Among all the possible risks of transfusion, TRALI isn't a new discovery. It took a long time to become Topic A in the blood banking world.
"If you look back at the history of TRALI [transfusion-related
acute lung injury], it was first described by Mark Popovsky in the early
1980s," says Patricia Kopko, MD, executive vice president medical affairs
and director of the histocompatibility laboratory, BloodSource, and assistant
clinical professor of medical pathology at the University of California
"But you remember what else was going on in transfusion
medicine at that time. That was before we ever had the first HIV test,
and it couldn't compete."
"Talking about fatalities, with TRALI it was maybe
one in 50,000 at worst, and at that point in certain cities in this country,
one in 100 units had HIV in it."
Now, all of a sudden TRALI has become the riskiest
part of transfusion, she says. In 2003 the Food and Drug Administration
for the first time reported TRALI as the No. 1 cause of transfusion death,
with Canada and Europe reporting the same. "Up until that point, the No.
1 cause was the wrong unit of blood. That's when we realized we have another
important risk from transfusion," Dr. Kopko says.
"We're not in the post-HIV era—that's not gone—but
it's been reduced along with HCV to such incredibly low levels that we
now have enough mental energy to direct to other risks of transfusion,"
says James P. AuBuchon, MD, E. Elizabeth French professor and chair of
pathology at Dartmouth- Hitchcock Medical Center, Lebanon, NH. "Bacterial
contamination a couple of years ago—that's not at an end either.
But we've made a beginning, and we have more and more progress on mistransfusion.
TRALI was the other one of the big three nonviral risks."
Since TRALI unseated hemolytic transfusion reaction
for first place, the blood banking community has mobilized to stem the
syndrome. An important consensus conference took place in 2004 in Canada,
from which came a standard definition adopted in North America and Europe.
Measures adopted by the United Kingdom's National Blood Service to reduce
TRALI from plasma were already cutting the number of cases in half by
2005. Experimental models and prospective studies have started dotting
the research landscape.
Most significant in accelerating the campaign against
TRALI were the AABB's two key recommendations issued almost a year ago:
that U.S. blood centers initiate measures to reduce the risk of TRALI
in plasma by November 2007, and that they initiate measures to reduce
the risk of TRALI in apheresis platelets by November 2008.
Mark Popovsky, MD, chief medical officer of Haemonetics,
Braintree, Mass., and associate professor of pathology at Harvard Medical
School, was a member of the AABB task force that developed the recommendations
and time frames for blood centers to address TRALI. "By issuing these
guidelines, the AABB is providing an opportunity for blood collectors
and hospitals to do more to reduce the impact of the syndrome," he says.
Under the AABB guidelines, however, "it's completely
left up to each center to determine the measures to reduce risk," Dr.
Kopko says. "So what we are going to do to meet those deadlines is an
exceedingly hot topic."
Unlike bacterial contamination and hemolytic reaction,
TRALI, which is believed to occur in one in 5,000 transfusions, remains
a syndrome with somewhat mysterious etiology.
It appears that patients who have had underlying hematologic
disease, patients who are in intensive care settings, and patients undergoing
surgery may be at increased risk, but the jury is still out on who fits
the high-risk profile, says Dr. Popovsky. "We're still lacking an understanding
of who the high-risk patient is, which persons are more likely to develop
However, researchers believe the causes of TRALI can
be both immunologic and nonimmunologic. "Acute lung injury and pulmonary
edema are the end-stage process, and how you get there is thought to occur
through two major but different mechanisms," says Steven H. Kleinman,
MD, clinical professor of pathology and laboratory medicine at the University
of British Columbia, Victoria, and senior medical advisor to the AABB.
"One is the antibody in the donor unit binds with the
antigen on patients' white cells. There has to be a match, and if recipients
do not have the antigen, there is no match to trigger the immunological
cascade." Or, as Dr. AuBuchon puts it: "That antibody has to go into just
the right unlucky recipient in order to find an antigen it's targeted
against; that explains the relative rarity of this type of reaction."
