Platelet Transfusion A Systematic Review of The Clinical Evidence

REVIEW
CME
Platelet transfusion: a systematic review of the clinical evidence

Ambuj Kumar,1,2 Rahul Mhaskar,1* Brenda J. Grossman,3 Richard M. Kaufman,4
Aaron A.R. Tobian,5 Steven Kleinman,6 Terry Gernsheimer,7 Alan T. Tinmouth,8 and
Benjamin Djulbegovic,1,2 on behalf of AABB Platelet Transfusion Guidelines Panel
BACKGROUND: Platelet (PLT) transfusion is indicated

either prophylactically or therapeutically to reduce the
risk of bleeding or to control active bleeding. Significant
uncertainty exists regarding the appropriate use of PLT
transfusion and the optimal threshold for transfusion in
various settings. We formulated 12 key questions to
assess the role of PLT transfusion.
STUDY DESIGN AND METHODS: We performed a
systematic review (SR) of randomized controlled trials
(RCTs) and observational studies. A comprehensive
search of PubMed, Web of Science, and Cochrane registry of controlled trials was performed. Methodologic
quality of included studies was assessed and a metaanalysis was performed if more than two studies with
similar designs were identified for a specific question.
RESULTS: Seventeen RCTs and 55 observational
studies were included in the final SR. Results from
RCTs showed a beneficial effect of prophylactic compared with therapeutic transfusion for the prevention of
significant bleeding in patients with hematologic disorders undergoing chemotherapy or stem cell transplantation. We found no difference in significant bleeding
events related to the PLT count threshold for transfusion or the dose of PLTs transfused. Overall
methodologic quality of RCTs was moderate. Results
from observational studies showed no evidence that
PLT transfusion prevented significant bleeding in
patients undergoing central venous catheter insertions,
lumbar puncture, or other surgical procedures. The
methodologic quality of observational studies was
very low.
CONCLUSION: We provide a comprehensive assessment of evidence on the use of PLT transfusions in a
variety of clinical settings. Our report summarizes
current knowledge and identifies gaps to be addressed
in future research.
1116 TRANSFUSION Volume 55, May 2015
he number of patients receiving platelet (PLT)

transfusions has increased over the past several
years.1 PLT transfusions are used either prophylactically to reduce the risk of bleeding or therapeutically to control active bleeding.2 AABB previously
estimated that more than 70% of PLT transfusions are performed prophylactically.3 Important questions for PLT
transfusion therapy include the appropriate PLT count
threshold for prophylactic transfusion, the dosage of PLTs
that should be used, and the clinical conditions that
should prompt transfusion. To address the existing uncertainties related to the appropriate indications for PLT
ABBREVIATIONS: DIC = disseminated intravascular
coagulation; GRADE = Grading of Recommendations
Assessment, Development and Evaluation; HUS = hemolytic
uremic syndrome; LP(s) = lumbar puncture(s); SR = systematic
review; TBI = traumatic brain injury; TTP = thrombotic
thrombocytopenic purpura.
From the 1Division of Evidence-Based Medicine, Department of
Internal Medicine, Morsani College of Medicine, University of
South Florida, and the 2Moffitt Cancer Center, Tampa, Florida;
the 3Washington University School of Medicine, St Louis,
Missouri; 4Brigham and Womens Hospital, Boston,
Massachusetts; 5Johns Hopkins Hospital, Baltimore, Maryland;
the 6Center for Blood Research, The University of British
Columbia, Vancouver, British Columbia, Canada; the
7
University of Washington Medical Center and Seattle Cancer
Care Alliance, Seattle, Washington; and the 8Ottawa Hospital
and Research Institute, Ottawa, Ontario, Canada.
Address reprint requests to: Ambuj Kumar, MD, MPH,
Division of Evidence-Based Medicine, Department of Internal
Medicine, University of South Florida & H. Lee Moffitt Cancer
Center & Research Institute, 3515 East Fletcher Avenue, MDT
1201, MDC 27, Tampa, FL 33612; e-mail:
akumar1@health.usf.edu.
*Equal contribution.
Received for publication June 17, 2014; revision received
October 9, 2014, and accepted October 9, 2014.
doi: 10.1111/trf.12943
2014 AABB
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transfusions, we conducted a systematic review (SR) with

the aim of synthesizing the current evidence for many
of the common situations in which PLT transfusions are
considered.
MATERIALS AND METHODS

