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DURHAM, N.C. –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, who reported the results of their studies in two
separate papers appearing early on-line in the Proceedings of
the National Academy of Sciences.

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."

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.