BLOOD COMPONENTS
Comparing the efficacy and safety of apheresis and whole
blood–derived platelet transfusions: a systematic review
Nancy M. Heddle, Donald M. Arnold, Diana Boye, Kathryn E. Webert, Ilona Resz, and
Larry J. Dumont
BACKGROUND: A systematic review and meta-
analysis was performed to determine if there were dif-
ferences between apheresis platelet concentrates
(APCs) or platelets (PLTs) derived from whole blood
(WBD) for the outcomes acute reactions, alloimmuniza-
tion, refractoriness, corrected count increment (CCI),
radiolabeled recovery and survival, time to next transfu-
sion, and bleeding.
STUDY DESIGN AND METHODS: We searched
Medline, Embase, the Cochrane Registry of Controlled
Trials, PapersFirst, ProceedingsFirst, and AABB and
ASH abstracts for randomized controlled trials (RCTs)
comparing APCs and WBD PLTs for clinical outcomes.
Study selection, data extraction, and methodologic
quality assessments were performed in duplicate.
Results were pooled using meta-analytic methods.
RESULTS: Ten RCTs met the inclusion criteria. Acute
reactions per patient were lower for APCs (relative risk
[RR], 0.65; 95% CI, 0.44-0.98); however, when control-
ling for leukoreduction, there was no significant differ-
ence (leukoreduced [LR]-APCs vs. LR-WBDs; odds
ratio, 1.78; 95% CI, 0.87-3.62). There was no difference
between products when reaction frequencies were
assessed per transfusion (RR, 0.65; 95% CI, 0.33-
1.28). APCs were associated with significantly higher
CCIs than WBD PLTs at both 1 hour (weighted mean
difference [WMD], 2.49; 95% CI, 2.21-2.77) and 18 to
24 hours (WMD, 1.64; 95% CI, 0.60-2.67). No conclu-
sions could be made for the outcomes of alloimmuniza-
tion and refractoriness. No studies addressed outcomes
of time to next transfusion or bleeding.
CONCLUSIONS: Owing to the small number of trials
and lack of comparability of PLT products for leukore-
duction, we were unable to draw definitive conclusions
about the clinical benefits of APCs compared with WBD
PLTs. Rigorous RCTs using clinically important end
points are needed to settle this issue.
P
latelets (PLT) for transfusion are prepared either
from apheresis or from whole-blood donations.
Whole blood–derived (WBD) PLTs are prepared
by the PLT-rich plasma (PRP) method or the
buffy coat (BC) method. Although all three methods are in
routine use throughout the world, there is uncertainty as
to the differences in efficacy and/or safety of these prod-
ucts. Advantages suggested for apheresis PLT concen-
trates (APCs) include fewer donor exposures, less bacterial
contamination, and operational efficiencies including
white cell (WBC) removal. Proposed advantages of WBD
PLTs include cost, efficient use of whole-blood donations,
and ease of neonatal and pediatric dosing. Comparisons
ABBREVIATIONS: APC(s) = apheresis platelet concentrates;
BC(s) = buffy coat(s); LR = leukoreduced; non-
LR = nonleukoreduced; post-LR = poststorage leukoreduced;
pre-LR = prestorage leukoreduced; PRP = platelet-rich plasma;
RCT(s) = randomized controlled trial(s); RR = relative risk;
UVB = ultraviolet light B; WBD(s) = whole blood–derived
platelets; WBD-BC = whole blood–derived platelets prepared
from buffy coats; WBD-PRP = whole blood–derived platelets
prepared from platelet-rich plasma; WMD(s) = weighted mean
difference(s).
From the Department of Medicine and the Department of
Molecular Medicine and Pathology, McMaster University,
Hamilton, Ontario, Canada; and the Department of Pathology,
Dartmouth-Hitchcock Medical Center, Lebanon, New
Hampshire.
Address reprint requests to: Nancy Heddle, MSc, FCSMLS
(D), McMaster Transfusion Research Program, McMaster Uni-
versity, 1200 Main Street West, HSC-3N43, Hamilton, Ontario,
Canada L8N 3Z5; e-mail: heddlen@mcmaster.ca.
Dr Arnold is a New Investigator with the Canadian Insti-
tutes of Health Research. Dr Webert holds a McMaster Univer-
sity, Department of Medicine Internal Career Research Award.
Received for publication September 19, 2007; revision
received January 7, 2008, and accepted January 29, 2008.
doi: 10.1111/j.1537-2995.2008.01731.x
TRANSFUSION 2008;48:1447-1458.
Volume 48, July 2008 TRANSFUSION 1447
HEDDLE ET AL.
of clinically important outcomes, such as bleeding and
prevention of transfusion reactions, have not been well
described and differences in surrogate outcomes such as
corrected PLT count increments (CCIs) and PLT recovery
are uncertain.1
There have been numerous in vitro studies that have
assessed the quality of the different PLT products during
storage using biochemical markers and measurements of
shape change and PLT function.2,3 Although differences in
some of these in vitro outcome measures have been dem-
onstrated, their clinical relevance is unknown because
they have generally not been shown to correlate with clini-
cal outcomes.
The objective of this systematic review was to assess
differences between APCs and WBD PLTs (whole blood–
derived platelets prepared from platelet-rich plasma
[WBD-PRP] or whole blood–derived platelets prepared
from buffy coats [WBD-BC]) for the clinical outcomes of
bleeding and acute transfusion reactions and for the
surrogate outcomes of CCI, alloimmunization and PLT
refractoriness, time to next transfusion, and PLT survival
and recovery. A secondary objective was to identify knowl-
edge gaps to focus future research programs.
MATERIALS AND METHODS
We performed a systematic review to identify all random-
ized trials comparing APCs and WBD PLTs. In duplicate,
we searched the electronic databases of MEDLINE (1966
to January 2007), EMBASE (1980 to January 2007), and the
Cochrane Registry of Controlled Trials using the following
key words and text words as search terms: “platelet trans-
fusions,” “plateletpheresis,” “buffy coat platelets,” “apher-
esis platelets,” and “whole blood derived platelets.” The
Dickersin filter was used to limit citations to randomized
controlled trials (RCTs).4 We identified abstracts through
the PapersFirst and ProceedingsFirst portal. All abstracts
from the American Society of Hematology and AABB
annual meetings (2000-2005) were searched by hand.
Manual searches of bibliographies of relevant articles and
reviews were also performed. The search strategy was
intentionally broad to minimize the risk of relevant article
omission.
After an initial screening of titles by one reviewer
(NMH), two independent reviewers (DMA, DB) screened
potentially relevant abstracts to select those that met the
following predefined inclusion criteria: RCT; comparison
of two or more types of PLT products (WBD-PRP, WBD-BC,
or APCs); clinical outcomes (primary or secondary)
including any of bleeding, adverse events, time to next
transfusion, alloimmunization, or refractoriness; and
laboratory outcomes including posttransfusion incre-
ments or PLT survival and recovery. Abstract-only publi-
cations were eligible, and there were no language
restrictions. Once potentially relevant studies were iden-
1448 TRANSFUSION Volume 48, July 2008
tified, the complete article was scrutinized to confirm
eligibility.
The following data were extracted independently in
triplicate (NMH, DB, IR): study design, source of funding,
inclusion and exclusion criteria, number of patients
eligible and randomly assigned, sex, age, type of PLT
product transfused, number of transfusions, dose of PLTs
transfused, WBC content of the transfused product,
product age at transfusion, outcome definitions, and
outcome events. Proportions were reported for dichoto-
mous outcomes, and means and standard deviations
(SDs; or medians with ranges [high-low] for skewed data)
were reported for continuous outcomes. The data
extracted by the three reviewers were compared for con-
sistency, and discrepancies were resolved by consensus.
Individual patient data were used for the analysis where
available.
Methodologic quality of the included trials was
judged by two independent reviewers (DMA and LJD)
except for the study authored by DMA, which was judged
by a third rater (S. Whittaker). The Jadad scale was used to
assess study quality.5 This scoring system assigns one
point for certain methodologic criteria and subtracts
points if certain information is not provided, including:
randomized treatment allocation, use of appropriate
method for randomization, the use of a double-blind
study maneuver and an appropriate method to achieve
double blinding, and a description of all withdrawals and
dropouts. An overall score of two or lower was considered
to represent “poor” methodologic quality. In addition,
reviewers were asked to judge the adequacy of the method
of allocation concealment. The reviewers were not
blinded to the authorship of the article during this process
because both reviewers were familiar with the literature
in this area. Discrepancies in scoring were resolved by
consensus.
The primary analysis was to compare the frequency of
the prespecified clinical outcomes between APCs and
WBD PLTs (WBD-PRP and/or WBD-BC). Leukoreduction
and product age were identified as potential confounding
factors that were considered when deciding whether or
not data should be pooled. Each outcome was consid-
ered independently of the others, with no adjustment for
multiple tests. Results were pooled across studies using
the random effects model of DerSimonian and Laird6 to
calculate the overall relative risk (RR) and 95 percent
confidence intervals (CIs).6 Pooled RRs were calculated
for the dichotomous outcomes of refractoriness, alloim-
munization, and alloimmune refractoriness. Weighted
mean differences (WMDs) were calculated by pooling
results of continuous variables (CCI) weighted by the
inverse of the variance. We used computer software
for these calculations (Review Manager Version 4.3, The
Nordic Cochrane Center, The Cochrane Collaboration
2003, Copenhagen, Denmark). The percentage of total
 COMPARISON OF APHERESIS AND WHOLE-BLOOD PLTs