Development of clinical questions
Clinical questions were developed by an AABB Guidelines
Panel consisting of 21 members with expertise in transfusion medicine, hematology, surgery, anesthesiology,
intensive care, and guidelines development method. The
panel was charged with providing direction for development of this SR, which in turn was used to inform the
development of clinical practice guidelines (reported in a
separate document). This SR was performed according to
the standards of The Cochrane Collaboration,4 using a
standardized protocol and reported as per the PRISMA
guidelines.5
Search methods for identification of studies

We searched the Cochrane CENTRAL, PubMed, and Web
of Science databases since inception until September 5,
2014. There was no restriction on eligibility criteria in
terms of when the studies were performed or language. We
first searched for existing guidelines/SR using the search
filter developed by Haynes and colleagues.7 We manually
scanned references of obtained articles from identified
guidelines and SRs to identify other potentially relevant
articles for inclusion in the review. We also canvassed
members of the AABB Guidelines Panel to identify potentially eligible unpublished or ongoing studies (a detailed
search strategy is shown in Appendix S1, available as supporting information in the online version of this paper).
When deemed necessary, study authors were contacted
for information not available or not well described in the
original papers.
Data collection and analysis

Criteria for considering studies for this review
Selection of studies
Types of studies
All titles, abstracts, and full-text reports were reviewed by

two authors of this SR (AK, RM); further review was conducted by a third author (BD or RK) when there was disagreement about eligibility of the study for inclusion in
this SR.
Randomized controlled trials (RCTs) and observational

studies (prospective or retrospective cohort studies, casecontrol studies, and those with no control arm) were eligible for inclusion. Although all observational studies
meeting the inclusion criteria were reviewed, data from
these studies were not used when more than two RCTs
addressed a particular question. The use of evidence
summaries based only on RCTs was favored due to
confounding-by-indication bias in observational transfusion studies: that is, PLT transfusion is often administered
based on disease severity.6
Data extraction
Data extraction forms were piloted. The final forms were
used to extract data in duplicate, and a further review for
accuracy was conducted by an independent member of
the panel.
Assessment of risk of bias in included studies

Types of participants
Patients undergoing PLT transfusions in RCTs or observational studies were eligible for inclusion.
Types of interventions
Apheresis or whole bloodderived (buffy coat or PLT-rich
plasma) PLT concentrates whether used as therapeutic or
prophylactic interventions for any clinical condition were
eligible for inclusion. The comparison group (if any) was a
medical management strategy without PLT transfusion or,
in the case of the PLT dosing or PLT count threshold question, PLT transfusion strategy using a different dose or
threshold.
Assessment of the risk of bias in the included RCTs was

done according to The Cochrane Collaborations tool for
assessing the risk of bias.4 The risk of bias in observational
studies was assessed using the Newcastle Ottawa Scale,8
supplemented by the guidance paper by Wells and
coworkers.9 Overall quality of the studies was categorized
in four categories according to the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) method (details on GRADE method are provided
in Appendix S2, available as supporting information in the
online version of this paper).10 A formal assessment of
publication bias was not performed, since a small number
of studies (<10) will typically generate false-negative
results.
Types of outcome measures
Measures of treatment effect
Outcome measures considered were all-cause mortality,

mortality due to bleeding, bleeding (major or significant bleeding as defined in each study), and number of
PLT transfusions.
We summarized dichotomous data using odds ratio (OR)

and pooled data using the random-effects model along
with 95% confidence intervals (CI) for cohort and RCT
studies.4 Continuous data were summarized using mean
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KUMAR ET AL.
difference or standardized mean difference and reported

with 95% CI for both prospective and retrospective
studies. Some prespecified subgroup analyses were conducted (see Results and appendices), but others could not
be conducted due to the limited amount of available data.
Assessment of heterogeneity
To evaluate heterogeneity between pooled studies, the I2
statistic was calculated.11 We planned to assess potential
sources of heterogeneity by conducting a sensitivity analysis on all aspects of study quality, but the number of
studies was too small to allow reliable statistical analysis.
We also assessed clinical heterogeneity according to the
PICO (patient, intervention, comparator, and outcome)
format.4 Based on this assessment, we were generally able
to pool data from individual RCTs. For observational
studies, data were pooled based on the consensus of three
research team members followed by concurrence of the
entire panel. We did not pool RCT data with observational
study data. Meta-analysis was performed using Review
Manager 5 (RevMan 2011, http://tech.cochrane.org/
revman). We constructed a GRADE evidence profile for all
outcomes.10 Where meta-analysis was not possible, evidence was summarized descriptively.
RESULTS
Figure 1 shows selection of eligible studies. Of 1594 citations, 17 RCTs and 55 observational studies were included
in the final SR. The 17 RCTs addressed four questions on
the role of PLT transfusion in nonbleeding adult patients.
Table 1 summarizes the overall results for main outcomes
based on evidence from RCTs and Table 2 does the same
for observational studies.
In general, the overall methodologic quality of
included RCTs was judged to be moderate based on evaluations of imprecision (low number of events for some
important outcomes such as mortality) and/or potential
outcome reporting bias (some trials did not report important clinical outcomes such as mortality). The overall
methodologic quality of the included observational
studies was generally judged to be very low because of: 1)
selection bias due to confounding by indication, 2) sparse
data, 3) the overall lack of comparability between the
group of patients who received PLTs versus those who did
not, 4) lack of standardization and blinding in assessment of bleeding outcomes, and 5) lack of information on
completeness of data. The details of the quality assessment are provided in evidence tables in Appendix S3
Tables 1 through 12 (available as supporting information
in the online version of this paper). This overall quality
assessment applies to all questions unless specified otherwise. All forest plots, where applicable, are shown in
Appendix S4 (available as supporting information in the
online version of this paper).
Results for specific questions

