review

Why implement universal leukoreduction?

Wafaa Y. Bassuni,a Morris A. Blajchman,b May A. Al-Mosharya
From the aCentral Laboratory and Transfusion Services, King Fahad Medical City, Riyadh, Saudi Arabia, and bMcMaster Transfusion Medicine
Research Program, McMaster University, Hamilton, Ontario

Correspondence and reprints: Wafaa Bassuni, MD · Consultant, Hematopathology Central Laboratory and Transfusion Services, King Fahad
Medical City · PO Box 51988 Riyadh 11553, Saudi Arabia · T: +966-1-470-7119 M: +966-506247993 · wafaa_bassuni@hotmail.com · Accepted
for publication February 2008

Hematol Oncol Stem Cel Ther 2008; 1(2): 106-123

The improvement of transfusion medicine technology is an ongoing process primarily directed at increasi-
ing the safety of allogeneic blood component transfusions for recipients. Over the years, relatively little
attention had been paid to the leukocytes present in the various blood components. The availability of
leukocyte removal (leukoreduction) techniques for blood components is associated with a considerable
improvement in various clinical outcomes. These include a reduction in the frequency and severity of feb-
brile transfusion reactions, reduced cytomegalovirus transfusion-transmission risk, the reduced incidence
of alloimmune platelet refractoriness, a possible reduction in the risk of transfusion-associated variant
Creutzfeldt-Jakob disease transmission, as well as reducing the overall risk of both recipient mortality and
organ dysfunction, particularly in cardiac surgery patients and possibly in other categories of patients.
Internationally, 19 countries have implemented universal leukocyte reduction (ULR) as part of their blood
safety policy. The main reason for not implementing ULR in those countries that have not appears to be
primarily concerns over costs. Nonetheless, the available international experience supports the concept
that ULR is a process that results in improved safety of allogeneic blood components.

T
he term paradigm was introduced into science
and philosophy by Thomas Kuhn in 1962 to
refer to the set of concepts that define particult
lar scientific thinking during a given period of time.1
The term refers to the predominant worldview in a partt
ticular realm of human thought. Kuhn hypothesized
that paradigm shifts occur when new and more accurate
theories (which represent approximations of the underst
standing about a topic) replace earlier, less comprehenst
sive theories.
The medical intervention known as blood transft
fusion is associated with both beneficial effects and
adverse events in recipients. Over the past 100 years,
transfusion medicine has experienced many challenging
periods resulting in the introduction of improvements
in technology to increase the safety of allogeneic blood
transfusion. There have thus been six major paradigmt
matic shifts associated with transfusion medicine sciet
ence and technology (Table 1). Conceptual and technolt
logical developments in transfusion medicine are thus
ongoing processes and more paradigm shifts are to be
expected in the future. These may include modification
of the red blood cell (RBC) surface to reduce antigenicit
ity11,12 and the development of novel ways to produce
blood products in vitro (for example, RBCs).13
Considerable progress has been made over the past
two decades to reduce the risk of the adverse events
associated with the transfusion of blood components.
However, significant transfusion-associated morbidity
and mortality remain a problem.14-17 Recent data from
various hemovigilance systems worldwide showed that
the most common causes of transfusion-associated
mortality include transfusion-related acute lung injury
(TRALI), ABO hemolytic transfusion events, and bactt
terial sepsis associated with the transfusion of bacteria
present in contaminated blood components (Tables
2, 3). The number of transfusion-associated mortalit
ity cases reported annually increased considerably over
the past 30 years, which is probably mostly related to
increased recognition of such events as being transfust
sion-associated. As can be seen in both Tables 2 and 3,
TRALI has become the most commonly reported cause
of transfusion-associated mortality.
The transfusion transmission risk of many pathogt
gens has been greatly reduced by the development of inct
creasingly sensitive screening methods; however, transft
fusion-transmitted infections still occur. Transfusion-
related infections continue to be reported as tests for

106 Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction review
Table 1. Major paradigm shifts in transfusion medicine.
Karl Landsteiner discovers the ABO blood groups and humoral immunity becomes the main paradigm explaining
Early 1900 the effects of allogeneic transfusion.2
1940 Edwin Cohn develops cold ethanol fractionation, the process of breaking down plasma into protein components
and products.3
Carl Walter and W.P. Murphy introduce the plastic bag for blood collection and component preparation,
1950 replacing breakable glass bottles with durable plastic bags and most importantly allowing sterile blood
component preparation.4,5
Post transfusion viral infections became a major concern affecting the blood recipient, resulting in the
1960 to 1980 development and implementation of effective screening methods to reduce pathogen transmission.6,7
Leukocyte reduction of blood components are shown to be associated with improved clinical outcome, which
1990 lead to the implementation of ULR in many countries.8
Development of pathogen inactivation (reduction) technology to reduce the risk of pathogen transmission by
1995 to 2010 blood components. This will lead to the development of pathogen inactivation technologies to treat the various
cellular blood components to further improve blood safety.9,10
ULR = universal leukoreduction

Table 2. Annual number of transfusion-associated cases reported to the US FDA over the three decades from 1976 to 2005.14

Period Total annual rate ABO/HTR TRALI Bacterial sepsis Others*

1976 - 1985 25.6 15.8 3.9 2.6 3.3

1986 - 1995 30.3 15.1 4.4 4.9 5.9

1996 - 2000 62.6 11.2 NA NA NA

2001 - 2003 88.3 12.6 14.4 12.5 48.8

2004 82.0 7.0 21.0 6.0 48.0

2005 105.0 5.0 30.0 9.0 61.0
*Includes graft-versus-host disease, delayed hemolytic transfusion reactions, transfusion transmitted infections other than bacterial sepsis, anaphylaxis, post-transfusion purpura,
transfusion-associated circulatory overload, and others. ABO/HTR=ABO/ hemolytic transfusion reaction, TRALI=transfusion-related acute lung injury, NA = data not available.

