FEATURE
ASH Clinical News turned to some experts
in the field for a review of the current data
on fresh versus stored blood, and what
those data mean for clinical practice.
With RBCs, Age Is Just a Number
As Dr. Zimring noted, RBCs undergo a
number of changes during storage. Free hemoglobin (from in-bag RBC breakdown)
can scavenge nitrous oxide (NO), which
may deprive blood vessels of necessary NO.
Studies have also shown that stored RBCs
acquire procoagulant activities and have
increased advanced glycation end (AGE)
products, which play a role in inflammatory pathologies post-transfusion, such
as transfusion-related lung injury.1 “The
bottom line is, you can look at red cells
that have been stored up to the limit of 42
days, and you can clearly document the
biochemical differences in those red cells
versus those that have been in storage for
just a few days,” Steven Kleinman, MD,
of the Centre for Blood Research at the
University of British Columbia in Vancouver, Canada, and senior medical advisor to
AABB, told ASH Clinical News.
In terms of patient outcomes, the data
supporting the hypothesis that older
blood is inferior to fresher blood come
mostly from retrospective and observational studies, as well as animal models.
For instance, in a 2008 retrospective
analysis of outcomes among patients
undergoing coronary artery bypass surgery who received transfusions of RBCs
stored for either <2 weeks or ≥2 weeks,
researchers found that 1.7 percent of the
2,000-plus patients who received fresher
RBCs died in the hospital, compared with
2.8 percent of patients who received older
blood (p=0.004). One-year mortality was
also significantly less in patients given
newer blood (7.4% vs. 11%; p<0.001).2
Another retrospective study of more
than 400,000 patient records in Scandinavia reported a 5 percent increased risk of
death among patients who had received
older blood (stored for >30 days). However, the researchers cautioned the “risk
pattern was more consistent with weak
confounding than with an effect of the
momentary exposure to stored RBCs.”3
Confounding was a limitation in both
of these observational studies, Dr. Kleinman agreed. “If you get older blood, you
are likely to get more units of blood,” he
said. “And if you get more units of blood,
you are probably sicker to begin with. The
people who received the older units had
lower survival, but that was most likely a
surrogate for their underlying conditions.”
But, in 2013, when researchers from the
National Institutes of Health conducted
the first randomized, blinded trial, they
showed that blood transfused at the end
of the storage period increased mortality. This was, though, an animal study:
Beagles infected with Staphylococcus
aureus pneumonia were randomized to
transfusion with either seven- or 42-day-
ASHClinicalNews.org
old canine universal donor blood.4
They observed a number of problems
associated with older-blood transfusion,
including increased mortality (p=0.0005),
increased arterial alveolar oxygen gradient
at 24-48 hours after infection (p<0.01),
and more severe lung damage as evidenced by increased necrosis, hemorrhage, and thrombosis (p=0.03).
Dr. Roback noted that these animal trials were done under fairly extreme conditions. “If you transfuse a big volume of red
cells stored for nearly 42 days, and if you
simultaneously add another insult – in
this case experimental pneumonia – the
test subjects that received older red cells
did much worse compared with those
who received fresher red cells. So, in those
extreme conditions, there is an adverse
effect caused by older red cells that doesn’t
happen when you use fresher red cells.”
“The stored
red cells look
different in the
bag in storage,
but does that
affect their usefulness when
transfused?”
—STEVEN KLEINMAN, MD
When Dr. Roback and co-authors explored this question in a limited number
of people, though, they found similar
outcomes. In the first study, 43 hospitalized patients with transfusion orders were
randomly assigned to receive either fresh
(<14 days) or older (>21 days) stored RBC
units; investigators noted a significant
reduction in NO-mediated vasodilation
at 24 hours post-infusion with older RBC
units (p=0.045), while fresh RBC transfusions had no effect (p=0.231).5
In a second study, Dr. Roback and colleagues evaluated blood stored up to 42
days, and found “previously unrecognized
vaso-inhibitory activity of stored RBCs,”
concluding that, “through this novel mechanism, transfusion of small volumes of stored
blood may be able to disrupt physiologic
vasodilatory responses and thereby possibly
cause adverse clinical outcome.”6
“In those very specialized systems in
which we specifically looked at one experimental parameter – in this case vascular
responsiveness – there was a difference
between receiving the freshest blood and
the oldest stored blood,” Dr. Roback said.
What Do the Studies Say?
But do these physiologic differences
between fresh and stored blood affect patient outcomes? And, if so, how can RBC
storage practices be changed to address
these adverse effects?
“The [stored] red cells look different in
the bag [in storage], but does that affect
their usefulness when transfused?” Dr.
Kleinman asked. “Some of the biochemical
elements in older blood are restored upon
transfusion and circulation. For instance,
there’s a compound called 2,3 DPG (2,3-diphosphoglycerate), which is part of an
energy metabolism circuit with adenosine
triphosphate (ATP). During storage, that
compound is depleted, but within 24 hours
of transfusion, it is replenished – just
through the act of being transfused.”
A number of randomized, controlled
trials (RCT) have recently made a strong
case for the vitality of old blood, or, at the
very least, that fresh blood is not necessarily superior.
First, there was the Age of Blood Evaluation (ABLE) pilot trial, which enrolled
critically ill adults from tertiary care
intensive care units (ICU) at 64 centers in
five countries.7
RBC units were leukoreduced (for an explanation of this process, see the SIDEBAR,
“What is the Big Deal About Leukoreduction?”) for storage in an addit