Should PLT transfusions be used to prevent bleeding
in patients with hypoproliferative thrombocytopenia?
(Appendix S3, Table 1)
We identified five RCTs;12-15,56 four RCTs12-15 that enrolled
1076 patients with hematologic malignancies had extractable data. Prophylactically transfusing PLTs compared
with therapeutically transfusing PLTs components was
associated with a significant decrease in overall incidence
of clinically significant bleeding (three RCTs,12-14 1047
patients). The pooled OR was 0.53 (95% CI, 0.32-0.87;
p = 0.01; high heterogeneity I2 = 65%; p = 0.06).
In a subgroup analysis, transfusing PLTs prophylactically compared with transfusing PLTs therapeutically was
associated with a significant decrease in overall incidence
of clinically significant bleeding in patients with acute leukemia (three RCTs;12-14 356 patients; pooled OR, 0.34; 95%
CI, 0.22-0.52; p < 0.0001; low heterogeneity, I2 = 0%;
p = 0.44). In the subgroup of patients undergoing autologous transplant, the overall incidence of clinically significant bleeding was not significantly different (two RCTs;12,13
621 patients; OR, 0.48; 95% CI, 0.12-1.92; p = 0.30; high
heterogeneity, I2 = 89%; p = 0.003).
A prophylactic strategy compared with a therapeutic
strategy of PLT transfusion was associated with a significant increase in mean number of PLT transfusions (three
RCTs;12,13,15 1020 patients; standardized mean difference, 0.86; 95% CI, 0.34 to 1.37; p = 0.001; high heterogeneity, I2 = 90%; p < 0.0001).
Prophylactically transfusing PLTs compared with
therapeutically transfusing PLTs components was not
associated with a significant difference in all-cause mortality (four RCTs;12-15 1076 patients; OR, 0.72; 95% CI, 0.341.55; p = 0.40; low heterogeneity, I2 = 0%) or mortality
from bleeding (four RCTs;12-15 1074 patients; per-protocol
analysis; OR, 0.54; 95% CI, 0.09-3.10; p = 0.49; low heterogeneity, I2 = 13%).
What is the appropriate threshold for PLT transfusion

in patients with hematologic malignancies undergoing
chemotherapy or stem cell transplant (autologous or
allogeneic)? (Appendix S3, Table 2)
We identified four RCTs enrolling a total of 658 patients
with hematologic malignancies.16-19 When a lower PLT
count threshold (below 10 109/L) was compared with a
higher PLT count (below 20 109 or 30 109/L) threshold
for prophylactic PLT transfusion, there was not a significant difference in overall incidence of significant bleeding
(10 109/L vs. 20/30 109/L; four RCTs; 658 patients16-19)
or mortality from bleeding (10 109/L vs. 20/30 109/L;
four RCTs; 658 patients16-19).
There was a significant difference in mean number of
PLT transfusions favoring a lower PLT count (below
10 109/L) threshold for prophylactic PLT transfusion
compared with a higher PLT count threshold (below
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Fig. 1. Flow diagram depicting the study selection process. (Left) RCTs; (right) observational studies.
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TABLE 1. Summary of evidence from RCTs on main outcomes

Question domain
Prophylaxis
Prophylaxis
Comparison
Prophylaxis vs. therapeutic
Prophylaxis
Optimal threshold <20 109/30 109 vs.

