Bad Blood
to some degree, particularly for acutely
ill patients, or perioperative patients that
are less sick. Chances are that fresh blood
won’t improve their lot either.”
Next up was the Red-Cell Storage
Duration Study (RECESS), a multicenter,
prospective trial examining 1,481 patients
12 years or older who were undergoing
complex cardiac surgery and were likely
to need an RBC transfusion.8
The RECESS patient population included 1,481 cardiac surgery patients who were
selected to receive blood either housed for
≤10 days or for ≥21 days. To determine the
effect of blood storage duration on patient
outcomes, the investigators measured the
change in each patient’s Multiple Organ
Dysfunction Score (MODS), then compared the scores from before surgery with
scores obtained seven days after surgery (or
until the patient’s time of death or discharge, whichever came first).
The investigators found no significant
differences between the two groups, even
after comparing the change in MODS
for only post-operative scores. The mean
change in the MODS score at seven days
(the study’s primary outcome was 8.5
(out of a 24-point scale) in the short-term
storage group and 8.7 points in the longerterm storage group (p=0.44).
There were also no significant differences between the groups for all-cause
mortality, 28-day change in MODS, length
of hospital stay, or length of ICU stay,
leading the authors to conclude that “a
between-group difference of 1 point or
less in the change in MODS is unlikely
What is the Big Deal About
Leukoreduction?
Leukoreduction is the process of removing white blood cells
(WBCs) from blood before storage.1 Decades’ worth of research
has shown that removal of leukocytes is associated with improved clinical outcomes, such as a reduction in the incidence and
severity of febrile transfusion reactions, a reduction in the risk of
cytomegalovirus transfusion, and a reduced risk of alloimmune
platelet refractoriness.2
Leukocytes are considered a contaminant of other cellular blood components, including RBCs, and they have been
recognized as a contributor to – if not the cause of – a number of
transfusion-related adverse events, including immunologically
mediated effects, infectious disease transmission, and reperfusion injury.
In other words, “leukocytes in the red cells have no clinical
value,” Dr. Hébert stated. “But the potential harms attributed to
them [in banked blood] are substantial. Generally speaking, the
white cells go along for the ride, but no good comes of them being
in the bag.”
Given the benefits of leukoreduction, 20 countries (including
Canada, New Zealand, much of the European Union, the United
Kingdom, the United Aram Emirates, and Qatar) have mandated
universal leukocyte reduction (ULR) as a matter of public blood
safety policy.
When Canada implemented its leukoreduction policy, Dr.
Hébert and colleagues evaluated its role in decreasing post-operative mortality and infection. Compared with a control period, they
noted that leukoreduction lowered the odds of death, but not
serious nosocomial infections. However, it did cut the frequency
of post-transfusion fevers.3
The U.S. FDA does not mandate ULR of RBCs, although the
agency’s blood product advisory committee has twice called for a
ULR protocol to be implemented.
However, the additional cost of leukocyte reduction has
delayed implementation of the policy in the United States. “The
differences in practice, belief, and opinion on how best to spend
money for blood components has formed the basis for the controversy in the United States over ULR,” according to one set of
experts. “In fact, the ULR debate has become so politicized that it
has become one of the most divisive issues in the history of U.S.
transfusion medicine.”4
REFERENCES
1. U.S. Department of Health & Human Services. “What is a blood transfusion?” Accessed
January 9, 2015 from https://www.nhlbi.nih.gov/health/health-topics/topics/bt.
2. Blajchman MA. The clinical benefits of the leukoreduction of blood products. J Trauma.
2006;60(Suppl 6):S83-90.
3. Hébert PC, et al. Clinical outcomes following institution of the Canadian universal
leukoreduction program for red blood cell transfusions. JAMA. 2003;89:1941-9.
4. Bassuni M, Blajchman M, Al-Moshary M. Why implement universal leukoreduction? Hematol
Oncol Stem Cell Ther. 200 8;1:106−123.