Table 3. Transfusion-associated causes of mortality reported to UK Serious Hazards of Transfusion (SHOT) program (1996-2004).15

Attributed cause of mortality Definite Probable Possible Total

Transfusion related acute lung injury 8 5 23 36
Incorrect blood component
6 3 11 20
transfused†
Graft-versus-host disease 13 0 0 13

Acute transfusion reaction ‡

2 3 7 12

Transfusion-transmitted infection 9 0 0 9

Delayed transfusion reaction 6 1 1 8

Post-transfusion purpura 1 0 1 2

Total 45 12 43 100
†
Patient transfused with component or product that did not meet the appropriate requirement, or was intended for another patient. ‡Acute transfusion reaction occurring within 24
hours following a transfusion, excluding that due to IBCT.

many known pathogens are not yet available or not beit
ing used.18-22 In addition, the ongoing emergence of new
agents demonstrates that potential threats to the blood
supply will continue to emerge worldwide.
Potential adverse effects associated with the transfust
sion of blood components containing donor leukocytes
and their soluble biological mediators, such as cytokt
kines, are known to have a number of biologic effects
associated with transfusion.23 Leukocytes with their
specific allogenic structure (the HLA class I and class II

Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com 107
 review
Table 4. Putative clinical benefits of leukocyte reduction, subdivided as to whether the
benefit has been proven by evidence-based guidelines to be relevant clinically, likely
relevant clinically, or clinical relevance is unproven.8
Proven relevant clinically:
− Reduced frequency and severity of NHFTRs;
− Reduced risk of CMV transmission;
− Reduced risk of HLA-alloimmunization and platelet refractoriness.
− Reduced mortality and organ dysfunction in cardiovascular surgery patients.
Likely clinically relevant:
− Reduced infectious risk associated with immunomodulation (TRIM);
− Reduced direct risk of transfusion-transmission bacteria.
Unproven clinically:
− Avoidance of vCJD transmission.
− Avoidance of HTLV I/II, EBV etc.
− Reduced risk of GVHD.
− Reduced risk of TRALI.
NHFTRs, non-hemolytic febrile transfusion reactions; CMV, cytomegalovirus; vCJD, variant Creutzfeldt-Jacob disease;
GVHD, graft-versus-host disease; TRALI, transfusion-associated acute lung injury.
antigens on their surface) appear to be the main targets
of a recipient’s immune system. In addition, some virt
ruses can be transmitted as they exist within leukocytes
(i.e. CMV, HHV-8, and HTLV-I/II). Another, not so
well characterized effect of transfused leukocytes, is the
potential modulating influence on the recipient’s immt
mune system.2 Leukocyte reduction is typically defined
as a blood processing step for reducing the leukocyte
content of whole blood, RBCs, or platelet units down
to 5×106 (1×106 in Europe) residual WBCs per unit
of component. Universal leukocyte reduction (ULR) is
the routine application of the blood-processing step to
all units of whole blood, RBCs, and platelets prior to
storage in a country or in a blood transfusion service.25
To attempt to prevent the adverse effects of the leukt
kocytes contained in blood components, several methot
ods have been developed to remove leukocytes from the
various blood components.25,26 Leukocyte reduction
procedures can be performed either pre-storage at the
blood collection facility, or post-storage either at the
hospital transfusion service or at the patient’s bedside
just prior to transfusion.27 Pre-storage leukocyte redt
duction of cellular blood components removes donor
WBCs before they undergo apoptosis or necrosis and
before they release breakdown products or cytokines.
The removal of leukocytes from various blood compt
ponents can be associated with several improved clinical
outcomes (Table 4). These outcomes, subdivided as to
whether each benefit has been proven by evidence-based
guidelines to be clinically relevant, likely to be clinically
relevant, and of unproven benefit (i.e. those that can be
considered only of theoretical relevance).8
The major disadvantages associated with leukocyte
108
universal leukoreduction
reduction are cost and logistics.28 The report from the
Canadian Coordinating Office for Health Technology
Assessment (CCOHTA) published in 1998 concluded
that ULR of both platelets and RBCs would add a signt
nificant expense to the Canadian health care system,
but that leukocyte reduction of all transfused platelets
might be cost effective.24 As a result, leukocyte reductt
tion of all platelets was introduced in Canada during
the first quarter of 1998. Leukocyte reduction of RBCs
was only introduced subsequently and ULR for all
blood products was fully implemented in Canada in
July 1999.29
There is some loss in product potency associated
with leukoreduction technology, although, at the preset
ent time, for RBCs this is unlikely to cause an increased
demand for RBC transfusions because of the concurrt
rent increase in the volume of whole blood collections
that offsets this loss in product potency. With regard
to the loss in platelet potency, there is considerable unct
certainty about the proper therapeutic dose of platelets,
such that a 10% to 15% quantitative reduction is unlt
likely to be noticeable clinically. As in the case of RBCs,
the increase in whole blood collections will also likely
increase platelet potency of whole blood-derived platelt
lets by negating the 11% filtration effect.30
Adverse effects associated with the use of leukocyte
reduction filters have been reported.31-33 The reported
severe hypotensive reactions to leukocyte reduced
blood components have been associated mainly with
the transfusion of blood components filtered at the bedst
side.34 These reactions are attributed to the generation
of bradykinin and possibly other vasodilators, as dont
nor plasma passes over the filter media.35,36 Bradykinin
generated during filtration has a short half-life and is
therefore biologically active only on direct intravenous
administration. Blood components that are leukocyte
reduced by pre-storage filtration appear not to cause
hypotensive reactions and current knowledge indicates
that transfusion of these blood components is generally
free from complications associated with the use of leukt
kocyte reduction filters.29 However, recent reports show
that hypotensive reactions can occur even with the
prestorage leukoreduction of blood products in which
a defect in the metabolism of kinins may be a risk factt
tor.37
The implementation of ULR has created some new
requirements relating to the need to standardize and
to quality control the whole process.38 In our opinion
the associated clinical benefits of leukocyte reduction
nonetheless far overweigh the adverse features, and in
the absence of considerations of cost, most transfusion
medicine professionals would readily endorse a policy
Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction
to implement ULR by pre-storage filtration. Others
argue that in the absence of adequate data suggesting
universal benefit the technology should be applied selt
lectively only to those patients who will clearly benefit
from this intervention.39
In the opinion of the authors, implementation of
ULR will improve transfusion safety, which should extt
tend to all patients receiving blood components at the
very least for the proven benefits of this intervention.
Although patients who have not had a febrile non-hemt
molytic transfusion reaction (FNHTRs), who are not
receiving long-term platelet transfusions, and are not
at risk of developing symptomatic CMV disease may
derive no immediate benefit from prestorage leukocyte
reduction, it is possible that they may accrue tangible
benefits in the future. There are also cost savings in rest
sources, time and effort associated with improvements
in the efficiency of the transfusion service and nursing
personnel, which will further reduce the net community
cost.
The current practice of transfusion in Saudi Arabia
and other countries around the world is selective leukoct
cyte reduction. This review will thus present an up-to-
date review of the clinical issues associated with leukort
reduction and the level of evidence indicating the efficact
cy, the current international status and the international
experience, that we hope will influence the decision to
implement ULR.
Evidence-based clinical efficacy of leukoreduct-
tion of cytokines, the accumulation of soluble cytokines relt
Evidence-based medicine has been defined as the integt
gration of best research evidence with clinical expertise
and patient values. Various classifications of the differet
ent types of scientific evidence available, to establish
the efficacy of a particular intervention, have been propt
posed. Table 5 provides such a scheme for assessing the
levels of medical and/or scientific evidence and is based
on the various publications of Sackett and colleagues.40
review
Many studies have been done to evaluate the efficacy of
leukocyte reduction to prevent or reduce adverse effects
caused by leukocytes present in blood components. The
following sections review the evidence for various clinict
cal outcomes.
Non-hemolytic febrile transfusion reactions
(NHFTR)
Historically, NHFTRs were thought to be associated
with the presence in the recipient of antibodies to transft
fused allogeneic leukocytes. NHFTRs, the most commt
mon adverse effect of blood transfusions, are thought
to be clinical manifestations of allo-immunization.41
The minimum number and type of WBCs needed to
generate a post-transfusion NHFTR in an alloimmunt
nized recipient of blood components remains unclear.42
Over the past decade, however, it has been established
that most NHFTRs are due to cytokines present in the
transfused blood components, having been elaborated
during storage by the leukocytes.43
Many studies make the point that the timing of filtt
tration is important for reducing the rate of NHFTRs.
The age of the blood component is also an accepted risk
factor. The older the component is, the greater the likelt
lihood of an adverse reaction. This is particularly the
case for platelet concentrates, which are stored at higher
temperatures (22±2°C) than RBC units. Thus, a more
obvious cause for a transfusion reaction than the numbt
ber of remaining leukocytes was postulated.41,44,45
Since older blood components have greater amounts
leased from leukocytes during storage may be the explant
nation for the higher rate of NHFTRs.44,46-48 It seemed
reasonable therefore that pre-storage of blood compont
nents would significantly reduce cytokine accumulatt
tion during storage. Some clinical trials (not prospectt
tive, randomized controlled trials) have demonstrated
such effects of pre-storage filtration for RBCs49 even
in previously alloimmunized patients.47 Many studies