The second mechanism has nothing to do with antibodies,
Dr. Kleinman says. "It's through substances called biological response
modifiers, such as breakdown products or cytokines, that are released
by cells and accumulate in the blood," he explains. "If they are transfused
to a recipient who already has neutrophils primed or activated—for
instance, through sepsis or inflammatory responses—and they happen
to have a critical concentration of one of these substances, they might
It's becoming better known that more than one mechanism
can trigger TRALI, Dr. Popovsky believes. "Both the antibody-mediated
model as well as the two-hit model are important. We know they both may
be operating in the same patient, and there may be other models as well."
But "there's an awful lot about TRALI that we don't
know," points out Morris Blajchman, MD, professor of pathology and medicine
at McMaster University, Hamilton, Ontario.
"We have all seen cases of TRALI occurring in patients
who receive blood products where no antibody is demonstrable in the offending
blood product. You can also have a donor with an antibody that can cause
severe TRALI in one individual and find that some of the recipients of
that donor's plasma will not have any ill effects. A lot of research will
be required to get a better handle on our understanding of the pathogenesis
Promising research is underway on several fronts. The
National Institutes of Health has funded two major efforts examining TRALI,
says Darrell J. Triulzi, MD, medical director of the Institute for Transfusion
Medicine, Pittsburgh. One is the SCCOR grant, a specialized center for
clinical research award made to the University of California at San Francisco.
Dr. Triulzi is an investigator on a study in the second
research project, a network of blood-center-based studies called REDS
II. His paper on leukocyte antibody prevalence is to be presented at the
AABB conference this month. "It is designed to provide the best data we
have on the prevalence of HLA and neutrophil antibodies in donors who
Unfortunately, a significant sector of the donor population—multiparous
women, or those who have had multiple pregnancies—has a stronger
likelihood of carrying these antibodies and may be a major source of TRALI.
These donors are considered to pose a particularly high risk to recipients.
The most commonly accepted explanation relates to the
body's capacity to reject transplants. "Pregnancy exposes the woman to
the fetus, and the fetus carries antigens inherited both from the mother
and the father," Dr. Kleinman explains. "Those from the father are 'foreign.'
So these HLA antigens are present on leukocytes but also present on many
other tissue cells."
"When the baby is in utero the pregnant woman is exposed
to these, and a proportion of women make antibodies to these antigens.
And we have evidence that this increases with the number of previous pregnancies."
The many unanswered questions about TRALI have made
diagnosing it a challenge. In the past, there were many cases that were
not properly diagnosed. Moreover, diagnosis remains difficult because
at present there is no diagnostic test that tells the physician this episode
of shortness of breath associated with a severe respiratory illness is
caused by the blood that person received.
"Most hospitals have a fairly well-developed system
whereby someone thinks something went wrong, and they call the laboratory
and begin a transfusion reaction investigation," Dr. AuBuchon says. In
the past, "the standard transfusion reaction investigation focused on
whether an ABO error occurred, so the usual investigation will be 'negative'
in the case of TRALI."
"The important thing for the laboratory to remember,"
he says, "is if they get a report of somebody having respiratory difficulty
shortly after transfusion, they too need to think about TRALI and initiate
appropriate consultative assistance to the clinician so the patient can
be properly cared for."
"That includes getting a chest x-ray to make sure the
problem is not fluid overload, because if it is, then the patient will
benefit from diuresis. If it's TRALI, some advocate not giving diuresis.
They believe the patient will do better and actually benefit from more
Ideally, the transfusion medicine director will have
read about TRALI and be able to step in, because the clinician probably
hasn't encountered a case of TRALI, Dr. AuBuchon adds.
"We just need to make the diagnosis," Dr. Blajchman
says, "and be aware of TRALI and support the patient based on the extent
of their respiratory embarrassment. If you support such patients for a
couple of days, the vast majority of patients—90 to 95 percent—actually
But there is strong evidence that many cases of TRALI
go undiagnosed. "It's very difficult sometimes at the bedside to tell
the difference between TRALI and transfusion-associated circulatory overload,"
says Lorna Williamson, MD, medical director of the National Blood Service
division of National Health Service Blood and Transplant in the United
Kingdom. "We're looking more critically at fluid balance charts from the
48 hours before an episode. In fact, when you look at some of these cases,
it's pretty obvious there is a very positive fluid balance."