<10 109/L
Optimal threshold <20 109 vs. <10 109/L
Outcome, number of studies

(number of patients)
Major bleeding, 3 (1047)12-14
All-cause mortality,
4 (1076)12-15
Mortality from bleeding,
4 (1074)12-15
Summary effect,
OR (95% CIs)
0.53 (0.32-0.87)
0.72 (0.34-1.55)
Quality
Comments
Moderate Favors prophylaxis
Low
No difference (wide CI)*
0.54 (0.09-3.10)
Low
0.74 (0.41-1.35)
Moderate No difference (wide CI)
3 (492)17-19
4 (658)16-19
0.7 (0.4-1.22)
0.37 (0.02-9.22)
0.91 (0.70-1.19)
0.43 (0.13-1.42)
Low
No difference (wide CI)
Not pooled/no events in Low

either arm
Optimal threshold <20 109/30 109 vs.

<10 109/L
Optimal dose
Standard dose 2.2 10112.6 1011/m2 vs. low dose
1.1 1011-1.3 1011/m2
Optimal dose
3 (1070)21-23
1.1 1011-1.3 1011/m2
Optimal dose
3 (1070)21-23
1.1 1011-1.3 1011/m3
Treatment
PLT/FFP vs. no specific
All-cause mortality, 1 (22)24
coagulation therapy
2.22 (0.37-13.18)
Very low
* See discussion.
Per-protocol analysis.
Patients with DIC.
20 109 or 30 109/L; four RCTs; 658 patients;16-19 mean

difference, 2.94; 95% CI, 0.39-5.49; p = 0.02). The results
were unchanged when the trial by Zumberg and colleagues19 was excluded based on protocol violations.
What is the appropriate dose to transfuse PLTs to

prevent bleeding in patients with hypoproliferative
thrombocytopenia? (Appendix S3, Table 3)
We identified seven RCTs, of which five RCTs enrolling 1660 patients with hematologic malignancies had
analyzable data.20-23,57 Dosage was reported differently in
different studies; to allow meaningful comparisons we
converted different dose metrics into the number of PLTs
per m2.
Data for PLT usage were not extractable for metaanalysis. However, Tinmouth and colleagues23 and Slichter
and colleagues22 found that patients in the low-dose
PLT group underwent a greater number of PLT transfusion
episodes (although the absolute numbers of PLTs they
received was actually lower when the mean count of each
transfused unit was considered). Heddle and colleagues21
also reported that the total number of PLT transfusion
episodes were significantly lower in the standard-dose
PLT group compared with the lower-dose PLT group,
although they did not report the mean or median number
of PLT units transfused per patient. There were no significant differences in incidence of significant bleeding (four
RCTs; 1132 patients20-23), all-cause mortality (three RCTs;
1070 patients21-23), or bleeding-related mortality (three
RCTs; 1070 patients21-23) when standard-dose PLTs
(2.2 1011 to 2.6 1011/m2) were compared with low-dose

PLTs (1.1 1011 to 1.3 1011/m2).
Similarly, there was no significant difference in the
overall incidence of significant bleeding (two RCTs; 951
patients22,57), overall PLT usage (one RCT; 96 patients;57
data from Slichter and colleagues22 were not extractable
for inclusion in the meta-analysis; however, the results
favored the standard dose compared with high dose;
p < 0.001), all-cause mortality (one RCT; 855 patients22),
and mortality from bleeding (two RCTs; 951 patients22,57)
when high-dose PLTs (4.4 1011 to 6.0 1011/m2) were
compared with standard-dose PLTs (2.2 1011 to
3.0 1011/m2).
Should patients with thrombocytopenia undergoing

central venous catheter placement receive
prophylactic PLT transfusion? (Appendix S3, Table 4)
We found two observational studies that compared PLT
transfusion to no PLT transfusion25,45 and seven observational studies without a comparison in the setting of
central venous catheter (CVC) placement.49-55 The observational study with a comparison group was a prospective
cohort study (105 patients)25 with three arms based on a
PLT count of fewer than 50 1012, 50 1012 to 100 1012,
and more than 100 1012/L. Patients in the cohort with a
PLT count of fewer than 50 1012/L received PLT transfusions before the procedure. There were no significant differences in incidence of bleeding, all-cause mortality,
incidence of sepsis, local infections, and thrombosis when
PLT transfusion was compared with no PLT transfusion.
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Study design
Comparison
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PLT transfusion vs. no
PLT transfusion