Table 5. Levels of scientific evidence that can be used to evaluate the efficacy of various transfusion medicine interventions (modified
from Sackett).40

Level Scientific Evidence

Data from RCTs that are sufficiently large to give clear cut results, with only a small risk of an error. This level of
1
evidence includes meta-analysis from such RCTs.
Data from small RCTs that give uncertain results and that may have a moderate to high risk of error. This level of
2
evidence includes meta-analysis from such RCTs.
3 Nonrandomized cohort observational studies that use concurrent cohort data.

4 Nonrandomized cohort observational studies that use historical cohort data.

5 Case series that use data from uncontrolled observations; or that represent unsubstantiated “expert” opinion.

Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com 109
 review universal leukoreduction

Table 6. Incidence of non-hemolytic febrile transfusion reaction (per transfusion, excluding allergic and other reaction) (modified from
CCOHTA).26

Pre-storage filtration Post-storage filtration No filtration

Platelets RBC Platelets RBC Platelets RBC
1.7% 1.1% 2.2%
Federowicz et al (1996)44 NA NA NA
59/3405 60/5412 139/6447
1.6% 2.2%
Dzieczkowski et al (1995)49+ NA NA NA NA
82/5197 152/7080
28% 37.5%
Heddle et al (1993)41++ NA NA NA NA
7/25 12/32
0.9% 5% 0.8%
Muir et al (1994)47+++ NA NA NA
2/223 14/280 4/467
+=apheresis platelets, FNHTR only; ++=pooled platelets, all reactions; +++=sensitized hematological patients, apheresis platelets. NA=Not available

published after 1990 have addressed the incidence of vention technology, may be as high as 30% per patient,
febrile reactions in the context of leukocyte filtration depending upon the frequency of allogeneic blood compt
(Table 6).26 All studies achieved a level of leukoreductt ponent transfusion.62 CMV-seronegative cellular blood
tion of <5×106 leukocytes in the transfused blood compt components have been the standard approach provided
ponent.26 to CMV-seronegative patient populations at high risk
Until recently the role of leukoreduction in ameliort for significant morbidity for primary CMV infections.63
rating the rate of NHFTRs had not been clearly establt However, the increasing number of immunosuppressed
lished. Several recent publications show clearly that leukt patients who might benefit from receipt of such compont
koreduction is associated with a significant reduction nents, the high prevalence of CMV antibody in some
in the NHFTR rate (level 1 evidence) (Table 7).8 The blood donor populations, and the logistics of maintainit
NHFTR rate following RBC transfusion was shown ing multiple inventories of blood components have led
to be reduced by approximately 50%, from 0.35% to to the exploration of pre-storage leukoreduction as an
0.18%.50-52 Similarly, the pre-storage leukoreduction of alternative strategy for the provision of “CMV-safe”
platelets, which is generally associated with an approximt blood components.57 The American Association of
mate frequency of a 30% rate of NHFTRs, has been Blood Banks (AABB) has thus suggested that residual
shown to be reduced significantly by transfusing pre- leukocyte levels less than 5×106 make a blood compont
storage leukocyte reduced platelets.50,51,53 nent “CMV-safe”.64
It has been shown that the use of CMV seronegative
Pathogen transmission
Viruses. Leukoreduction is a known effective strategy
for reducing the risk of the transmission of cell-associat Table 7. Reports describing non-hemolytic febrile transfusion
ated viruses. The most prominent among these are the reactions (NHFTR) rate reduction associated with the pre-stage
herpes viruses, particularly CMV, also known as humt leukoreduction (LR) of RBCs and platelets.8
man herpes virus (HHV) 5.54-60 CMV is transmitted NHFTR rate reduction associated
For RBCs
by the leukocytes present in transfused blood compont with LR
nents. To acquire CMV from a blood donor, a blood Paglino et al50 0.34% to 0.18%
transfusion recipient must be exposed to donor WBCs Yazer et al 51
0.33% to 0.19%
that are latently infected with CMV. CMV then must
be reactivated and the cell must survive long enough in King et al 52
0.37% to 0.19%
the host to release infectious virus particles.61 Several For Platelets
patient populations are at risk for serious morbidity as Heddle et al53 21.3% to 12.3%a
a result of transfusion-associated CMV infection (TA-
CMV), including low birth weight infants, some oncolot 4.1% to 1.6%b
ogy patients, allogeneic bone marrow transplant recipiet Paglino et al50 2.18% to 0.11%
ents, but most particularly immunosuppressed patients. Yazer et al 51
0.45% to 0.11%
Early studies of TA-CMV indicate that the prevalence *Comparing NHFTR rate reduction of platelets from which in supernatant plasma was
of post-transfusion CMV, without employing any prevt removed with that seen with pre-storage LR platelets. aAll NHFTR, bSevere NHFTR.