Dr. AuBuchon, who is chair of the CAP Transfusion Medicine
Resource Committee, pointed to a recent paper that reported results when
a medical center tracked back to determine how frequently TRALI might
be occurring in its ICU patients. Of the cases identified, none had been
reported to transfusion services at the time. "They were only found by
retrospective review of this group of experts."
Dr. Kopko had similarly startling results from a BloodSource
study. "We actually had a local fatality from a unit of plasma and we
found antibodies in the donor's blood to human neutrophil antigen 3a [HNA
3a, formerly HNA 5b],"she says.
"So when the FDA came to investigate, they asked if
we would perform a lookback. The woman was a frequent plasma donor, and
a number of the patients receiving this woman's plasma and who had TRALI
reactions had been unreported to either the transfusion service or the
blood collection facility. She had a very strong antibody. In a number
of cases they found either the patient ended up on a ventilator or there
was new pulmonary edema that hadn't been there before." There were also
less severe febrile reactions.
The AABB recommendations have quickly brought fundamental
policy changes to U.S. blood centers. Says Dr. Kleinman, "We don't have
any absolute figures as to how many U.S. blood banks have done this, but
there is a general idea that the majority of institutions have moved toward
meeting their plasma needs with male plasma, to reduce the number of units
with leukocyte antibodies." The American Red Cross blood centers, Dr.
AuBuchon reports, are well on their way to using 100 percent all-male
plasma. The Community Blood Center of Greater Kansas, which collects about
145,000 units of red cells a year, switched to all-male plasma last spring,
as well as to plasma that's frozen in 24 hours rather than fresh frozen,
says Jay E. Menitove, MD, a hematologist who is executive and medical
director of the blood center.
But it's not as drastic a step as it seems. Though
shortages of AB plasma continue to be a problem, Dr. Menitove says, "if
you look at how we tried to implement male-only, you have half male/half
female whole blood donors, and only about 45 percent or so of plasma derived
from whole blood donations is actually used as direct plasma transfusions.
So if you have 45 percent needed and half the donors are male, you can
meet the needs for plasma transfusions."
The Community Blood Center estimated there would be
an additional $5,000 to $10,000 per month in transportation costs, but
that has been trimmed, and the center did not increase its charges to
This is an evidence-based approach, Dr. Menitove explains.
"Again, it's an intervention not to address 100 percent of the risk hypotheses,
but it addresses the parts we can address, the part we can change, and
for the rest, we'll just have to keep watching it."
But will all-male plasma do the trick?
Some of the data have started to come in. The United
Kingdom has already witnessed a striking decline in TRALI cases after
implementing its all-male plasma policy (see "All-male plasma makes UK
TRALI tumble"). And preliminary data are to be presented at the October
AABB annual meeting from one center that implemented a male-only or primarily
male-only plasma program, Dr. Popovsky says. "The number of case reports
to that blood center dropped dramatically, indicating there is value in
using such a policy." Though it will take another year to see what impact
the policies have in the U.S., "I would predict we will see a significant
However, it may be difficult to determine that in the
U.S. because of underreporting and underdiagnosis and the lack of central
data collection. "If you get a fatality from a transfusion, that has to
be reported to the FDA," Dr. Kleinman points out. "But a very sick patient
doesn't get reported, so there's no good way to keep track of reactions
in a given category like TRALI, although since certain organizations like
the American Red Cross require reporting, we can look at part of the pie."
"One of the troubles with the whole field of transfusion
medicine is there is not too much time devoted to the subject in medical
school," says Walter "Sunny" Dzik, MD, co-director of the blood transfusion
service at Massachusetts General Hospital, Boston.
As a result, "Until we recognized that TRALI was pretty
common and pretty serious, we kind of took plasma for granted as a relatively
safe product." For example, as several articles in the medical literature
reported recently, physicians often order plasma to address a mild to
moderate elevation of INR on a prothrombin test. "We have the suspicion
doctors think they are fixing the lab test results with plasma, but it
really does not have much effect on the lab test," Dr. Dzik says.