PLT transfusion

PLT transfusion
Retrospective cohort

PLT transfusion
PLT transfusion
PLT transfusion
Prospective/retrospective
cohort
Case series
Treatment/patients with TTP-HUS
Treatment/patients with ITP
Prophylaxis/patients with
thrombocytopenia undergoing
paracentesis and
thoracocentesis
Quality
Very low
Very low
4.76 (1.65-13.73)
1.55 (0.75-3.18)
7.59 (0.36-161.99)
0.58 (0.27-1.27)
0.41 (0.07-2.41)
0.36 (0.09-1.39)
2.58 (1.18-5.63)
All-cause mortality, 15 (466)45,46
Major bleeding, 1 (608)48
All-cause mortality, 1 (4536)
42
No significant difference in
mortality (11.8% vs. 8.5%;
p = 0.12)
0/608
2.19 (1.18-4.1)
Very low
0/95
All-cause mortality, 1 (187)
Very low
22/95 (23%)
47
Very low
442/3399 (13%)
In-hospital mortality, 1 (3399

undergoing surgery/6321
patients)33
All-cause mortality, 1 (95
patients)34
Mortality from bleeding, 1 (95
patients)34
All-cause mortality, six
RCTs + one non-RCT (1720)35
All-cause mortality, 5 (804)36-40
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
Very low
0/1536 (0/6440 procedures)
Major bleeding, 7 (1536)
2.43 (0.89-6.66)

26-32
0.19 (0.01-3.65)
Summary effect, OR
(95% CIs) or
events/number of patients
Major bleeding, 1 (105)25
Outcome, number of studies

(number of patients)
Comments
Implies that PLT transfusion

may be omitted
Unclear if mortality is affected

by PLT transfusion
Favors no PLT transfusion
Unclear if bleeding mortality is

affected by PLT transfusion

by PLT transfusion

by PLT transfusion (wide CI)
Low bleeding rate with or
without PLTs
by PLT transfusion
ICH = intracerebral hemorrhage; ITP = immune thrombocytopenic purpura; NR = not reported.
None of the patients in this study received PLT transfusion.
tion was broken) and used in this database analyses.
See Discussion.
Individual patient data from six randomized, double-blinded, placebo-controlled trials evaluating aprotinin use in CABG surgery were pooled together (not at an individual study level: that is, randomiza-
mortality rates with PLT transfusion ranging from as low as 0% to as high as 9%.
* Only one study reported comparison of PLT versus no PLT transfusion in patients undergoing CVC insertion. There were seven additional single-arm studies49-55 without comparison, which reported

PLT transfusion

PLT transfusion

PLT transfusion
PLT transfusion
Prophylaxis/patients undergoing
CABG
thrombocytopenia and TBI
receiving preinjury anti-PLT
medication
Prophylaxis/patients without
thrombocytopenia and TBI
medication
thrombocytopenia and
nontraumatic ICH receiving
preinjury anti-PLT medication
Prophylaxis/patients without
thrombocytopenia and
nontraumatic ICH receiving
preinjury anti-PLT medication
thrombocytopenia and TBI not
medication
Treatment/patients with TTP
PLT transfusion
Case series
Treatment/patients undergoing
surgery
PLT transfusion

PLT transfusion
PLT transfusion
PLT transfusion
PLT transfusion
Case series
Case series
Case series
Prospective cohort
Prospective cohort
surgery
CVC*
CVC*
LP
surgery
Question domain/patient
population
TABLE 2. Summary of evidence from observational studies on main outcomes
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However, since all patients with counts of fewer than

50 1012/L were transfused, this study did not address
whether there is increased bleeding in patients with
thrombocytopenia who do not receive PLT transfusion.
The second retrospective study by Duffy and Coyle,45
which involved patients with thrombotic thrombocytopenic purpura (TTP) undergoing apheresis catheter placement, also suggested that PLT transfusion may be safely
omitted in this setting.
Results from seven single-arm studies without comparison reported bleeding rates with PLT transfusion
ranging from as low as 0% to as high as 9%.49-55 The PLT
counts at which procedures were performed ranged from
15 109 to 150 109/L. As no comparisons were included,
the effect of PLT transfusion on bleeding was impossible
to deduce.

