Studies Probe Weaknesses in Donated Blood

MONDAY Oct. 8, 2007 -- Researchers have spotted a chemical deficiency that renders donated blood stored in blood banks less effective at delivering oxygen to tissues, compared to fresh blood.

But in a second study, the same group of scientists may have also found a way to remedy the problem.

Though unlikely to change current clinical practice in the short term, the findings help explain why, in many cases, blood transfusions do more harm than good by boosting risks for heart attack, organ failure and even death, experts say.

The studies "reinforce that conservatism [in giving transfusions] is important," said Dr. Louis Katz, executive vice president for medical affairs at the Mississippi Valley Regional Blood Center in Davenport, Iowa, and past president of America's Blood Centers, a network of community blood banks. "First, do no harm -- don't transfuse unless you must," he said. Katz was not involved in either study.

Both reports were published this week in the early online edition of the Proceedings of the National Academy of Sciences.

Drs. Jonathan Stamler and Timothy McMahon, of Duke University Medical Center in Durham, N.C., led separate research teams that independently examined the ability of fresh and banked human blood to serve its medical purpose -- to increase oxygen availability to tissues that need it.

This activity is based on two parameters -- how much oxygen, and how much nitric oxide the red blood cells hold. Nitric oxide (NO) is a vasodilator -- a compound that opens (dilates) blood vessels. It is carried in red blood cells by hemoglobin, the oxygen-delivering protein that gives red blood cells their color. When hemoglobin encounters a tissue with relatively little oxygen, it releases NO, thereby causing blood vessels to open and ease the red cells' entry into the tissue, where they can release their oxygen.

Stamler and McMahon (previously a research fellow in Stamler's lab) found that stored blood rapidly loses the bulk of its NO within three hours of collection. Its ability to induce vasodilation likewise diminishes, they said.

"Everybody thinks if you give back oxygen-carrying red blood cells, you will get more oxygen to tissues," said Stamler. "No, that's not the case. The blood we give cannot open vessels, and thus cannot deliver oxygen, and we think that's because it's missing nitric oxide gas."

The researchers also found that stored red cells gradually lose their "membrane flexibility" -- a physical attribute of red cells that allows them to squeeze into narrow capillaries, and which may also be related to NO depletion.

Some five million patients receive blood transfusions annually in the United States, amounting to almost 14 million units of blood, according to a 2005 report.

Yet, except in cases of trauma, there are few guidelines on exactly who should receive blood transfusions, and little agreement over how much they should get. Existing clinical trial data, mostly in the form of retrospective analyses, suggest that, if anything, giving blood may harm patients more than it helps them.

"Overall, the [previous clinical] trials have shown that while bleeding is bad, and while decreases in blood count is bad, giving blood back is not good -- that's the paradox," explained Stamler. He said extensive data exists to support an association between blood transfusions and elevated risk of heart attack, organ damage, and death.

The new studies provide a molecular rationale for these observations. Not only can NO-depleted, stored red blood cells not open blood vessels, they may actually block capillaries in already oxygen-starved tissues, exacerbating tissue damage. Furthermore, donated blood cells may act as a "sink" to soak up NO, thereby causing vessels to contract and become even more impassible.

"This [study] is an important reminder that while transfusions are lifesaving in some settings, there are also settings where we know patients do better with a restrictive transfusion strategy," McMahon said.

According to Katz, the results must now be replicated in controlled clinical trials. "If it is true, it raises the question of, are there things we can do in the bag [of donated blood] that would make this not a problem? Can you put nitric oxide in the bag?"

Stamler's group addressed that challenge in a study conducted with dogs. They found that human red cells' vasodilatory activity could be restored at any point up to 40 days following collection by treatment with NO, thereby improving blood flow to the heart in blood recipients.

"The hope would be that this will also work in humans," Stamler said. "We already know that the blood we give people is not normal and that it cannot open vessels properly. Our hope is if we put the nitric oxide back in, we could cure this problem."

In the meantime, those patients in need of a blood transfusion would do well to stay informed, Katz said. "The bottom line on transfusion is to ask what is the functional benefit of transfusion in this patient at this time," he said. "We (docs) are often guessing, but good docs make good guesses."

Both Stamler and McMahon noted conflicts of interest in their reports, including grant support and consulting fees from, and equity holdings in, Nitrox/N30 Pharma, "a company that is developing strategies for treating disorders of oxygen delivery," according to Stamler's manuscript.

More information

For more on blood transfusions, visit the U.S. National Library of Medicine.

Posted: October 2007


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