In fact, Dr. Kopko wonders whether the success of the
UK program can be replicated in the United States, because British doctors
actually use less plasma. "I think clinicians tend to have a perception
that plasma is the safest component to transfuse because you tend not
to have the incompatibility you have with red cells," she says.
While some experts believe that pooling plasma dilutes
the antibodies that can cause TRALI from any one individual, Dr. Blajchman
says there is a flip side to the dilution benefit of pooling. "Theoretically,
pooling can reduce the risk of TRALI. But variant CJD can be transmitted
by blood transfusion, and if you pool 1,000 units, receiving a pooled
product theoretically increases your chance of getting vCJD by 1,000-fold.
So pooling can be a double-edged sword."
A study being funded by the National Institutes of
Health is actively looking for cases of TRALI in a couple of big U.S.
hospitals, Dr. Kleinman says. "They have one year's worth of data prior
to these interventions, and they will get a year or more after the interventions,
so it might be the most controlled environment available to tell whether
the measures made a difference."
Providing male-only plasma or male-only platelets is
not a trivial matter to resolve, Dr. Blajchman emphasizes, "because women
represent 40 to 50 percent of blood donors, and if they stop donating,
we're in trouble."
He's not alone in that concern, especially since addressing
TRALI from platelet donations is an even thornier problem. The United
Kingdom has already moved forward successfully with all-male or nearly
all-male pooled platelets, which in Europe are made from a pool of four
donors. But it is not doing anything just yet to address platelets collected
by apheresis, says Dr. Williamson of NHS Blood and Transplant. "What we're
about to do is to test any new female donor who wants to come onto the
apheresis program for HLA antibodies. We could exclude all female donors,
but we're concerned we would lose rather a lot of donors at once, and
many have given apheresis platelets for years and not caused TRALI in
The United Kingdom is planning to conduct trials of
platelet additive solution in early 2008. "That is a method for suspending
platelets that combines additive solution with some plasma," Dr. Williamson
says. "So instead of having 300 mL of plasma in the platelets, you'd only
have maybe 100 mL, which you need because platelets don't store properly
in a 100 percent additive solution. We're not really sure whether that
would be particularly effective, because that's still quite a lot of plasma
and could still cause TRALI if the donor has a strong antibody."
However, Dr. AuBuchon notes, no platelet additive solution
is licensed in the United States. "A few companies are interested in pursuing
it, but as of yet there is not even one in the application phase before
Dr. Menitove says some strategies now under discussion
at his blood center include questioning women about their history of pregnancy
or conducting testing to determine if there are HLA antibodies. "We could
then decide which female donors to accept for platelets. We're not asking
that yet on the questionnaire, but I suspect we will over time."
Many blood centers in the United States are worried
about how to address the AABB's second recommendation on apheresis platelets.
"That's a big deal right now. We haven't quite figured out what to do,"
Dr. Kopko says. "We are hoping that one of the automated platforms for
HLA antibody testing gets licensed in the next couple of months." The
technology that's available now is manual and not suited to the high-throughput
testing needed to test hundreds to thousands of donors each day.
"With plasma, you can go to predominantly male, because
female plasma will be sent to manufacturers of albumin, IVIg, and various
drugs. That part was easy. But if we were to say no women can donate platelets,
we would have a horrendous platelet shortage in this country."
The implications of that are enormous, she cautions.
"There were 30 reported fatalities from TRALI last year, mostly from plasma.
So if you reduce fatalities by five percent but you have hundreds of thousands
of fatalities because there are no platelets and patients can't get chemotherapy
or surgery—that's the reason it's become such a timely topic."
Coinciding with the plans to reduce TRALI through screening
are some companies' efforts to try to inactivate the pathogens that may
be present, Dr. Blajchman says. "Pathogen inactivation of blood products
is coming down the pike. Octapharma is a European company with a pathogen-inactivated
plasma product which they claim has not been associated with any TRALI.