lumbar puncture receive prophylactic PLT transfusion,
and if so, what is an appropriate threshold for PLT
transfusion? (Appendix S3, Table 5)
We identified seven observational studies enrolling a total
of 1536 patients with thrombocytopenia undergoing a
total of 6440 lumbar punctures (LPs; two studies did not
report number of LPs).26-32 Five of these studies (1450
patients) enrolled children27-30,32 while two studies (86
patients) enrolled adults.26,31 Two of seven studies
reviewed data from consecutive patients.28,30 The PLT
counts at which the LP procedures were conducted varied
among the studies. Some patients in some studies
received PLT transfusion28,29,31,32 and some did not.26,27,30
Moreover, the outcomes data did not differentiate
between patients receiving versus those not receiving PLTs
transfusion.
The pooled incidence of major bleeding complication among thrombocytopenic children with acute
lymphoblastic leukemia (five case series studies; 1450
children27-30,32) undergoing LP was 0% (0/1450 patients).
The pooled incidence of spinal hematoma among adults
with thrombocytopenia undergoing LP (two case series
studies; 86 adults26,31) was 2.3% (2/86 patients). Although
the studies did not clearly describe eligibility criteria or
the criteria for transfusion, the enrollment of consecutive
patients (two studies) and rarity of bleeding events indicates that LP may not be associated with serious bleeding
events even when it is performed in patients with relatively low PLT counts.
What is the role of PLT transfusions in patients

undergoing surgical procedures? (Appendix S3,
Table 6)
We identified two observational studies enrolling a total of
6756 patients with thrombocytopenia undergoing a total
of 3566 surgical procedures.33,34 The study by Palo and colleagues33 included a total of 6321 adult patients (3399
patients with surgery and 2922 patients without surgery)

transfused with 37,761 PLT products. The incidence of
in-hospital mortality among patients with thrombocytopenia undergoing surgical procedure was 13% (442/3399).
The study by Bishop and colleagues34 included 435
consecutive patients with acute leukemia of whom 95
underwent 167 surgical procedures. Some patients
received prophylactic PLT transfusion for counts of fewer
than 50 109/L; however, the number of such patients was
not reported. It was not possible to assess the impact of
PLT transfusion on clinical outcomes because other
potential causes of bleeding (e.g., drugs, kidney or liver
dysfunction) were not reported. The incidence of all-cause
mortality among patients with thrombocytopenia undergoing a surgical procedure was 23% (22/95). The incidence
of mortality due to bleeding was 0% (0/95), indicating that
surgery is feasible in patients with thrombocytopenia;
however, these data do not address whether there is
increased bleeding in thrombocytopenic patients who do
not receive PLT transfusion.
Should patients undergoing coronary artery bypass

graft surgery receive prophylactic PLT transfusion?
(Appendix S3, Table 7)
We identified one observational study enrolling a total of
1720 patients with thrombocytopenia undergoing coronary artery bypass graft (CABG) surgery.35 This observational study pooled individual patient data from one pilot
study and six RCTs after breaking the randomization. All
seven studies were designed to address the role of
aprotinin compared with placebo in CABG surgery.
PLT transfusion compared with no PLT transfusion
was associated with a significant increase in mortality
among patients undergoing CABG surgery (OR, 4.76; 95%
CI, 1.65-13.73; p = 0.009). PLT transfusion compared with
no PLT transfusion was also associated with a nonsignificant trend toward increased incidence of stroke among
patients undergoing CABG surgery. Although the authors
used propensity score analysis, it is not clear if the
increased mortality was due to PLT transfusion or because
sicker patients received PLTs.
Should patients with traumatic brain injury or

nontraumatic intracerebral hemorrhage receive
prophylactic PLT transfusions? (Appendix S3, Table 8)
We identified 11 observational studies analyzing a total
of 1300 patients with traumatic brain injury (TBI) or
nontraumatic intracerebral hemorrhage.36-44,58,59 Two of
the 11 studies were single-arm studies addressing the role
of PLTs among patients with TBI.58,59 Nine studies compared PLT transfusion versus no PLT transfusion. Six
studies included TBI patients receiving preinjury anti-PLT
medications; some of these patients had thrombocytopenia and others did not.36-41 Two studies included patients
with nontraumatic intracerebral hemorrhage receiving
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preinjury anti-PLT medications of whom some patients

had thrombocytopenia and others did not.42,43 One study
included patients with thrombocytopenia and TBI who
did not receive preinjury anti-PLT medication.44 The
overall results indicate no significant difference in mortality for all comparisons. Bleeding outcomes were not
reported.
Should PLT transfusion versus no PLT transfusion be

used in patients with TTP or TTP-hemolytic uremic
syndrome? (Appendix S3, Table 9)
We identified a SR46 of 14 observational studies (411
patients) with comparison plus an additional study by
Duffy and Coyle45 (55 patients) resulting in a total of 15
studies with extractable data (n = 466). A determination
on whether the studies were prospective or retrospective
could not be made on the basis of reporting in the published SR. PLT transfusion compared with no PLT transfusion was associated with a significant increase in mortality
(OR, 2.58; 95% CI, 1.18-5.63; p = 0.02; low heterogeneity,
I2 = 38%; p = 0.07). We also identified one retrospective
cohort study47 with comparison (n = 187) evaluating the
effect of PLTs in TTP-hemolytic uremic syndrome (HUS).
This study confirmed a significant increase in mortality or
deterioration associated with PLT transfusion (OR, 2.19;
95% CI, 1.18-4.10; p = 0.01). No other clinical outcomes
were reported.
What is the role of PLT transfusions to prevent