110 Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction
allogenic transfusions in these patients will reduce this
post-transfusion CMV risk to approximately 1.3%.58
In comparison, a recent study has shown that the use
of pre-storage leukoreduced RBCs or platelet transfust
sions can reduce the risk of post-transfusion CMV to
approximately 2.5%.65 Over the years there have been
a large number of studies examining strategies to prevt
vent TA-CMV. Interpretation of some of these studies
is difficult as many were not randomized, failed to use
a control group, used historical controls, or were retrost
spective.57
Nonetheless, the balance of the evidence from the
available clinical studies suggests that acceptable CMV
safety can be achieved by pre-storage leukoreduction.
Although it is likely that leukoreduced blood compont
nents are effective in reducing the risk of TA-CMV,
there is insufficient evidence at this time to firmly recot
ommend the discontinuation of CMV testing even in
the face of ULR.66 Considerable debate thus exists as
to whether leukoreduction and the use of serologically
negative CMV allogenic transfusion can be considered
equivalent. A recent (2001) Canadian consensus conft
ference that has examined this issue in detail recommt
mended that high-risk patients (i.e. allogenenic bone
marrow transplant patients) receive leukoreduced blood
products that are also seronegative for CMV.61
A recent study provides strong evidence (level 2
evidence) that human herpes virus 8 (HHV-8) can be
transmitted by allogeneic transfusion, particularly in
high prevalence geographic regions.67 Based on the expt
perience with CMV, it is likely that pre-storage leukoct
cyte reduction may prevent the transmission of HHV-
8 due to its WBCs associated nature. HHV-8 can cause
a lifelong infection, with periodic reactivations, during
which virus may circulate in peripheral blood WBCs
and be transmissible through transfusion (level 5 evidt
dence).68
For other viruses such as Epstein-Barr virus (EBV),
human T-cell lymphotrophic virus type I and II (HTLV
I and II), no conclusive studies exist that demonstrate a
similar efficacy of virus removal by leukoreduction as
seen for CMV. Some experimental in vitro studies indict
cate a significant reduction of HTLV I virus from blood
components by pre-storage leukoreduction but the prevt
vention of clinical HTLV I infections with leukoreductt
tion in humans has not been proven. 69 Nonetheless, it
is reasonable to assume that leukoreduction adds more
safety to transfusion of blood components, since not
all HTLV I infected donors express HTLV I antibodit
ies.70
Bacterial/protozoal infections. Bacterial contaminatt
tion of blood components can result in a severe compt
Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
review
plication of allogeneic blood transfusion in recipients.
The risk of contaminated pooled platelet transfusion
has been estimated to be as high as 2% (asymptomatic
cases) since platelet concentrates are stored at room
temperature (a temperature that facilitates bacterial
growth) to preserve their viability and function.71-73
Asymptomatic bacteremias and/or infections in a dont
nor and the ability of Yersinia enterocolitica to grow at
low temperatures in an iron-rich environment such as
in stored RBC components makes Y entercolitica the
most commonly encountered serious bacterial contamint
nant associated with RBC transfusion.74,75 Several studit
ies have demonstrated that the bacterial overgrowth of
blood components by Y enterocolitica inoculated into
blood components under experimental conditions is dimt
minished or prevented by pre-storage leukoreduction,
after a room temperature holding period.75,76 One way of
reducing the risk of bacterial contamination in platelet
concentrates is to reduce the level of leukocytes present.
Filtration to remove leukocytes does not prevent bactert
rial growth, although it can reduce the level of bacterial
contamination for some organisms. This process is not
effective against some species of bacteria (for example, S
epidermidis). This method, therefore, does not provide
full protection against the risk of bacterial contaminatt
tion, but has been shown to significantly reduce the risk
of transfusion-associated sepsis.77
The mechanisms by which leukoreduction removes
bacteria are complex and several possibilities have been
proposed, based on experimental data. First, bacteria
are phagocyted during the proposed 8-hour storage of
blood at ambient temperatures and then removed with
the leukocytes upon leukoreduction. Secondly, bacteria
are adsorbed directly by the filter matrix or indirectly
by binding to leukocytes and platelets or on activated
complement components, which are removed by negatt
tively charged filters.78
Recent data from the Hemovigilance Network in
France clearly indicates that the bacterial sepsis rate, as
the percentage of all transfusion event rates, was significt
cantly reduced (1.7% versus 3.8%) following the implemt
mentation of ULR in France compared with before the
implementation of ULR (Table 8).79 Of particular relet
evance is the fact that 1 in 3000 cellular blood compont
nents have been shown to contain bacteria.77
The risk of the transmission of Trypanosoma cruzi,
the causative agent of Chagas’ disease, which is common
in South America, but rare in other parts of the world,
was shown to be decreased by leukoreduction, in an expt
perimental study in susceptible mice.80
Variant Crutzfeldt-Jacob Disease transmission (vCJD).
vCJD is a major concern of the transfusion medicine
111
 review universal leukoreduction

Table 8. Occurrence of transfusion incident report (TIR) before and after implementation of universal leukocyte reduction in France.79
Before universal WBC After universal WBC
reduction reduction
Number % Number % Variation P value†
RBCs transfused 3 124 649 3 053 807 Before/After (%)

HLA antibodies and NHFTR 112 6 33 2.3 -71 <.001

Isolated NHFTR 615 32.9 363 25.8 -41 <.001

Bacterial contamination 71 3.8 24 1.7 -66 <.001

Anaphylactoid 266 14.2 224 15.9 -16 .10

Hemolytic reactions (excluding
26 1.4 23 1.6 -12 .73
ABO & D)
D incompatibility 12 0.6 11 0.8 -8 .88
ABO incompatibility 30 1.6 33 2.3 10 .64
Analysis of RBCs transfusion 18 months before and after implementation of universal WBC reduction shows as expected no significant impact on anaphylactoid reactions, ABO
and D incompatibility and hemolytic reactions duo to other RBC antibodies. Conversely, there is dramatic reduction of TIRs related to HLA immunization, non-hemolytic febrile
transfusion reactions (NHFTR) and bacterial contamination. †Comparison of rates (i.e. 1408/3 053 087 vs. 1872/3 124 649) using the chi–square test.

