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http://www.dukemednews.duke.edu/news/article.php?id=10149

http://www.physorg.com/news111083922.html  

Studies: Stored Blood Lacks Nitric Oxide 

Red Cross worker Nelson Wilson, right, prepares a volunteer blood donor prior to the Oakland Raiders-New Orleans Saints preseason game in Oakland, Calif. in this Sept. 1, 2005 file photo. (AP Photo/Ben Margot)

(AP) -- Much of the stored blood given to millions of people every year may lack a component vital for it to deliver oxygen to the tissues. Nitric oxide, which helps keep blood vessels open, begins breaking down as soon as blood goes into storage, two research teams report in separate studies in this week's online edition of Proceedings of the National Academy of Sciences. 

In recent years, doctors have become increasingly concerned about levels of heart attack and stroke in patients receiving transfusions and the new findings may help explain that. 

"It doesn't matter how much oxygen is being carried by red blood cells, it cannot get to the tissues that need it without nitric oxide," said Dr. Jonathan Stamler of Duke University, leader of one of the research groups. 

Blood vessels relax and constrict to regulate blood flow and nitric oxide opens up blood vessels, allowing red blood cells to deliver oxygen, he explained. 

"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. 

"The issue of transfused blood being potentially harmful to patients is one of the biggest problems facing American medicine," said Stamler. 

Several of the researchers, including Stamler, have consulting and/or equity relationships with Nitrox/N30, a company developing nitric oxide based therapies. 

The second research team, led by Dr. Timothy McMahon, also at Duke, studied the changes in stored blood over time. Currently blood is allowed to be kept in blood banks for up to 42 days. After that it must be discarded. An estimated 14 million units of red blood cells are administered to about 4.8 million Americans annually. 

"We were surprised at how quickly the blood changes - we saw clear indications of nitric oxide depletion within the first three hours," McMahon said in a statement. 

Stamler said in a telephone interview that the researchers knew that nitric oxide is responsible for opening up small blood vessels, but had not previously measured the amount of that chemical in stored blood. 

"Surprisingly, we found blood depleted profoundly by day one and it remained depleted through day 42," he said. 

But if they restored the nitric oxide at any point, the red blood cells were again able to open blood vessels and deliver oxygen to tissues, they said. They tested the blood with added nitric oxide both in the laboratory and in dogs. 

"This is an important observation and it needs to be followed up," said Dr. Louis Katz, a past president of America's Blood Centers, which provides about half the nation's blood. 

"If you are going to store red cells, is there a way to make sure appropriate nitric oxide levels are maintained?" said Katz, who was not part of the research teams. 

It is possible that these findings may make the public concerned about transfusions, Katz said: "There is no doubt, if you are bleeding to death from a trauma" you need a transfusion. 

Stamler agreed that "physicians need to be able to give blood if people are bleeding profusely." 

Overall, Katz said: "This is neat research. It needs to be proven that it's clinically relevant." 

Stamler agreed on the need for clinical trials. 

"Banked blood is truly a national treasure that needs to be protected," Stamler 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. In principle, 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." 

The research was supported by the National Institutes of Health, Duke Anesthesiology Fund, the American Heart Association and N30 Pharma, which has a license agreement with Duke to develop nitric oxide-based therapies. 

http://www.cbbsweb.org/enf/2007/nitox_bankbld.html
Experts respond to this article.

What are expert thoughts about the recent articles on Nitric Oxide and banked blood?
The medical director of a transfusion service in Southern California asks "What are expert thoughts about the recent articles on Nitric Oxide and banked blood?"
Neil Blumberg, Professor of Pathology & Laboratory Medicine, University of Rochester Medical Center (attribution used with permission) writes:
"I think it is well established in the scientific literature that stored red cells do weird things to the microcirculation ('functional capillary density' is decreased in animal models). It is also well established in observational studies that patients with acute coronary syndromes (e.g., MI, unstable angina) seem to do markedly worse when transfused than not transfused at similar hematocrits. Cause and effect remain hypothetical, but, in my view, very likely to be the case.
Red cells that are nitric oxide poor will presumably scavenge nitric oxide, a vasodilator, and thus cause vasoconstriction and reduced oxygen delivery, and this is an attractive partial explanation for increased MI's and such. So I think these data are probably a true bill and something that may yield clinical improvement if red cell nitric oxide and 2,3 DPG levels can be restored just prior to transfusion. And thus actually deliver oxygen acutely rather than impair its delivery, which may well be what's happening, at least initially after a red cell transfusion.
The actual papers from the Duke investigators aren't available yet on the PNAS website, so I don't know if the authors address the additional issue that non-leukoreduced red cells in particular are rich in supernatant sCD40L and other pro-thrombotic and pro-inflammatory molecules that could be deleterious to patients with vascular disease. Most of the clinical correlative studies in the literature mentioned above involve patients getting non-leukoreduced transfusions rich in inflammatory, pro-thrombotic mediators, as well as residual platelet microparticles, white cell membranes and microparticles, and Lord knows what else. So it's not clear how much either factor, nitric oxide scavenging and infusion of a mixture of deleterious mediators contributes to the clinical observations, if either. My bet is on both.
What is clear to me and some others in the field is that fewer patients should be transfused and we are doing more harm than good with our current transfusion practices in many cases."
The editors welcome additional questions or discussion. Articles on the topic include: Banked Blood Loses Ability to Deliver Oxygen to Tissues (DukeMedNews) and Studies: Stored blood lacks nitric oxide (SanLuisObispo.com) and Why Banked Blood Goes Bad (Time).

Hazards from Nitric Oxide missing in Donor Blood