Initial search
product type was transfused (n = 96),
936 citations no comparison of PLT transfusion
440 excluded: Titles screened for
relevance products was performed (n = 192),
96- 1 product only
192- not relevant the article did not report original
64- original data not data (n = 64), nonrandomized design
included 496 identified as (n = 46), clinical outcomes were not
46- not randomized potentially relevant
39- in vitro reported (n = 39), and redundant pub-
Duplicate independent
3- duplicates review of abstracts based on lications (n = 3). The abstracts of the
inclusion criteria remaining 496 citations were retrieved
and were assessed for eligibility in
19 possible inclusions duplicate. Nineteen articles appeared
to meet the inclusion criteria and the
Duplicate review of full full text publications were further
articles. Disagreement evaluated. Of those 19 articles, 6 were
resolved by consensus
Ineligible:
excluded for the following reasons: ran-
4-APC and WBD PLTs not domization was not based on APC and
randomized 13 studies were WBD products (n = 4),7-10 duplicate
1- foreign included:
publication (duplicate study) - 10 original publication uncovered after translation
1-not relevant when reports to English (n = 1),11 inclusion criteria
translated - 3 secondary not met (n = 1).12 Of the 13 remaining
publications
articles,13-25 2 were secondary publica-
tions from the TRAP trial data,23,24 and 1
Fig. 1. Results of the article search and selection. article was a preliminary report of a
trial which was published in full 1 year
later.16 Hence, there were 10 original
variance across studies was assessed using the I2 test for
studies: 8 full articles13,15,17-20,22,25 and 2 abstracts14,21
heterogeneity.
(Fig. 1). These 10 RCTs represented work performed
For acute transfusion reactions, exploratory analyses
independently in eight different countries: Canada (2
were performed by combining results across all studies by
studies both from the same site); the United States (3
product type (APCs-leukoreduced [LR], WBD-non-LR,
studies from two different sites); and 1 study each in the
WBD-LR) using a logistic regression model. These analy-
Netherlands, Germany, Switzerland, Belgium, and the
ses were performed using reactions per patient and reac-
United Kingdom.
tions per transfusion as outcomes. The WBD PLTs in that
analysis included only products prepared using the PRP
method.
Study characteristics
The characteristics of the studies included in this review
(including secondary publications [n = 2]23,24 and prelimi-
Role of the funding source
nary report [n = 1]16) are summarized in Table 1. The
The study sponsor was Gambro BCT (Lakewood, CO). studies were published between 1981 and 2006 and ran-
LJD (a former employee of the sponsor) and NMH con- domized a total of 1137 patients between the ages of 14
ceived the idea for the study formulating the hypothesis and 89. Of the 10 original trials, 7 (70%) were single-
and general study design while LJD was still employed at center studies13-15,17,18,21,25 and 319,20,22 were multicenter
Gambro BCT. The search strategies, article selection, data involving three to seven sites. Eight of the studies
extraction, review criteria, and primary analyses were enrolled patients with hematologic malignancies and/or
performed by the authors other than LJD. LJD partici- solid tumors who were receiving prophylactic and thera-
pated in the critical review of the eligible studies and peutic PLT transfusions,13-15,17-20,22 1 study did not specify
manuscript review after leaving the employment of the the patient population,21 and 1 study recruited healthy
sponsor. volunteers to assess radiolabeled PLT recovery and sur-
vival.25 All trials randomly allocated either patients or
RESULTS transfusions to APCs or WBD PLTs (WBD-PRP and/or
WBD-BC). The follow-up period varied from 6 days to
Literature search 8 weeks (from 4 studies). Sources of funding, disclosed in
We identified 936 citations from the initial literature 5 of the 10 studies, were industry (n = 1),19 peer-reviewed
search. After screening titles for relevance, 440 citations funding (n = 3),13,20,25 and a combination of both (n = 1).22
were excluded for the following reasons: only one Two reports were published as abstracts only.14,21 No