community, because infectivity can be detected in the
lymphoreticular system as well as in blood.81 Evidence
from an immunodeficient animal model of scrapie suggt
gests that host lymphocytes and/or follicular dendritic
cells play a role in peripheral neuroinvasions.82,83 The
abnormal prion protein PrPSc of vCJD has been dett
tected in lymph nodes, tonsillar tissue, spleen and the
appendix in clinical cases of vCJD.84 Animal studies
have shown that B lymphocytes might play a key role
in disease transmission.85 In several countries, partt
ticularly in western Europe, ULR was instituted over
the past 6 years in an attempt to reduce the theoretict
cal risk of vCJD transmission via transfusion of allogt
geneic blood and blood components.86,87 Four cases of
probable transfusion transmission of vCJD infection
have recently been diagnosed in patients in the United
Kingdom. All four cases had received transfusions of
non-leukoreduced RBCs between 1996 and 1999 from
donors who developed symptoms of vCJD after blood
donation. These four cases of vCJD infection associated
with blood transfusion increases the level of concern
about the possible risk of vCJD transmission between
humans by blood transfusion, although much remains
unknown. This concern reinforces the importance of
the existing precautions that have been introduced to
reduce the risk of transmission of vCJD infection by
blood and blood components.88 Blood screening assays
are currently under development but are not yet ready
for application.89 A recent study by Gregory et al, in a
hamster model of blood-born transmissible spongiform
encephalopathy (TSE) transmission, showed that filtratt
tion leukoreduction was associated with a reduced risk
of TSE infection (from 48.1% to 31.5%).90 The authors
of this study showed that filtration leukoreduction was
associated with reduced TSE infectivity, but that this
intervention was not sufficient to remove all TSE inft
fectivity.91 Specific prion reduction filters for RBCs offt
fer the possibility of a further substantial reduction in
vCJD infectivity and in the overall risk of vCJD transmt
mission. However, concerns persist about how best to
assess the efficacy of these technologies, since current
assays are not sufficiently sensitive to detect infectivity
in the blood of patients with clinical vCJD.92
Alloimmunization and platelet refractoriness
Alloimmunization is defined as a recipient immune
response against antigens on tissue from a genetically
dissimilar donor. The direct allo-recognition pathway
occurs when recipient T-helper cells directly interact
with class II molecules encoded by the major histocompt
patibility complex (MHC) on donor antigen-presentit
ing cells (APCs). This pathway is the strongest known
stimulator of immunity and the one targeted for remt
moval by leukoreduction strategies.93 The reduction in
alloimmunization is a well documented beneficial effect
of using leukoreduced blood component transfusions,
and is especially important for repeatedly transfused
patients and transplant recipients.93-98 Table 9 provides
a cumulative meta-analysis of seven randomized, contt
trolled trials which clearly showed that the relative risk
of HLA alloimmunization can be reduced considerably
through the use of leukoreduced blood components
(level 1 evidence). In the years 1983 to 1995 there were
seven reports whose cumulative relative risk reduction
with the use of leukoreduced allogenic blood compont
nents was 0.32, with 95% confidence intervals of 0.18

112 Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction
Table 9. Cumulative meta-analysis of randomized, controlled trials on the efficacy of leukoreduction in preventing HLA
alloimmunization.99
Cumulative sample size
Study Publication Year
(study n)
Schiffer et al100 1983
Sniecinski et al 95
1988
Andreu et al 96
1988
Kooy et al 101
1991
Oksanen et al 102
1991
Williamson et al 103
1994
Sintnicolas et al 104
1995
TRAP 105
1997
to 0.56. These seven studies involved a total of only 418
patients.8 In 1997, the TRAP study which examined
the relative risk of HLA alloimmunization and platelet
refractoriness in 400 patients provided level 1 evidence
(a large randomized controlled trial) that the relative
risk of HLA alloimmunization and platelet refractorint
ness with the use of leukoreduced blood components
was statistically significant.99 The cumulative relative
risk reduction of HLA immunization for all the publt
lished studies, following the use of leukoreduced blood
components, was recently estimated to be 0.30 (95%
confidence intervals; 0.20 to 0.46).99
A recent retrospective analysis of 13 902 platelet
transfusions in 617 Canadian patients undergoing chemt
motherapy for acute leukemia or stem cell transplantatt
tion before (n=315) and after (n=302) the introduction
of ULR showed a significant reduction in alloimmunizt
zation (19% to 7%, P<.001) and in alloimmune platelet
refractoriness (14% to 4%, P<.001). Alloimmunization
and alloimmune refractoriness in 318 patients who were
previously pregnant and/or transfused were also redt
duced after ULR (P=.23 and P=.005, respectively).106
Transfusion-related immunomodulation (TRIM)
Most animal studies using whole blood transfusion
have found immunosuppressive-like responses in rect
cipients, primarily due to the leukocyte content of
the donor blood.107 Moreover, evidence from a variety
of sources indicates that allogenic blood transfusion
(ABT) enhances the survival of renal allografts,108 and
may increase the recurrence rate of resected malignanct
cies,109 increase the incidence of postoperative bacterial
infections,110-112 reduce the recurrence rate of Crohn’s
disease,113 and reduce the risk of recurrent spontaneous
abortion.114 This clinical syndrome, whose mechanisms
Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
review
Cumulative relative risk (RR) of HLA
alloimmunization (95% Confidence intervals)
56 (56) 0.35 (0.10–0.16)
96 (40) 0.32 (0.17–0.60)
165 (69) 0.26 (0.16–0.49)
218 (53) 0.21 (0.12–0.35)
249 (31) 0.23 (0.13–0.38)
372 (123) 0.27 (0.16–0.46)
418 (46) 0.32 (0.18–0.56)
818 (400) 0.30 (0.20–0.46)
still remain to be defined, has been referred to in the
transfusion medicine literature as transfusion-related
immunomodulation (TRIM).115
TRIM and surgery. The value of leukoreduction for
preventing postoperative complications in patients undt
dergoing surgery has been investigated in many observt
vational studies as well as in 12 randomized controlled
trials, which were recently the subject of a meta-analysis
that looked at the association between allogenic blood
transfusion and postoperative infection.110-112,116-124,125
The hypothesis of homogeneity was rejected across the
12 trials (P<.01 for the Q-test statistic). When the rest
sults were combined under conditions of heterogeneit
ity, the effect of the WBC-containing allogenic blood
transfusion on postoperative infection did not quite
attain statistical significance (summary OR=1.24; 95%
CI, 0·98-1·56; P>.05). Four of these trials showed an
increased association between allogenic blood transfust
sion and postoperative infection, but the others did not
(Figure 1).116,120,122,123 One possible explanation for the
lack of consistency among the trials is that the TRIM
effect may in fact be quite small (i.e. less than 10%).8
Vamvakas and Blajchman have postulated that to dett
tect a 5% to 10% reduction in the risk of postoperative
infection, a randomized trial enrolling 10 000 to 20 000
subjects would be required. Such a study has not been
done and is unlikely to be done in the foreseeable futt
ture.126
There is also evidence that the use of leukoreduced
blood components is associated with improvement in
morbidity and mortality in cardiac surgery.110,119,121-123-
125
A randomized trial involving a large series of patients
in whom the mortality rate was 50% less in patients rect
ceiving leukoreduced blood also reported a significantly
lower postoperative infection rate.110 The findings of
113
 review universal leukoreduction

100

Favors leukoreduction
10
1

Does not favor

leukoreduction
0.1

Jensen et al111

Titlestad et al118
Jensen et al117

Wallis et al119

Van Hilten et al120

Tartter et al112

Bilgin et al121
Houbiers et al116

van de Watering et al110

Boshkov et al123

Nathens et al124
Bracey et al122
Figure 1. Randomized controlled trials (RCTs) investigating the association of white blood cell (WBC)-containing allogeneic blood
transfusion (ABT) with postoperative infection.125 For each RCT, the figure shows the odds ratio (OR) of postoperative infection in
recipients of non-WBC-reduced vs. WBC-reduced allogeneic red blood cells (RBCs) or whole blood, as calculated from an intention-
to-treat analysis. Each OR is surrounded by its 95% confidence interval (CI). If the 95% CI of the OR includes the null value of 1, the
immunomodulatory (TRIM) effect is not statistically significant (P>·05). A deleterious effect of ABT is indicated by an OR >1, provided
that the associated 95% CI does not include the null value of 1.