68
ASH Clinical News
to be clinically significant or to warrant
a major change in the practice of blood
banking,” according to lead investigator
Marie Steiner, MD, of the University of
Minnesota in Minneapolis.
Although RECESS looked at fresher
blood versus middle-aged blood (not the
oldest stored blood), Dr. Roback praised
the trial for being one of the largest, most
well-designed RCTs published on the age
of transfused blood.
The Fresher, the Better?
Of course, RECESS and ABLE were not
performed specifically in patients with
blood disorders. For hematologists, results
from the TOTAL trial hit closer to home,
according to Dr. Kleinman.
In TOTAL, the findings of which
were presented at the 2015 ASH Annual Meeting, 290 children (age range =
6-60 months) with malaria or sickle cell
disease were randomized to receive leukoreduced RBCs that had been stored for
one to 10 days versus 25 to 35 days.9 Investigators looked specifically at whether
refrigerated blood storage diminished
the blood’s ability to transfer oxygen
to tissues, as measured by transfused
patient’s blood lactate levels, explaining
that, when tissue oxygen levels are critically low, lactate levels rise, and when
tissues are successfully re-oxygenated,
lactate levels may fall again.
”We still don’t
know at what
point blood gets
‘very old’ and
potentially dangerous. To push
the limit ... in
patients becomes
unethical.”
—PAUL HÉBERT, MD
Mean lactate levels were not statistically different between the two groups
and neither were 30-day recovery rates,
they stated, suggesting that longer-storage
RBCs are not inferior to shorter-storage
RBCs.
In Dr. Kleinman’s estimation, the results
from the TOTAL trial have been overlooked. “This study hasn’t been talked
about much, but I believe it moves the
debate a little more in favor of the argument that stored blood doesn’t affect clinical outcomes,” he said. Additionally, the
TOTAL results may have significance for
global health policy decisions regarding
the acceptable duration of RBC storage,
particularly in developing nations where
blood supplies are already limited.
Another pediatric study, ARIPI, echoes
the TOTAL results, demonstrating that
the use of fresh RBCs (≤7 days) compared with standard stored blood did not
improve outcomes (including major neonatal morbidities such as intraventricular
hemorrhage or nosocomial infection) in
premature, very-low-birth-weight infants
who required a transfusion.10
Lastly, Dr. Kleinman described a metaanalysis and systematic review evaluating
12 trials with over 5,000 participants that
reported the following:11
• Similar risk of death for fresh
versus old transfused blood
(relative risk [RR] = 1.04; p=0.45)
• No difference in adverse event with
age of red cells (RR=1.02; p=0.74)
• A 9% relative increase in the risk
of infection with fresh blood
(RR=1.09; p=0.04)
An ongoing Canadian multicenter trial,
INFORM, may bolster this conclusion,
the authors noted. The three-year trial,
started in 2012 and completed last year,
“aims to determine the effect on in-hospital death rates of transfusing the freshest
available blood compared with standardissue blood.”
The experts who spoke with ASH Clinical News were divided on how INFORM
results may, or may not, affect the “fresh
versus old” debate – especially in terms
of patients who receive large volumes of
end-date blood.
“If the investigators are able to do a subgroup analysis of patients who did receive
the oldest blood, INFORM may completely change the course of the debate,”
Dr. Roback pointed out.
Dr. Hébert expressed more skepticism,
though. “We all hope that it will give us
new information, but the trial is basically
comparing ‘front of the fridge’ versus
‘back of the fridge’ blood policies,” he said.
“The chances of the investigators finding
something beyond what we found [in
ABLE] are not likely.”
The Debate Rages On
Given the similar rates of patient outcomes among ABLE, RECESS, TOTAL,
and ARIPI, clinicians may feel that the
new-versus-old debate has been settled –
but not quite.
“In the scientific, academic community, the topic has seen advancement,” Dr.
Kleinman said. “These trials offer fairly
definitive data, but have those people
who are strong proponents of fresh blood
changed their minds? That we don’t quite
know.”
February 2016