Volume 48, July 2008 TRANSFUSION 1449

 HEDDLE ET AL.

1450 TRANSFUSION
Author(s) and year
Sintnicolaas et al. (1981)13
TABLE 1. Summary of the study demographics and patients enrolled
Total number of patients Single or multicenter
Years of recruitment randomized (number of sites) Funding source Patient population Age (years)
Not reported 34 Single Peer review Acute leukemia; other 14-75
hematologic malignancies

Volume 48, July 2008

Gmur et al. (1983)15 Jun 1977-Dec 1981 54 Single Not reported Acute leukemia 17-71
Bishop et al. (1995)16* Not stated Not reported Multicenter Not reported Not reported Not reported
Muylle et al. (1996)17 5 months, year not reported 64 patients, 39 included in Single Not reported Acute leukemia; other 19-89
analysis hematologic malignancies
Kluter et al. (1996)18 Not reported 36 Single Not reported Oncology, acute leukemia; 19-79
other hematologic
malignancies
Anderson et al. (1997)19 Not reported 51 Multicenter (5) Industry Acute leukemia; other Not reported
hematologic malignancies
TRAP (1997)20 Jan 1991-Feb 1995 603 randomized, 530 Multicenter (7) Peer review Acute leukemia 16-88
included in analysis
Kakaiya (1981)14 [abstract] Not reported 16 Single Not reported Acute leukemia adults 21-78
Slichter et al. (1998)21 Not reported 118 Single Not reported Not reported Not reported
[abstract]
Heddle et al. (2002)22 Mar 1997-Mar 1999 129 Multicenter (3) Peer review and industry Acute leukemia; other 17-67
hematologic malignancies
Enright et al. (2003)23† Jan 1991-Mar 1995 603 randomized, 598 Multicenter (7) Peer review Acute leukemia 53 ⫾ 16 (SD)
included in analysis
24
Slichter et al. (2005) † Jan 1991-Feb 1995 603 enrolled, 533 analyzed Multicenter (7) Peer review Acute leukemia 52 ⫾ 17 (SD)
Arnold et al. (2006)25 Not reported 32 randomized, 22 Single Peer review Healthy volunteers 18-60
completed the study
* Bishop is early report of Anderson study. The latter study was used as the primary data source.
† The reports by Enright (2003) and Slichter (2005) are substudies using data from the TRAP study (1997).
 COMPARISON OF APHERESIS AND WHOLE-BLOOD PLTs

