but treated blood cells in dogs was associated was a modest but significant (P<0.02) increase in coronary blood flow, compared with stored and untreated cells.

On the other hand, when the dogs were hypoxic, the treated cells caused a significantly greater increase (P<0.001) in coronary blood flow, the researchers found.

The finding "suggests that adding nitric oxide to human banked blood could theoretically improve its ability dilate blood vessels and thus prevent heart attacks and even death in patients," Dr. Stamler said.

Dr. Stamler's group originally discovered the role of red blood cell nitric oxide in oxygen delivery.

"Nitric oxide opens up the tiny blood vessels, allowing red blood cells to pass and deliver oxygen," he said. "If the blood vessels cannot open, the red blood cells back up in the vessel and tissues go without oxygen."

"The result can be a heart attack or even death," he said.

Dr. McMahon and colleagues tested stored human blood cells for a range of parameters and - like Dr. Stamler's group - they observed declines in S-nitrohemoglobin and related molecules that were significant at P<0.01 as early as three hours after storage.

They concluded that it would be "rational to test in future clinical trials" whether replenishing S-nitrohemoglobin or preventing its loss would improve patient outcomes.

The study by Dr. Stamler and colleagues was supported by the NIH and the Duke University Anesthesiology Fund. Dr. Stamler and co-author James Reynolds, Ph.D., have consulting and/or equity relationships with Nitrox/N30, which is developing ways to treat disorders of oxygen delivery.

The study by Dr. McMahon and colleagues was supported by the American Heart Association and Nitrox/N30. Dr. McMahon and several co-authors have financial relationships with Nitrox/N30, while two of the study's co-authors were employees of the company. Dr. McMahon is co-inventor of a patent: "Red blood cells loaded with S-nitrosothiols and uses therefore."

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