bleeding in patients with disseminated intravascular
coagulation? (Appendix S2, Table 10)
We identified one RCT24 with three arms (exchange transfusion, plasma and PLTs, and control) enrolling a total of
22 patients to assess the role of PLTs and plasma compared with no specific coagulation therapy in neonates
with coagulation (DIC). The experimental arm involved
administration of PLT and plasma; it was not possible
to determine how many patients exclusively received
plasma or PLTs. There was no significant difference in allcause mortality (2.22; 95% CI, 0.37-13.18; p = 0.38) in
patients receiving PLTs and plasma transfusions compared with controls. The study also reported outcomes on
resolution of DIC and days to normalization of coagulation studies, none of which differed among the treatment
arms.
Should PLT transfusion versus no PLT transfusion be

used in patients with immune thrombocytopenic
purpura? (Appendix S3, Table 11)
We identified eight observational studies of which three
studies involved a comparison,60-62 four were single-arm
case series,63-66 and one was a prospective single-arm
cohort study.67 These studies enrolled a total of 4723
patients and the sample size ranged from eight to 4536
patients. Heterogeneity of the enrolled population was
8
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large: adults and children and chronic, acute, and refractory immune thrombocytopenic purpura, in and outside
of the surgical setting, were included in these studies. The
threshold for administration of PLTs was reported in seven
of eight studies and ranged from 3.2 109 to 20 1012 L.
None of the studies provided data on significant bleeding.
The mortality ranged from 5% to 11%. Because the quality
of evidence was very low, the effect of PLT transfusion on
bleeding or mortality could not be ascertained.

paracentesis and thoracocentesis receive prophylactic
PLT transfusions? (Appendix S3, Table 12)
We identified one observational study enrolling a total of
395 patients with thrombocytopenia undergoing 608
paracentesis and/or thoracocentesis procedures.48 All
patients presented with mild coagulopathy and thrombocytopenia (PLT count, 50 109 to 99 109/L). None of the
patients in this study received a PLT transfusion. The
pooled incidence of major bleeding complication was 0%
(0/608 procedures). Although the overall methodologic
quality of the study was judged to be very low, 0% major
bleeding complications indicates that thrombocytopenia
with mild coagulopathy may not be a contraindication for
the procedure.
DISCUSSION
We summarized the body of evidence on the effects of
PLT transfusions in 11 common clinical conditions. The
overall findings of this SR are in line with other similar
published evaluations.6,68-70 However, our SR uses GRADE
methodology, which is increasingly being accepted as the
gold standard for guidelines development. GRADE has
previously been used by AABB to synthesize evidence and
formulate guidelines for the use of fresh-frozen plasma
(FFP) and red blood cells.71,72
In general, the magnitude of information addressing
each question was small in this SR, in terms of both
number of studies per question and number of patients
enrolled in eligible studies. In addition, the event rates for
important outcomes such as mortality were rare. This
often led to imprecise results. For a number of outcomes it
was not possible to determine if PLT transfusion was superior, inferior, or not different from control intervention.
That is, it was often not possible to differentiate between
absence of evidence versus evidence of absence73 of the
effects of PLT transfusion. In addition to imprecision, the
quality of the randomized evidence (i.e., confidence in
effects of PLT transfusions) was dominated by possible
outcome reporting bias (e.g., some studies reported
bleeding outcomes but not mortality). Nevertheless, evidence on the critical outcome of bleeding appears to be
sufficiently solid to inform current transfusion practice in
some settings. Since bleeding remains common among
KUMAR ET AL.
hematologic malignancy patients receiving prophylactic