this large study suggest that leukoreduction should transfused leukoreduced RBCs might benefit from a
be applied for all patients undergoing cardiac surgery decrease in postoperative infections. A decrease in mortt
in order to improve patient outcome. Figure 2 shows tality may have been realized if more patients had been
the summary odds ratio of short-term mortality in rect enrolled in the various randomized trials.132
cipients of non-leukocyte reduced versus leukocyte-redt The results of a retrospective before/after study follt
duced allogeneic RBCs, from 5 randomized, controlled lowing the institution of ULR in Canada compared
trials conducted in cardiac surgery. When the 5 trials cardiac surgery, hip fracture repair, and intensive care
were studied in a meta-analysis, WBC-containing allogt unit patients and found decreased mortality, fewer fever
geneic blood transfusion was associated with a 72% inct episodes, and subsequent use of antibiotics in high-risk
crease in postoperative mortality (summary OR=0.99; patients (Table 10).133 Subsequent reduced length of
95% CI, 0.73-1.33; P>.05) compared to patients receivit hospital stay and cost of hospital care may be an addt
ing leukoreduced allogeneic blood.127 ditional financial benefit.134,135
A prospective randomized study by Alexiou et al TRIM and cancer. A higher rate of tumor growth
reported that leukoreduction reduces the numbers and recurrence with allogenic transfusion and lower
of circulating activated leukocytes and pulmonary inft rates with leukoreduced ones have been reported in a
flammations during cardiopulmonary bypass (CPB).128 number of experimental animal model studies.136,137
Improved lung function and reduced mechanical ventilt Approximately 90 observational studies in man have
lation requirements also have been reported following examined the effect of TRIM on tumor growth promt
the use of leukoreduction in patients having abnormt motion.138 Of these, 33 (30 observational and 3 randt
mal preoperative pulmonary function.129-131 Recently domized, controlled trials) have been in patients with
two meta-analyses of 10 randomized, controlled trails a colorectal malignancy; 14 in patients with a head and
evaluated the efficacy and effectiveness of RBC leukort neck malignancy; 10 in patients with a breast malignt
reduction and demonstrated that patients who were nancy; 8 in patients with a gastric malignancy and 8 in

114 Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction review
100

Favors leukoreduction
10
1

Does not favor

leukoreduction
0.1

van de Watering et al110

Bilgin et al 121

Wallis et al119

Bracey et al122

Boshkov et al123

Summary
odds ratio
Figure 2: Randomized controlled trials (RCTs) conducted in cardiac surgery investigating the association of WBC-containing
allogeneic blood transfusion with short-term (up to 3 months post transfusion) mortality from all causes.127 The odds ratio (OR) of short-
term mortality in recipients of non-WBC-reduced versus WBC-reduced allogeneic RBCs, is shown. These ORs are calculated from
intention-to-treat analysis. The figure also shows the summary ORs of short-term mortality across the depicted RCTs, as calculated
from a meta-analysis.110,119,121-123

Table 10. Before-after study evaluating the effect of the implementation of universal leukoreduction on various primary and secondary
outcomes in 14 786 patients.79
Leukoreduction (%) Non-leukoreduction (%) Odds ratio (95%
P Value
(n=7804) (n=6983) confidence interval)
Primary outcomes
In-hospital mortality 6.19 7.03 0.87 (0.76-1.00) .04
Suspected infections 12.7 13.9 0.91 (0.83-1.00) .05

