REVIEW

CURRENT
OPINION Current options for transfusion-related acute lung
injury risk mitigation in platelet transfusions
Nancy M. Dunbar

Purpose of review
The approach to transfusion-related acute lung injury (TRALI) risk mitigation in the United States has evolved
over the past decade. Currently, AABB Standards require that all plasma and whole blood for direct
transfusion must be collected from men, women who have not been pregnant, or women who have tested
negative for human leukocyte antigen antibodies since their most recent pregnancy. These requirements
must be expanded to include apheresis platelets by October 2016.
The current review briefly summarizes current understanding of the pathogenesis, diagnosis and treatment
of TRALI, reviews ongoing efforts to mitigate TRALI risk specifically for platelets in the United States, and
explores additional options that may further reduce risk.
Recent findings
Current data indicate that TRALI mitigation efforts have been successful at reducing risk from plasma. This
implies that expansion of the requirements to include apheresis platelets should further decrease TRALI risk.
Additional options currently available for apheresis platelets include plasma replacement with platelet
additive solution, washing, and volume reduction. However, there are insufficient data to support the
adoption of any of these strategies once existing TRALI mitigation strategies are fully implemented.
Summary
Substantial progress has been made in reducing risk for antibody-mediated TRALI in plasma. The upcoming
expansion of existing strategies for plasma mitigation to include apheresis platelets is expected to further
decrease risk.
Keywords
platelet transfusion, transfusion-related acute lung injury, transfusion safety

INTRODUCTION model for TRALI was able to differentiate TACO

Transfusion-related acute lung injury (TRALI) is a and TRALI based on evidence of systemic inflam-
complication of transfusion characterized by the mation [elevated interleukin (IL)-6 and IL-8] prior to
development of noncardiogenic pulmonary edema, transfusion among patients who developed TRALI
&

typically within 6 h of blood product transfusion.
Diagnosis is based on clinical and radiographic
findings and temporal association with transfusion
[1]. Clinical findings commonly include dyspnea,
tachypnea, and hypoxemia, sometimes accom-
panied by rigors, tachycardia, fever, hypothermia,
and hypotension or hypertension [2]. Bilateral inter-
stitial infiltrates are present on chest radiograph but
this finding is nonspecific. Management of TRALI is
supportive care including supplemental oxygen or
mechanical ventilation when necessary [2].
TRALI may be difficult to distinguish from other
acute transfusion reactions with similar presenta-
tions including transfusion-associated circulatory
overload (TACO), septic transfusion reactions, and
anaphylaxis [2]. A recently described predictive
[3 ]. This testing is currently only being used for
research purposes.
Although our understanding of TRALI has
increased significantly over the last several decades,
the pathogenesis remains incompletely understood.
Although strong cognate antibody alone is enough
to cause TRALI, most cases are postulated to occur
via a two event model [4]. The first or priming
Department of Pathology, Dartmouth-Hitchcock Medical Center, Leba-
non, New Hampshire, USA
Correspondence to Nancy M. Dunbar, MD, One Medical Center Drive,
Lebanon, NH 03756-0001, USA. Tel: +1 603 650 5000; fax: +1 603
650 4845; e-mail: Nancy.M.Dunbar@hitchcock.org
Curr Opin Hematol 2015, 22:554558
DOI:10.1097/MOH.0000000000000187

www.co-hematology.com Volume 22  Number 6  November 2015

Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.