study compared APCs to WBD PLTs for the outcomes of

Score
bleeding or time to next transfusion.

1
4
0
0
4

3
0

0
5

3
withdrawals and dropouts?
Was there a description of
Assessment of methodologic quality
Initial agreement between reviewers on quality assess-

(yes = 1 point)
ment was moderate (k = 0.55), and disagreements were

Yes

Yes

Yes

Yes

Yes
No

No
No

No

No
resolved by consensus in all cases. Of the 10 studies, 5 were
found to be of poor methodologic quality, scoring 2 or
less on the Jadad scale. Failure to report the method of
randomization, allocation concealment, and/or losses to

TABLE 2. Assessment of the methodologic quality of the studies using the scoring system of Jadad5
follow-up were the primary reasons for low scores
(Table 2).

Yes—sealed envelopes
Yes—sealed envelopes

Yes—sealed envelopes
(yes = 1 point; no = subtract
described and appropriate?
Was the blinding method
Transfusion reactions

1 point)
Four trials, reported in six publications, assessed the fre-
quency of acute transfusion reactions by PLT product

Yes
NR
NR

NR
No
No

No
type.16,17,19,20,22,23 The study by Bishop and colleagues16 was
reported in full by Anderson and colleagues;19 hence, the
latter was used as the data source for the analyses. Defini-
tions of acute transfusion reactions varied across studies

Was the study double

blind? (yes = 1 point)

No—single blinded
with the primary differences related to the temperature
increase (ⱖ1 or ⱖ2°C) and reaction severity. Heddle and
coworkers22 reported all grades of severity while the other
studies reported only severe reactions. The period of

Yes

Yes

Yes
observation after transfusion was also variable, ranging
NR
NR

NR

NR
No

No
from 2 to 4 hours. The methods for assessing reactions
were reported in all publications except Bishop and col-
Yes—random number table
point; no = subtract 1 point)

randomization was done

and appropriate? (yes = 1

Yes—computer-generated

Yes—computer-generated
leagues,16 and all involved prospective assessments of
randomization stated
Was the method of

adverse events by the treating health care provider with or

No—just stated that

without chart review.

The characteristics of the PLT products used in each

schedule

schedule
study are summarized in Table 3. The PLT products trans-
centrally

fused in these studies were not comparable for two factors

that are known to influence the frequency of acute
No

No
No

No
No

No

reactions: leukoreduction (before and after storage);9,22

and age of the PLT product at the time of transfusion.26,27
randomized? (yes = 1 point)
Was the study described as

Therefore, we did not pool these data in a meta-analysis.

Reaction frequencies were reported by patient and/or by
PLT transfusion episodes. Summary data on the frequency
Yes

Yes

Yes

Yes

Yes

of reactions by PLT product type are reported in Table 4. In

No

No
No

No

No

the exploratory analysis by product type across all studies,

WBD-PRP non-LR were associated with a higher propor-
tion of reactions per patient than APC-LR (odds ratio [OR],
1.87; 95% confidence interval [CI], 1.12-3.12), whereas
there was no difference in risk of reaction when all WBDs
Kakaiya (1981)14 [abstract]
Sintnicolaas et al. (1981)13

(PRP and BC) and all APCs were LR (OR, 1.78; 95% CI,
Anderson et al. (1997)19

Slichter et al. (1998)21

Heddle et al. (2002)22

0.87-3.62). When examining reactions per transfusion, dif-

Muylle et al. (1996)17

Arnold et al. (2006)25

Kluter et al. (1996)18
Gmur et al. (1983)15

NR = not reported.

ferences were not observed when WBD-PRP non-LR and

TRAP (1997)20

APC-LR were compared (OR, 0.82; 95% CI, 0.63-1.07) or

[abstract]

when comparing WBD-PRP-LR and APC-LR (OR, 0.99;

95% CI 0.63-1.58). For the outcome of transfusion reac-
Study

tions, there were no studies that compared non-LR APCs

to non-LR WBD PLTs.

Volume 48, July 2008 TRANSFUSION 1451

 HEDDLE ET AL.