Confirmed infections 10.1 10.7 0.93 (0.84-1.04) .21

Secondary outcomes
Respiratory failure 9.6 10.1 0.94 (0.84-1.05) .30

Hemodynamic failure 1.9 1.9 1.02 (0.80-1.13) .93

Renal failure 1.0 1.1 0.93 (0.67-1.30) .72

Fever 22.5 24.7 0.88 (0.82-0.95) <.01

Antibiotic use 14.8 16.4 0.89 (0.81-0.97) <.01

Transfusion reactions 0.46 0.64 0.71 (0.45-1.13) .16

Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com 115
 review
patients with a lung malignancy. Approximately 50%
of the available observational studies (level 3 evidence)
indicate that patients having allogeneic transfusions
(compared with those not having such transfusions)
had a higher incidence of cancer recurrence or death as
a result of cancer recurrence as well as a shorter overall
survival after the cancer resection operation.138-141
The three randomized, controlled trials in colorectal
cancer patients that compared the incidence of cancer
recurrence in recipients of buffy coat-reduced allogeneic
RBCs with that of recipients of control blood, showed
no statistical difference in the incidence of cancer rect
currence.106,109,116 The randomized, controlled trials
in human are thus still inconclusive. This may be due
to the lack of homogeneity among the studies, the difft
ference in blood component preparation used (buffy
coat method versus leukofiltration), multicenter versus
single center trials and the type of data analysis by invt
vestigators (multivariate versus univariate). Studies in a
rabbit allogenic transfusion tumor growth model clearly
indicated that buffy coat reduction was associated with
a significant reduction in pulmonary tumor nodule formt
mation.142,143
Transfusion-associated graft-versus-host-disease
(TA-GVHD)
TA-GVHD is an infrequent, although almost uniformlt
ly fatal complication of blood transfusion, caused by a
proliferation of T-cell lymphocytes derived from the dont
nor. Patients with cell-mediated immunodeficiency are
at particular risk for TA-GVHD. Another risk group
includes patients who have an HLA genotype that is
haploidentical with that of the donor.144 No studies exit
ist investigating the efficacy of leukoreduction for the
prevention of TA-GVHD. There are only single case
reports and animal studies.145 These reports conclude
that the minimum threshold of transfused lymphoct
cytes which prevents the development of TA-GVHD
cannot currently be defined.146-148 A very recent report
describes a reduction in reports of TA-GVHD to the
United Kingdom Serious Hazards Of Transfusion
Program (UK SHOT) since the introduction of ULR
in the UK (11 reports of GVHD associated with non-
leukoreduced blood components, and only two with the
use of leukoreduced blood components). This low rate
has occurred with the use of a combination of ULR and
the provision of gamma-irradiated blood components
for patients at risk.149 The gamma-irradiation of blood
components has been demonstrated as the best current
technology to reduce the risk of TA-GVHD.150 In any
event, most patients who need gamma-irradiated blood
components also should receive leukoreduced blood
116
universal leukoreduction
components as well. Both measures simultaneously appt
plied in order to prevent TA-GVHD will result in the
increased safety of allogeneic transfusions. Another appt
proach might be the use of pathogen inactivation.151This
report also describes a reduction in cases of post-transft
fusion purpura (PTP) following the introduction of
ULR (mean number of reports/year before ULR 10.3;
post ULR 2.3).149
Transfusion-related acute lung injury (TRALI)
TRALI is a severe, often fatal, and complex complication
of transfusion. TRALI has become the most common
cause of transfusion-associated mortality reported to
both the United States Food and Drug Administration
(US FDA) and UK SHOT.14,15,151 Although the pathopt
physiology of TRALI is not well understood,152 sevet
eral mechanisms for TRALI have been postulated:
Popovsky’s immune-mediated model,153 in which donor
antibodies and less frequently recipient antibodies causit
ing an immune reaction targeting leukocyte antigens
and Silliman’s two-hit model.154 In the latter model, the
first hit is a physiological insult that activates pulmont
nary endothelium and promotes priming, resulting in
the adhesion of neutrophils, (sepsis and trauma). The
second hit is an event that activates the neutrophils,
causing the release of biological active mediators present
in the blood components.155 If Silliman’s model is valid,
pre-storage leukocyte filtration and the use of younger
blood components in at-risk patients should reduce the
incidence of TRALI. Leukoreduction reduces biologict
cally active mediators associated with prolonged storat
age,154-158 but whether leukoreduction can reduce the
incidence of TRALI is not currently known.
Current international status of ULR
Internationally, 19 countries (Table 11) have implemt
mented ULR as part of their blood safety policy. Several
other countries are also currently moving toward impt
plementing ULR, including Sweden, Denmark, Italy,
Belgium, Cyprus and Japan.159 The motivation to implemt
ment ULR varies from one country to another. Some
countries, including the United Kingdom and Portugal,
decided to adapt ULR in an effort to comply with the
precautionary principle concerning the theoretical risk
of TA-vCJD.160 This decision was taken because of
evidence that indicated that the pathogenic prion, the
causative agent of vCJD, was associated with B-lympt
phocytes. The precautionary principle calls for reducing
potential serious risks to public health even if cause and
effect relationships are not fully established scientifict
cally. Other countries, such as Germany and Canada,
have relied on the evidence of clinical benefit in other
Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction review
Table 11. Countries that have mandated universal leukocyte the basis for the controversy in the United States over
reduction as a matter of public blood safety policy. ULR. Both the FDA blood product advisory committt
Country Date tee (BPAC) in 1998 and the blood safety and availabilit
ity (BSAC) in 2001 recommended ULR for the United
France April 1998
States blood supply.162,163
Canada July 1998 (platelets only) Both the additional cost of ULR and the controversy
Luxembourg December 1998 over the available clinical evidence to support the use of
leukoreduction for all patients has delayed implementatt
Austria January 1999
tion of ULR in the United States, despite the BPAC
Eire (Southern Ireland) January 1999 and BSAC recommendations. In fact, the ULR debate
Canada July 1999, ULR has become so politicized that it has become one of the
most divisive issues in the history of US transfusion
Wales August 1999
medicine. In 2005, approximately 65% to 70% of the
Scotland August 1999 blood supply was leukocyte reduced in the US.161 It is
Switzerland September 1999 important to note in this context that many centers and
hospitals in the US provide ULR blood components.
England October 1999
At present ULR is practiced in only approximately
Northern Ireland October 1999 20 countries. The main reason for not implementing
Malta January 2001 ULR universally appears to be financial. Other reasons
include the opinion that there is not yet sufficient evidt
Spain (Portugal) May 2001
dence to justify adopting the policy of ULR.164,165
New Zealand June 2001

United Arab Emirates July 2001 International experience

Germany October 2001
Qatar January 2002
Holland January 2002
Norway January 2002
Finland November 2002
ULR=Universal leukocyte reduction, platelets and RBCs.
clinical areas to justify the adoption of ULR for all
transfused patients. In some countries, such as Canada,
blood safety is considered paramount, and the use of
safer blood components, such as those that are leukoct
cyte reduced cannot be restricted and must be applied
to all patients.161
The adoption of ULR in the United States has been
delayed primarily because of economic issues, leading to
the approach of selective leukocyte reduction protocols
for patients thought to be at greatest risk for adverse
effects associated with the presence of leukocytes in
blood components. The selective patient populations
include those who are immunocompromised or chronict
cally transfused. The well-established leukocyte mediat
ated reactions include febrile reactions (fever), alloimmt
munization and its clinically significant consequence
known as platelet refractoriness, and transfusion transmt
mitted leukocyte associated viruses such as CMV. The
differences in practice, belief, and opinion on how best
to spend money for blood components has formed
Hebert et al133 evaluated clinical outcomes after the
adoption of ULR in Canada by conducting a retrost
spective before and after cohort study in 23 academic
and community hospitals (n=14 786). Although an
increased risk of nosocomial infections was not demonst
strated in this trial, in-hospital mortality was found to
be significantly lower (P=.04) following the introductt
tion of ULR in Canada.133 The authors of this study
indicate that assuming a 7% mortality rate in the contt
trol period, the decreased odds of death based on these
results would translate to one life saved for every 120
patients who received leukocyte reduced blood as oppt
posed to non-leukoreduced blood. This observation,
according to the authors, was consistent among all subgt
groups and throughout the range of blood exposures. In
addition, this study also found that ULR was associated
with a decreased frequency of febrile episodes and subst
sequent use of antibiotics.133
Fergusson et al166 evaluated the clinical outcome follt
lowing implementation of a ULR program in prematt
ture infants admitted to neonatal intensive care units
(NICUs) by conducting a retrospective before and aftt
ter study in three Canadian tertiary care NICUs from
January 1998 to December 2000. Thus study demonst
strated no significant reduction in NICU mortality or
bacteremia, but reported an improvement in several
clinical outcomes in premature infants requiring RBC
transfusions (Table 12).166 The authors therefore recot
ommended the adoption of ULR in the care of all low

Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com 117
 review universal leukoreduction

Table 12. Outcomes and odds ratios among 515 premature infants who underwent transfusion before and after implementation of ULR
in Canada.166

Odds Ration (95% confidence interval)†

Outcomes*
Non-leukoreduction period Post-leukoreduction period Adjusted‡

Primary outcomes
Bacteremia 79 (29.6) 63 (25.6) 0.59 (0.34-1.01)

Mortality 45 (16.8) 44 (17.8) 1.22 (0.59-2.50)

Major NICU morbidities

Retinopathy of prematurity 130 (59.1) 96 (41.7) 0.56 (0.33-0.93)

Bronchopulmonary dysplasia 141 (52.6) 86 (34.8) 0.42 (0.25-0.70)

Necrotizing enterocolitis 32 (12.5) 16 (6.7) 0.39 (0.17-0.90)

Grade 3 or 4 IVH 45 (17.4) 33 (13.7) 0.65 (0.35-1.19)