KEY POINTS
 TRALI is a multicausal transfusion reaction whose
pathogenesis remains incompletely understood.
 Approaches to identify and exclude donors with HLA
antibodies have been successful at reducing TRALI risk
for plasma components.
 Extension of these approaches to platelets is expected
to reduce risk for TRALI from platelets when fully
implemented.
 Additional options to further reduce risk for TRALI from
platelets include the use of PAS, volume reduction,
and washing.
 These additional options are associated with increased
costs and confer uncertain benefit when mandated risk
mitigation requirements for apheresis platelets are
fully implemented.
event is a clinical condition that causes activation of
the pulmonary endothelium, leading to the seques-
tration and priming of neutrophils in the lung.
Clinical risk factors that may function as the first
event include high IL-8 levels, liver surgery, chronic
alcohol abuse, shock, high peak airway pressure
during mechanical ventilation, current smoking,
and positive fluid balance [5]. The second event
results from the blood product transfusion, which
activates the primed neutrophils causing endo-
thelial damage and subsequently TRALI. This can
either result from passive transfer of antibodies
(immune-mediated) or pro-inflammatory mediators
(nonimmune mediated) in the transfused com-
ponent [6,7]. Multicausal models, including the
threshold model and the sufficient cause model,
offer alternative ways to describe the complex inter-
play of factors, which leads to the development of
&
TRALI in susceptible patients [8 ,9].
Antibody-mediated TRALI occurs following pass-
ive transfer of human leukocyte antigen (HLA) or
human neutrophil antigen (HNA) antibodies present
in the plasma fraction of the transfused unit. High-
volume plasma containing products from single
donors (plasma, whole blood, and apheresis platelets)
poses the greatest risk for antibody-mediated TRALI;
however, TRALI can also occur in the setting of
pooled platelets, red blood cell transfusions, and
following infusion of fractionated derivatives [10
12]. Strong cognate HLA class II and HNA antibodies
appear to confer the greatest risk for TRALI in suscept-
ible patients [5]. Pregnancy is the strongest stimulus
for the formation of HLA antibodies and the risk for
the development of these antibodies increases with
&&
increasing parity [13 ,14].
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TRALI risk mitigation in platelet transfusions Dunbar
Nonantibody-mediated TRALI, a less well under-
stood entity, appears to result from the transfusion
of soluble mediators that accumulate during
product storage including bioactive lipids, cyto-
kines, CD40L, and red cell-derived microparticles
&&
[15 ,16]. Research to clarify the pathogenesis of
nonantibody-mediated TRALI is ongoing.
TRALI RISK REDUCTION
Over the past 12 years, efforts to mitigate risk have
primarily focused on antibody-mediated TRALI. In
the United Kingdom, interventions implemented in
2003 include use of only male donors for plasma and
plasma used for suspension of buffy coat-derived
platelet pools, preferential recruitment of male
donors for apheresis platelets, and screening female
apheresis platelet donors for HLA/HNA antibodies
with retesting after pregnancies [17]. There have
been no reported cases of TRALI involving platelets
reported to the U.K. hemovigilance system in the
past 3 years of published data (20112013) [18].
In the United States, progress towards TRALI risk
mitigation of platelets has been slow but steady. In
November 2006, the AABB-mandated implementa-
tion of interventions to minimize the preparation of
high plasma-volume components from donors
known to be leukocyte alloimmunized or at
increased risk for alloimmunization [19]. Complete
implementation of measures relating to plasma and
whole blood was required by November 2007 and as
soon as possible, but no later than November 2008,
for platelet components. The additional time per-
mitted for implementation of platelet risk mitiga-
tion was based on concerns regarding impact on
platelet supply. It was estimated that the adoption of
approaches that eliminated female donors with
anti-HLA antibodies might decrease availability of
apheresis platelets by as much as 10% [19]. By 2009,
87% of 47 surveyed U.S. blood collection organiz-
ations had implemented polices to reduce TRALI
risk for apheresis platelets. The most common inter-
vention was increasing collection from male donors
(70%) followed by HLA antibody testing in selected
donors (43%).
Currently available evidence indicates that
these interventions have significantly reduced
TRALI risk. After implementation of a male predom-
inant plasma distribution strategy, the American
Red Cross observed a significant decrease in the rate
of suspected TRALI from 18.6 cases per million
plasma units distributed to 4.2 cases per million;
half of the remaining TRALI cases were associated
with plasma containing HLA or HNA antibodies
collected from untested female group AB donors
&&
[20 ] In a retrospective study of TRALI diagnoses
www.co-hematology.com 555
Transfusion medicine and immunohematology
in elderly Medicare beneficiaries from 2007 to 2011,
the risk of TRALI associated with platelet transfu-
&
sions decreased in 2010 and 2011 [21 ]. A recently
published meta-analysis summarizes the existing
studies to date and also concludes that the imple-
mentation of TRALI risk mitigation strategies has
&&
reduced TRALI risk [22 ].
In spite of this success, TRALI remains the lead-
ing cause of transfusion related fatalities reported to
the U.S. Food and Drug Administration (FDA) and in
the last 5 years of available data (20092013) there
have been 10 TRALI deaths associated with apheresis
platelets and two associated with pooled platelets
[23]. Pooled platelets may confer lower risk for
TRALI because of the dilution, which results from
combining plasma from multiple donors [24].
In January 2014, the AABB announced more
stringent requirements for TRALI risk mitigation to
address reported limitations of a male predominant
&&
plasma mitigation strategy [20 ]. Effective April 1,
2014, all plasma and whole blood for allogeneic
transfusion shall be from men, women who have
not been pregnant, or women who have tested nega-
tive for HLA antibodies since their most recent preg-
nancy [25]. In an effort the further reduce risk of
TRALI from apheresis platelet transfusions, the AABB
recently expanded the above requirements to include
apheresis platelets with an implementation deadline
of October 1, 2016 [26]. Implementation of these
measures is estimated to reduce TRALI risk for aphe-
resis platelets from 2.8 : 100 000 to 1 : 100 000 [27].
Although implementation of HLA antibody test-
ing of female apheresis platelet donors with a
history of pregnancy will reduce risk, it may not
eliminate TRALI in the setting of apheresis platelet
transfusion. HLA antibodies have been identified in
4.3% of male donors without a history of trans-
fusion and 10.6% of female donors without a history
of pregnancy or transfusion [28]. In addition, cur-
rent U.S. risk mitigation requirements do not
require screening for HNA antibodies because of a
&&
lack of an acceptable screening test [20 ]. Current
interventions also do not address nonimmune-
mediated TRALI.
ADDITIONAL OPTIONS TO FURTHER
REDUCE RISK
Currently available options for further TRALI risk
reduction in the setting of platelet transfusion
include use of platelet additive solutions (PAS), vol-
ume reduction, and washing of platelets [29].
Although our current understanding of TRALI pro-
vides a theoretical rationale for the effectiveness of
each of these strategies, the cost of each must be
weighed against the potential benefit. Evidence
556 www.co-hematology.com
Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
supporting these approaches is extremely limited
and the incremental risk reduction will be challeng-
ing to detect once mandated platelet mitigation
strategies are widely implemented.
Various PAS formulations are available and are
extensively used in Europe; however, use in the
United States remains limited as only one solution
(Intersol/PAS 3) has obtained FDA approval [30].
This solution replaces approximately 65% of the
plasma in an apheresis unit, which increases the
amount of plasma available for other uses [31].
Use of PAS decreases the ABO isohemagglutinin titer
and this provides a plausible mechanism for anti-
body-mediated TRALI risk reduction [32]. However,
given that red blood cells in additive solution con-
tain less residual plasma than platelets in additive
solution and are still associated with antibody-medi-
ated TRALI, the use of PAS is unlikely to entirely
eliminate risk of TRALI from apheresis platelets.
Available data suggest that use of PAS is effec-
tive in reducing some types of transfusion reac-
tions. In a recent single-center study, PAS platelets
were associated with a 46% reduction in allergic
transfusion reactions when compared with stand-
&
ard apheresis platelets suspended in plasma [33 ].
These study investigators also observed, however,
that PAS platelets were associated with lower cor-
rected count increments (CCI) at 1 4 h post trans-
fusion. In spite of this difference, the mean CCI at
12 24 h was not significantly different. The
impact of these observations on clinical risk for
bleeding remains unknown.
A recent large multicenter study also observed a
reduction in allergic transfusion reactions for PAS
apheresis platelets compared with plasma apheresis
&&
platelets [34 ]. In addition, a significant decrease in
febrile nonhemolytic reactions was noted in the PAS
platelet group. Although greater than 14 000 plate-
let transfusions were administered, there were no
TRALI cases observed in either study arm. It is
important to recognize, however, that this study
was not powered to detect differences in TRALI rates.
Furthermore, the platelets used in the study were
already TRALI mitigated (i.e. collected from males,
nulliparous females or parous females negative for
HLA antibodies).
Volume reduction and washing of platelet com-
ponents are other potential strategies to reduce
TRALI risk but both approaches involve additional
manipulation of the platelet product, increased
work-load for the hospital blood bank, and potential
for delays in product availability. Washing effec-
tively removes most of the plasma and any soluble
mediators that have accumulated during storage but
does so at the expense of lower corrected count
increments [35].
Volume 22  Number 6  November 2015