1452 TRANSFUSION
TABLE 3. Characteristics of the PLT products used in the studies that reported adverse events*
UK study TRAP study
PLT product Bishop et al. (1995)16 Anderson et al. (1997)19 Muylle et al. (1996)17 Initial report† (1997)20 Enright et al.‡ (2006)23 Heddle et al. (2002)22
Collection system
WBD-PRP NR ACD split CPDA-1 NR NR Nutricel
WBD-BC NR NR Optipac/Optipress

Volume 48, July 2008

APCs NR Cobe Spectra 3.6 Cobe Spectra 2.6 or 3.6 Cobe Spectra 2.6 or 3.6 Spectra LRS
Leukoreduction
WBD-PRP NR Non-LR Bedside post-LR PL100§ and non-LR PL100§ and non-LR Pre-LR
WBD-BC NR Non-LR Bedside post-LR
APCs NR NR PL100 (Lab) post-LR PL100 (Lab) post-LR Pre-LR during collection
6
Number of WBCs (¥10 /product)
WBD-PRP NR 365 (NR) 270 (⫾220) 2-742¶ 1.6-792储 >5
WBD-BC NR 5.68 (NR) 150 (⫾100)
APCs NR 0.33 (0.03-13.5)** 1 (⫾14) >5
Pool size
WBD-PRP NR 5 7⫾1 6 6 4 or 5
WBD-BC NR 4 4
Product age (days)
WBD-PRP NR ⱕ6 hr 2.51 (⫾1.15) NR NR 3.7 (⫾1.1)
WBD-BC NR 2.98 (⫾1.2) 3.04 (⫾1.13)
APCs NR 2.98 (⫾1.3) NR NR 3.0 (⫾1.4)
* Data are reported as mean (⫾ SD).
† Analysis included 530 of 603 patients randomly assigned.
‡ Analysis included 598 of 603 patients randomly assigned.
§ Post-LR at the bedside.
¶ Consisted of three product types: non-LR (742 ⫾ 607), bedside post-LR (2 ⫾ 20), and UVB (704 ⫾ 564).
储 Consisted of three product types: non-LR (792 ⫾ 606), bedside post-LR (1.6 ⫾ 18.1), and UVB (743 ⫾ 552).
** Mean (range).
NR = not reported.
 TABLE 4. Frequency of reactions reported by patient and by transfusions in the eligible studies
UK study TRAP study
Product Anderson et al. (1997) Bishop et al. (1995) Initial report (1997)* Enright et al. (2006)† Muylle et al. (1996) Heddle et al. (2003)‡
Reactions expressed per number of patients transfused (%)
APCs
APCs post-LR 20/132 (15.2)
APCs pre-LR 4/18 (22)
WBD-PRP 8/13 (62)
WBD-PRP post-LR
WBD-PRP pre-LR
WBD PRP UVB
Overall 94/398 (23.6)
WBD-BC 5/17 (29)
Reactions expressed per number of PLTs transfused (%)
APCs
APCs post-LR 29/1450 (2) 36/2192 (1.6)
APCs pre-LR 5/162 (3.1) 6/169 (3.6) 67/504 (13.3)
WBD-PRP 20/117 (17.1) 20/117 (17.1) (2)§ 47/1880 (2.5)
WBD-PRP post-LR (2)§ 38/2101 (1.8) 37/398 (9.3)
WBD-PRP UVB (3)§ 63/2159 (2.9)
WBD-PRP pre-LR 59/517 (11.4)
Overall 131/5650 (2.3) 148/6140 (2.4)
WBD-BC 6/158 (3.8) 7/169 (4.1) 5/186 (2.7)
* 530 of 603 randomly assigned patients included in the analysis.
† 598 of 603 randomly assigned patients included in the analysis.
‡ Reported all severity grades (mild, moderate, severe), whereas other studies reported only severe reactions.
§ Proportions not provided in the article.

Volume 48, July 2008

TRANSFUSION 1453
COMPARISON OF APHERESIS AND WHOLE-BLOOD PLTs
HEDDLE ET AL.

Review: Apheresis vs whole blood derived platelet transfusions

Comparison: 05 CCI (1hr)
Outcome: 01 corrected count increment

Study Apheresis Whole blood-derived WMD (random) Weight WMD (random)

or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

Gmur 1983 162 15.60(5.60) 148 12.48(3.70) 7.32 3.12 [2.07, 4.17]
Kluter 1996 58 18.48(12.73) 232 15.87(10.86) 0.63 2.61 [-0.95, 6.17]
Anderson 1997 162 12.00(14.64) 275 10.27(16.29) 0.92 1.73 [-1.23, 4.69]
TRAP 1997 1498 14.70(5.20) 4756 12.23(5.15) 88.68 2.47 [2.17, 2.77]
Slichter(a) 1998 118 11.58(8.12) 118 10.03(5.93) 2.45 1.55 [-0.26, 3.36]

Total (95% CI) 1998 5529 100.00 2.49 [2.21, 2.77]

Test for heterogeneity: Chi² = 2.69, df = 4 (P = 0.61), I² = 0%
Test for overall effect: Z = 17.20 (P < 0.00001)

-10 -5 0 5 10
Higher with WBD Higher with APC

Fig. 2. Forest plot showing the weighted mean difference in the 1-hour CCI of all WBDs versus APCs.