How carefully that data has been collected is unclear, but it makes sense
scientifically." The value of pathogen-inactivated plasma with respect
to TRALI reduction comes not from the pathogen inactivation but from the
fact that it is a pooled product, Dr. Blajchman emphasizes.
At Massachusetts General Hospital, a study is being
conducted of the utility of asking additional questions of the donor about
pregnancy history, since the Uniform Donor Questionnaire does not ask
about number of pregnancies, says Dr. Dzik.
He considers switching to all-male plasma to be possibly
too blunt an instrument. "It's one approach, but at my hospital we feel
it might be a little bit drastic on the blood supply and might have unintended
consequences, for reasons that might only be known in hindsight," Dr.
Dzik says. "After all, there have been times in the past when receiving
male-only blood products would not have been to the advantage of the recipient,"
he adds. Furthermore, many female donors have not had children. "It is
a shame to defer them when they can't possibly produce TRALI."
Evidence is emerging, Dr. Dzik adds, that TRALI is
even more common than previously realized. "We see cases that do not meet
the Canadian consensus conference definition but when investigated are
obviously TRALI. It's like the tip of an iceberg. The consensus conference
has defined for us the big piece above the water, but there is ice below
the water as well, cases of TRALI that are milder but still important.
These milder cases prove that clinical severity depends not only on donor
factors but also on characteristics of the recipient." Identifying mild
cases may be important because if the donor is not excluded, then "the
next time it might be a fatal case," Dr. Dzik says.
But Dr. Popovsky tends not to believe the all-male
policy will have an impact on the availability of plasma units or platelets.
"I know there are blood centers that have that concern because of the
number of females they have in their donor base and the number of females
they have found to be antibody-positive." Effective recruitment of new
donors, and use of technology such as automated collection, he thinks,
will make it possible for blood centers to keep donations stable.
The Community Blood Center of Greater Kansas City has
not seen an impact as of yet on its donor base, says Dr. Menitove. "I
think we'll have to really monitor that when we start making changes related
to platelet collection, because there it will be more obvious that we
are changing the mix of male to female donors, and probably saying to
females that we prefer they donate whole blood," he says.
In the UK, Dr. Williamson says, "we mention it in our
leaflet, but we haven't felt the need to make a big splash about it with
the donors. There are no implications for their health if they have these
antibodies, so we don't particularly want to get people worried they might
have something to indicate future illness."
Another important prong of the AABB recommendations
is education about appropriate blood use, and specialists in transfusion
medicine see this as a boon to their efforts to tame usage.
"We're talking about manipulating components that are
transfused, but one of the major ways is to only use blood products in
appropriate indications," says Dr. Kleinman. "We have lots of evidence
that there is over-transfusing, even when patients really need blood,
and it's an issue not just for TRALI but in general, when complications
are preventable because the patient should never have gotten a unit. So
general education about appropriate use of transfusion remains an important
message. That's a message that the transfusion medicine community has
been trying to get to clinicians for 10 or 20 years now."
Dr. Kopko hopes that the spotlight being shone on TRALI
will raise clinicians' awareness. "I have encountered residents who did
not know a case was TRALI until the attending came in the next day because
they had not heard of it. That's one of the things we've really worked
on locally. We've provided ourselves to anybody who will let us speak
about TRALI, whether it's at grand rounds, physician group meetings, or
medical staff meetings at the hospitals."
When Dr. AuBuchon gives lectures to residents these
days and begins discussing TRALI, he sees heads nodding, "which is good,"
he says. "It means the information is getting down into the medical school
curriculum, and there will be a broader understanding of TRALI."
But pathologists need to do even more than they are
in educating the physicians at their hospitals about what TRALI is, because
early intervention makes a difference in prognosis, Dr. Popovsky maintains.
"It's fair to say there is more attention paid to transfusion medicine
now than 10 or 15 years ago, but still, compared to other subjects, there
is relatively little attention."
"Often that leadership role has to fall on the shoulders
of the blood bank or transfusion service director. But the better armed
the physicians are who transfuse blood, whether they're surgeons or medical
practitioners, the more likely they will actually recognize TRALI, and
do the right thing."
Anne Paxton is a writer in Seattle.