Novel methods for TRALI risk reduction are
currently under investigation. A technique for pres-
torage experimental filtration for TRALI risk miti-
gation of red blood cells has been developed [36].
This filter removes antibodies, lipids, whereas blood
cells and platelets and mitigates TRALI in an animal
model. Although the current method would only be
applicable to red cell products, because of platelet
trapping in the filter, modifications may lead to the
development of a configuration that could success-
fully be applied to platelets.
CONCLUSION
Although recent risk mitigation efforts have signifi-
cantly decreased risk, TRALI remains the leading
cause of transfusion-related fatalities in the United
States. Although it is too soon to determine the
impact of mandated HLA antibody testing for parous
female platelet donors on TRALI incidence, it is clear
that this approach has been successful at decreasing
TRALI risk for plasma. Additional options such as
PAS, volume reduction, and washing are intellectu-
ally appealing, but also costly to implement and may
result in lower count increments. It also remains to be
proven whether any of these approaches really
diminish TRALI risk when applied as an adjunct to
existing mitigation strategies. As our understanding
of the pathogenesis of TRALI continues to expand,
additional options for risk mitigation may emerge.
Although the bulk of this review has focused on
manufacturing-based mitigation strategies, there
are also interventions available to clinicians. These
include awareness of patient risk factors for TRALI,
efforts to address any modifiable risks prior to trans-
fusion, and adherence to a restrictive transfusion
policy in stable, nonbleeding patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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