Review: Apheresis vs whole blood derived platelet transfusions

Comparison: 06 CCI (24 hr)
Outcome: 01 Corrected count increment at 24 hours

Study Apheresis Whole blood-derived WMD (random) Weight WMD (random)

or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

Gmur 1983 162 8.40(4.70) 148 6.50(2.90) 40.92 1.90 [1.04, 2.76]
Kluter 1996 58 10.78(8.71) 232 11.86(8.00) 13.50 -1.08 [-3.55, 1.39]
Anderson 1997 162 8.63(21.51) 275 6.39(23.16) 5.29 2.24 [-2.06, 6.54]
Heddle 2002 380 6.60(7.04) 384 4.40(5.31) 40.29 2.20 [1.32, 3.08]

Total (95% CI) 762 1039 100.00 1.64 [0.60, 2.67]

Test for heterogeneity: Chi² = 6.06, df = 3 (P = 0.11), I² = 50.5%
Test for overall effect: Z = 3.09 (P = 0.002)

-10 -5 0 5 10
Higher with WBD Higher with APC

Fig. 3. Forest plot showing the weighted mean difference in the 18- to 24-hour CCI of all WBDs versus APCs.

CCIs vented or delayed by transfusing only APCs.13-15 The fourth

Six studies compared the 1-hour and/or 18- to 24-hour
CCI between WBDs (WBD-PRP or WBD-BC) and
APCs.15,18-22 The study by Heddle and coworkers22 reported
the 18- to 24-hour CCI by PLT product as a dichotomous
variable (successful increment, CCI ⱖ 4.5; unsuccessful
increment, CCI < 4.5); however, the raw data were
obtained and reanalyzed as a continuous variable for the
meta-analysis.22 Overall, APCs had a superior 1-hour CCI
(WMD, 2.49; 95% CI, 2.21-2.77) as shown in Fig. 2. When
WBD PLTs were stratified into WBD-BC and WBD-PRP, a
significant difference remained between APCs and WBD-
PRP (WMD, 2.50; 95% CI, 2.19-2.81), but there was no
significant difference between APCs and WBD-BC (WMD,
1.80; 95% CI, -0.77-4.38). The 18- to 24-hour CCI was sig-
nificantly higher for APCs compared with WBD products
(WMD, 1.64; 95% CI, 0.60-2.67; Fig. 3). Moderate hetero-
geneity was noted between studies (I2 = 50.5%), predomi-
nately due to the study by Kluter and colleagues.18 As with
the 1-hour CCI, there was a significant difference between
APCs and WBD-PRP for the 18- to 24-hour CCI (WMD,
2.05; 95% CI, 1.44-2.66); but APCs and WBD-BC were not
significantly different (WMD, -0.39; 95% CI, -2.95-2.17).
Alloimmunization and refractoriness
Three of the studies were designed to determine whether
alloimmunization and/or refractoriness could be pre-
study (the TRAP trial) was designed to determine if
post-LR or ultraviolet light B (UVB) treatment of WBD-PRP
PLTs could prevent alloimmunization and refractoriness.20
This study compared APCs with three types of WBD PLTs:
WBD-PRP non-LR, WBD-PRP post-LR (bedside filtration),
and WBD-PRP UVB-treated. The definitions of alloimmu-
nization and refractoriness varied between the studies. All
studies used a lymphocytotoxicity assay as the primary
determinant of HLA alloimmunization; however, several
of the studies also included the presence of PLT-associated
antibodies in their assessments of alloimmunization
using radioimmunoassay, enzyme-linked immunosor-
bent assay, and/or flow cytometry techniques. The
definitions of refractoriness included three poor post-
transfusion PLT responses defined as a 24-hour CCI of less
than 2500 m2 per mL per unit in the absence of other clini-
cal causes or a 1-hour CCI of less than 4000 m2 per mL per
unit in the absence of other clinical causes; percent recov-
ery of 10 percent or less at 1 hour; a 24-hour CCI of less
than 2500 m2 per mL per unit or a 1-hour CCI of less than
4000 m2 per mL per unit without coexisting disseminated
intravascular coagulation, sepsis, or splenomegaly; and a
CCI of less than 5000 m2 per mL per 1011 PLTs after two
sequential transfusions of fresh ABO-compatible PLTs.
The frequencies for alloimmunization and refractori-
ness are summarized in Table 5. We performed a meta-
analysis combining only the three studies that used