Any major NICU morbidity §
207 (83.5) 157 (66.5) 0.31 90.17-0.56)
Abbreviations: IVH, Intraventricular hemorrhage; NICU, neonatal intensive care unit; ULR, universal leukoreduction. * All outcomes data are expressed as No. (%). Denominators
vary from 268 and 247 because of missing data. †Odds ratios of less than 1.00 indicate a beneficial effect of leukoreduction. ‡All multivariate models included site, admission status
(outborn/inborn), gestational age, sex, birth weight, mode of delivery, antenatal steroids, volume transfused, apgar score at 5 minutes, score for Neonatal Acute Physiology on day
1, any cardiovascular pressor on day 1, continuous positive airway pressure, (0, 1-10. 11-25, or >25 days), influenza season (December-March), mechanical ventilation on day 1,
high-frequency ventilation on day 1, supplemental oxygen support on day 1, surfactant use on day 1, steroids on day 1, umbilical catheter, and percutaneous catheter, § Including
retinopathy of prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, and grade 3 or 4 IVH.

birth weight infants requiring RBC transfusions.
Another before and after study (n=2095), conductet
ed in the United Kingdom by Llewelyn et al167 examit
ined 11 hospitals with patients undergoing cardiac bypt
pass surgery or total hip and/or knee replacement and
found no impact of ULR on postoperative infections,
as reported in the Canadian study, but this study was
considerably smaller than the Canadian study (n=2095
versus n=14 786).
Yazer et al,51 Paglino et al50 and King et al52 demot
onstrated that hospitals moving from a selective prott
tocol to ULR had a significantly reduced rate of fevers
associated with RBC and platelet transfusions. These
fevers occurred in patients who would have been unlt
likely to receive leukocyte reduced blood with a selectt
tive protocol. The difficulty in conducting such studies
will increase over time because there are few European
countries that do not currently use ULR and because
approximately 70% of the blood in the United States
is already leukocyte reduced. Finding study sites which
will also have a parallel and appropriate control arm to
receive non-leukocyte reduced blood is becoming inct
creasingly difficult.
Conclusions
The ongoing development of safer transfusion options
for use in the care of patients has created many contt
troversies for the field of transfusion medicine. In the
debate concerning the implementation of ULR, some
experts believe that the clinical benefit for ULR has
been shown for many potential recipients who suggest
therefore that this technology be applied universally, as
the only downside is cost.168 Others argue that in the
absence of data suggesting universal benefit, the technt
nology should be applied only selectively to patients
who will clearly benefit.165
All the data presented in this review clearly indicate
that leukoreduction is associated with a reduced risk to
patients for some clinical indications, but not for others.
In some instances the available evidence is quite strong,
but in others the evidence for instituting ULR is not
as strong. It is nonetheless clear that ULR does reduce
the risk and severity of NHFTRs (level 1 evidence), the
risk of CMV transmission (level 1 evidence), and is asst
sociated with a reduced risk of HLA alloimmunization
and platelet refractoriness (level 1 evidence). A causal
relationship between allogeneic blood transfusions and
cancer recurrence seems to be indicated by the observt
vational studies (level 3 evidence) reported between
1985 and 2000 but not by the available randomized,
controlled trials in colorectal cancer patients (level 1
evidence). Specifically, the three available randomized,
controlled trials provide no indication that perioperatt
tive allogeneic blood transfusion causes an increase in
cancer recurrence or death as a result of cancer recurrt
rence. Relevant experimental animal studies nonethelt
less indicate that allogenic blood transfusions enhance
tumor growth promotion in animal models. Concerning

118 Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
universal leukoreduction
whether leukoreduction is associated with a decreased
incidence of preoperative mortality and postoperative
infections, there is evidence, particularly in patients
undergoing cardiac surgery,125 that the use of leukoredt
duced blood components is associated with a decreased
risk for bacterial infection (level 1 evidence); reduces the
risk of multi-organ dysfunction (level 3 evidence); and
most importantly leukoreduction significantly reduces
the risk of mortality (level 1 evidence in cardiac surgery
patients).125,127
Some have noted that there are significant problems
with the use of selective transfusion protocols. One
problem involves the selection of a patient who might
meet the criteria for the selective use of leukoreduction,
but who is not being recognized. Such patients thus do
not get the best blood component and thus will not benet
efit from this intervention. This could result from physt
sician ignorance, incomplete hospital databases, or patt
tients undergoing allogeneic transfusions at sites where
leukoreduced blood components are not provided.169
What about female patients with multiple pregnanct
cies? Transfusion with non-leukocyte reduced blood
will likely further alloimmunize them. Does this then
represent the mortgaging of their medical future? For
example, if certain treatments might be required by
such patients, such as kidney allograft transplantation,
or the need for chemotherapy to manage a malignancy
for which transfusion therapy support might be reqt
quired?161
It seems illogical to support laboratory-based progt
grams of quality management to reduce the errors and
accidents affecting blood transfusion recipients without
recognizing that selective transfusion programs are a
major source of error. Thus, the implementation of good
manufacturing practices and quality initiatives in blood
centers and transfusion services will be inherently inct
complete until they can assure that transfusion requiremt
ments can be met without error.170
In discussing public policy considerations, Vamvakis,
Dzik and Blajchman stated the following: “In the abst
Hematol Oncol Stem Cell Ther 1(2) April 2008  hemoncstem.edmgr.com
review
sence of considerations of cost, there is both scientific
and medical consensus that leukocyte reduction is appt
propriate medical practice. The WBCs are not a compt
ponent of blood generally intended to be transfused
and they can be viewed as undesirable. Furthermore,
leukoreduction is almost entirely risk free at least in
most situations”.170
Blajchman ended his 1999 editorial by quoting Sir
Anthony Bradford Hill,168 the father of randomized
controlled trials: “All scientific work is incomplete,
whether it is observational or experimental. All scientt
tific work is liable to be upset or modified by advancing
knowledge. This does not confer on us a freedom to ignt
nore the knowledge we already have, or to postpone the
action that it appears to demand at a given time”.171
If zero risk is the goal of transfusion medicine, the
legacy from the HIV/HCV experience over the last two
decades dictates that all risks should be considered and
the resources allocated for each according to priority
goals. As important as the direct financial cost is the posst
sibility of re-direction of resources away from risks that
have already been documented. In this regard it is impt
portant to note that most early manufacturing interventt
tions or changes in practice in transfusion medicine were
not introduced based on quality of evidence! Moreover
ULR should also be seen as an important processing
step that will contribute to improving the safety and
purity of blood components. In addition, it can also be
seen as an important but necessary preliminary processit
ing step both resulting in safer products for transfusion
recipients, but also one that will be required in anticipatt
tion of the next new paradigm in transfusion medicine:
pathogen inactivation (see Table 1).172
Acknowledgement
Dr. Bassuni and Dr. Al-Moshary would like to thank
McMaster transfusion medicine research program staff
for their cooperation. Special thanks to Professor Morris
Blajchman for sharing his extensive knowledge and experier
ence.
119
 review
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