Almost immediately after it is donated, human blood begins to lose a key gas that opens up blood vessels to facilitate the transfer of oxygen from red blood cells to oxygen-starved tissues.
Thus, millions of patients are apparently receiving transfusions with blood that is impaired in its ability to deliver oxygen, according to Duke University Medical Center researchers.
They also found that adding this gas back to stored blood before transfusion appears to restore red blood cells' ability to transfer oxygen to tissues. These studies go a long way toward answering a major problem which many physicians are beginning to appreciate -- blood transfusions with banked human blood may do more harm than good for a majority of patients, according to the researchers.
Over the past five years, many studies, including some performed at Duke, have demonstrated that patients who receive blood transfusions have higher incidences of heart attack, heart failure, stroke and even death. While it is known that the banked blood is not the same as blood in the body, the reasons behind blood's association with worse outcomes have not been well-understood.
The key to the current findings is that nitric oxide in red blood cells is crucial to the delivery of oxygen to tissues. Nitric oxide keeps the blood vessels open. The new studies demonstrated that nitric oxide in red blood cells begins breaking down almost immediately after red blood cells leave the body.
"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 Duke's Jonathan Stamler, M.D., senior author of one of the PNAS papers, whose 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. 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.
"The issue of transfused blood being potentially harmful to patients is one of the biggest problems facing American medicine," continued Stamler, who is a professor of cardiovascular and pulmonary medicine. "Most people do not appreciate that blood has the intrinsic capacity to open blood vessels, thereby enabling oxygen to get to tissues. Banked blood cannot do this properly."
However, transfusions are still critically important, Stamler said.
"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."
It is estimated that close to 14 million units of red blood cells are administered to about 4.8 million Americans each year. National blood banks require that blood be stored for no more than 42 days after donation. After that time, unused blood must be discarded.
One team of Duke researchers, led by Timothy McMahon, M.D., Ph.D., wanted to document exactly what happens to banked blood over those 42 days. Using human blood stored according to national standards, the researchers sampled the blood at regular intervals.
"We were surprised at how quickly the blood changes -- we saw clear indications of nitric oxide depletion within the first three hours," said McMahon, an associate professor of pulmonary medicine. "Of concern to us is that nitric oxide levels become depressed soon after collection, suggesting that even 'fresh' blood may have adverse biological characteristics."
Nitric oxide is not only needed for red blood cells to off-load oxygen, it may also influence the flexibility of the saucer-shaped cells. As nitric oxide levels decrease, the red blood cells become stiffer, making it more difficult for them to deform their shape in order to squeeze through tiny blood vessels.
Stamler's team confirmed that nitric oxide levels started dropping quickly in stored human blood, and that this resulted loss of its ability to dilate blood vessels. So they wanted to see if adding the gas back to stored blood might restore the ability to open vessels, using dogs as a model.
Since blood is often given to patients to prevent heart attacks, and yet paradoxically may cause heart attacks, the investigators measured blood flow to the hearts of oxygen-deprived animals.
"When we gave stored blood it couldn't increase blood flow properly," Stamler said. "However, after replacing the nitric oxide, blood flow to the heart was increased, reflecting increased blood vessel dilation. This 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."
Both McMahon and Stamler believe that a large-scale randomized clinical trial in humans is needed, arguing that blood has both benefits and risks, and therefore should be evaluated in the same manner as medications.
"There is little doubt that transfused blood can be harmful," said Stamler. "We are only uncertain about how serious the problem is. The availability of a potential solution will hopefully focus the attention of the medical community on the potential magnitude of this problem."
These results are reported in two separate papers appearing early on-line in the Proceedings of the National Academy of Sciences.
Stamler's research was supported by the National Institutes of Health and Duke Anesthesiology Fund. McMahon's study was supported by the American Heart Association and N30 Pharma, a company that has a license agreement with Duke to develop nitric oxide-based therapies.
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