1454 TRANSFUSION Volume 48, July 2008


TABLE 5. Summary of the frequency of alloimmunization and refractoriness in the four studies that assessed
these outcomes
Outcome by product type Sintnicolaas et al. (1981)13
Number (%) alloimmunized
WBD-PRP non-LR 2/16 (12.5)
WBD-PRP post-LR
WBD-PRP UVB
APCs non-LR 1/17 (5.9)
APCs post-LR
Number (%) refractory
WBD-PRP non-LR
WBD-PRP post-LR
WBD-PRP-UVB
APCs non-LR
APCs post-LR
* p < 0.05 when compared with apheresis.
non-LR products to determine the impact of APCs or WBD
PLTs on alloimmunization. The overall RR was not signifi-
cant (RR, 0.63; 95% CI, 0.15-2.54), and significant hetero-
geneity was observed (I2 = 65.5%).
Radiolabeled recovery and survival
One study compared PLT recovery and survival for APCs
and WBD-PRP using autologous radiolabeled PLTs.25 This
study was performed in 22 volunteers using a crossover
study design where each volunteer donated in random
order both WBD-PRP pre-LR and APCs pre-LR. In vivo PLT
recovery and survival for the two products were measured
simultaneously using a double PLT label technique. The
authors concluded that APCs had 18.8 percent better
recovery (p = 0.032) and 32.9 percent longer survival
(p < 0.001) than WBD-PRP PLTs.
DISCUSSION
The effectiveness of various types of PLT products has
been debated for many years. The lack of consensus is
apparent in day-to-day practice where patients continue
to receive either APCs or WBD PLTs primarily at the dis-
cretion of the local blood supplier and often based on
availability of supply. The goal of this review was to try to
settle the debate by systematically reviewing and carefully
pooling the data from existing literature. In the end, due to
the small number of trials identified and the lack of com-
parability of LR and non-LR products, we were unable to
draw definitive conclusions about the clinical benefits of
APCs compared with WBD PLTs.
We identified 10 randomized trials comparing APCs
to either WBD-PRP or WBD-BC; however, all had impor-
tant methodologic limitations.13-15,17-22,25 First, none of the
studies compared products for the outcomes of bleeding
or time to next transfusion. Such endpoints are important
for any determination of efficacy and should be the drivers
for changes in transfusion practices. In addition, half of
COMPARISON OF APHERESIS AND WHOLE-BLOOD PLTs
Gmur et al. (1983)15 Kakaiya (1981)14 TRAP (1997)20
15/27 (55.5)* 2/7 (29) 64/131 (45)*
25/137 (18)
26/130 (20)
4/27 (14.8) 5/9 (55.5)
22/132 (17)
14/27 (51.9)* 17/131 (13)*
4/137 (3)
7/130 (5)
4/27 (14.8)
5/132 (4)
the studies failed to report sufficient detail about the
process of randomization and the integrity of blinding
resulting in low quality scores. Although the score was not
used to exclude studies of poor methodologic quality from
the analysis, it provides readers with additional informa-
tion about the validity of the individual study results. Also,
information about the presence or absence of confound-
ers such as product age and ABO compatibility was fre-
quently missing from reports, calling into question the
comparability of groups and limiting the potential for sen-
sitivity analyses. Owing to these limitations and the small
number of trials, conclusions about the benefits of one
product over another could not be made with certainty.
Rigorous randomized trials using clinically important
endpoints are needed to settle this issue. This has been
previously emphasized with respect to other trials in
transfusion medicine.28
The studies that reported acute reactions were not
amenable to pooling in a formal meta-analysis because of
differences between treatment arms related to LR. It is well
known that LR is an effective strategy for preventing acute
transfusion reactions especially when performed before
storage.9,22 The BC method results in a pre-LR PLT product,
and although there is only a 1 log reduction in contami-
nating WBCs, this level is sufficient to prevent most febrile
nonhemolytic transfusion reactions.29 As summarized in
Table 4, the PLT products assessed in these studies repre-
sented both LR (before and after storage) and non-LR
products. Furthermore, even within studies, the degree of
LR for different products was not always comparable. For
these reasons, we were unable to conclude whether one
PLT product was associated with fewer transfusion reac-
tions in the primary analysis.
LR (pre-LR and post-LR) and product age at the time
of transfusion were identified as potential confounding
factors, which could influence the outcome of acute
reactions.9,22,26,27 Insufficient information was provided to
permit a secondary analysis of the effects of product age.
The effect of LR was evaluated in a secondary analysis
Volume 48, July 2008 TRANSFUSION 1455
HEDDLE ET AL.
based on stratification by product type (APC-LR, WBD-BC,
WBD-PRP non-LR, WBD-PRP-LR, and WBD-PRP non-LR
UVB-treated). When PLT product type was considered
with LR status, APC-LR were superior to WBD non-LR PLTs
in avoiding transfusion reactions (p = 0.016), while the
odds of a reaction with a post-LR WBD PLT were not sig-
nificantly higher than with APC-LR (OR, 1.775; p = 0.1139).
This is consistent with our current understanding that
although most PLT reactions are caused by WBC-derived
cytokines released during storage of the PLT product,
approximately 10 percent of reactions are antibody-
mediated; hence, post-LR will prevent some reactions.30
When acute reactions are evaluated by transfusion
rather than by patient, no significant difference is seen
between APCs and WBD PLTs; however, significant hetero-
geneity was present. To explain this heterogeneity, we per-
formed an exploratory analysis comparing product types
across studies. In contrast to the analysis by patient, no
differences were seen between PLT types where transfu-
sions were used as the denominator. This observation sug-
gests that some patients are more prone to reactions than
others. This should be an important consideration with
future study designs ensuring that analyses are performed
per patient or by using study designs that account for
interpatient variability such as randomizing transfusions
rather than patients. There are very little data on acute
reactions in patients transfused with WBD-BC (158 trans-
fusions in 17 patients in one study).
The TRAP study was a pivotal study addressing the
hypotheses of the effect of LR and UVB irradiation on
alloimmunization and refractoriness to PLT transfusion
and compared APCs to WBD PLTs.20 Although we identi-
fied three other studies that also compared APCs to WBD
PLTs,13-15 they were all small (ranging from 16 to 54
patients) compared to the TRAP study. The TRAP study
demonstrated that LR was a dominant factor in reducing
the risk of these outcomes; hence, any analyses performed
would be influenced heavily by the TRAP study results.
The frequencies of both alloimmunization and refractori-
ness were significantly lower when LR or UVB-treated
PLTs were transfused compared to WBD-PRP non-LR
products. The TRAP study did not support an advantage
for either APCs or WBD PLTs in reducing the risk of alloim-
munization or refractoriness; however, because this study
was designed to show superiority, no valid conclusions
can be made about equivalence.20 Overall, there is no evi-
dence to suggest that APCs are more effective than WBD-
PRP in decreasing the frequency of alloimmunization
and/or refractoriness. There are no data on the frequency
of alloimmunization and/or refractoriness with WBD-BC
PLTs.
The only outcome for which a formal meta-analysis
could be performed was CCI. Both the 1-hour and the 18-
to 24-hour CCIs were significantly higher with APCs than
with WBD PLTs (WMD, 2.5; 95% CI, 2.2-2.8; and WMD,
1456 TRANSFUSION Volume 48, July 2008
1.64; 95% CI, 0.6-2.7). This finding is consistent with pre-
vious observations from two clinical trials of acute trans-
fusion reactions where 53 percent of the APCs transfused
had a successful 18- to 24-hour CCI (defined as a
CCI < 4.5) compared with 35 percent of WBD-PRP trans-
fusions.9,22 The results are also consistent with observa-
tions from a volunteer study of radiolabeled autologous
PLTs, which showed that PLT recovery and survival were
significantly higher with APCs.25 These data suggest the
posttransfusion CCI will be higher with APCs; however,
there are no RCTs that have correlated the posttransfusion
CCI with bleeding or a longer interval between
transfusion; hence, the clinical relevance of this finding
needs further investigation.
There were a number of challenges when performing
this systematic review and meta-analysis. The reporting of
information varied with the different studies. In some
studies, relevant information was not specified in the
article; hence, such reports could not be included in the
analyses or assumptions had to be made to estimate
and/or calculate the required information. With a few
exceptions, the studies scored low on the critical appraisal
scale, most often as a result of missing information; hence,
study quality may have biased the overall results. Finally,
it was difficult to compare data from different studies
because of the lack of standardized definitions for acute
reactions, alloimmunization, and refractoriness. In addi-
tion the generalizability of the results is limited because all
9 of the 10 studies were performed in patients with hema-
tologic malignancies. The generalizability of the radiola-
beled recovery and survival study performed using
healthy volunteers to patients with malignancies being
treated with chemotherapy is also unknown.
A secondary goal of this review was to identify areas of
research that require further pursuit. There were few trials
comparing PLT products and little evaluative clinical data
for WBD-BC. Additional clinical studies are needed to
determine the differences between APCs and WBD-BC,
the effectiveness of various PLT products in populations
other than patients with chemotherapy-induced thromb-
ocytopenia, the validity of CCI as a surrogate outcome
measure for bleeding, and the difference between APCs
and WBD PLTs in the frequency and severity of acute
transfusion reactions, independent of leukoreduction.
Future studies using the outcomes of bleeding and time to
next transfusion would also provide useful information for
evidence-based transfusion practice.
This systematic review has also identified important
methodologic concerns that should be addressed to opti-
mize the design of future clinical trials to compare PLT
products. In particular, a standardized definition of acute
transfusion reactions should be developed and validated
for reproducibility and validity; the optimal analysis plan
should be derived to account for nonindependent events
such as transfusion reactions; the optimal unit of random-

ization (either the patient or the transfusion) should be
debated; and the important, clinically relevant outcomes
to be used in PLT transfusion trials, including bleeding,
should be identified.
Other factors such as PLT age and ABO compatibility
that may influence CCI and other outcomes should also
be considered in trial designs. Finally, standardized and
comprehensive reporting of PLT studies would facilitate
more informative systematic reviews and meta-analyses
in the future.
In summary, only the CCI data and the data from one
radiolabeled survival study in healthy volunteers provided
evidence that APCs were superior to WBD PLT products;
however, we do not know whether these observations con-
tribute to a longer interval between transfusions or less
bleeding, so their clinical relevance remains unknown. No
conclusions can be drawn about superiority of one PLT
product over another based on the outcomes of acute
reaction and alloimmunization and/or refractoriness.
There are no data comparing the two product types using
outcomes of bleeding and time to next transfusion, and
data assessing clinical outcomes using WBD-BC are
lacking. Hence, we are unable to draw definitive conclu-
sions about the clinical benefits of APCs compared with
WBD PLTs.
ACKNOWLEDGMENTS
We thank Dr Susan Whittaker for assisting with the adjudication
of study quality and Heather Patterson for her clerical assistance.
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