PLT (approx. 43% [18%-66%] in most randomized trials),
future research is needed to examine how to decrease this
rate.
The quality of observational studies was downgraded
in part because of the possibility of selection bias. In most
studies, selection of subjects was based on convenience
sampling rather randomized sampling or consecutive
enrollment. Only three observational studies were
prospective; all others were retrospective with unclear
ascertainment of exposure and outcomes. Only a few
observational studies included control groups. This also
contributed to observed heterogeneity, which was particularly high in observational studies. Often it was not
possible to determine the exact study design, severity of
disease, baseline covariates, and patient and intervention
characteristics. In addition, the effect of possible confounders, uneven outcome reporting along with likely
publication and outcome reporting bias plague this literature. All of these factors are likely reasons for observed
heterogeneity.
This SR does not include a summary of evidence on
harms because: 1) adverse events were reported sporadically in the studies eligible for review, 2) the guidelines
panel felt that adverse events associated with PLT transfusion are well known, and 3) it would be prohibitively
resource intensive to include PLT-related adverse events
in the scope of the SR. Another limitation is noninclusion
of gray literature.
Despite these limitations, the guidelines panel judged
the quality of evidence to be sufficient to make recommendations on a subset of the questions addressed in this
SR. Quality of evidence is only one factor in formulating
guideline recommendations. Other factors include the
overall judgment of benefit versus harms, resource use,
and patient preferences.
Our SR has identified several research priorities. We
were surprised by the small quantity and low quality of the
existing observational evidence, particularly in the setting
of commonly performed invasive procedures. While RCTs
would be very difficult to perform in these settings on
ethical and logistic grounds, it would be relatively straightforward to establish registries in which outcomes of consecutive patients undergoing a given procedure would be
recorded. We believe that this should be a high priority.
The same conclusion was reached by Lieberman and colleagues69 who recently reported a SR on PLT transfusions
for critically ill patients with thrombocytopenia which
stated that for critically ill adults with severe thrombocytopenia and no evidence of bleeding, there is insufficient
evidence to make a recommendation for or against PLT
transfusion.
In conclusion, this SR serves as the scientific background for the AABB PLT transfusion guidelines and helps
to identify research priorities for AABB and others inter1124 TRANSFUSION Volume 55, May 2015
ested in better characterizing the role of PLT transfusions

in patients with thrombocytopenia. This SR and the
resulting AABB guidelines have the potential to affect PLT
transfusion practice and to reduce the current variation in
the way PLTs are used in many clinical circumstances.
CONFLICT OF INTEREST
AK, RM, and BD received financial compensation as consultants
for the conduct of this systematic review and for the development
of guidelines related to use of platelet transfusion from AABB. All
other authors have disclosed no conflict of interest.
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SUPPORTING INFORMATION
Appendix. S1. Search strategy.

Appendix. S2. GRADE system classifies the quality of evidence in one of four grades.
Appendix. S3. Evidence profiles.
Appendix. S4. Should PLT transfusions be used to
prevent bleeding in patients with hypoproliferative
thrombocytopenia?
Additional Supporting Information may be found in the

online version of this article at the publishers Web site:
12
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Platelet Transfusion A Systematic Review of The Clinical Evidence

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REVIEW

Platelet transfusion: a systematic review of the clinical evidence

BACKGROUND: Platelet (PLT) transfusion is indicated

1116 TRANSFUSION Volume 55, May 2015

he number of patients receiving platelet (PLT)

PLT TRANSFUSION SYSTEMATIC REVIEW

transfusions, we conducted a systematic review (SR) with

MATERIALS AND METHODS

Search methods for identification of studies

Data collection and analysis

All titles, abstracts, and full-text reports were reviewed by

Randomized controlled trials (RCTs) and observational

Assessment of risk of bias in included studies

Assessment of the risk of bias in the included RCTs was

Types of outcome measures

Measures of treatment effect

Outcome measures considered were all-cause mortality,

We summarized dichotomous data using odds ratio (OR)

Volume 55, May 2015 TRANSFUSION 1117

PLT TRANSFUSION SYSTEMATIC REVIEW

difference or standardized mean difference and reported

Results for specific questions

What is the appropriate threshold for PLT transfusion

PLT TRANSFUSION SYSTEMATIC REVIEW

Volume 55, May 2015 TRANSFUSION 1119

PLT TRANSFUSION SYSTEMATIC REVIEW

TABLE 1. Summary of evidence from RCTs on main outcomes

Prophylaxis vs. therapeutic

Optimal threshold <20 109/30 109 vs.

Outcome, number of studies

Moderate No difference (wide CI)

Moderate No difference (wide CI)

Moderate No difference (wide CI)

Moderate No difference (wide CI)

No difference (wide CI)

Not pooled/no events in Low

No difference (wide CI)

Optimal threshold <20 109/30 109 vs.

No difference (wide CI)

No difference (wide CI)

20 109 or 30 109/L; four RCTs; 658 patients;16-19 mean

What is the appropriate dose to transfuse PLTs to

(2.2 1011 to 2.6 1011/m2) were compared with low-dose

Should patients with thrombocytopenia undergoing

PLT transfusion vs. no

PLT transfusion vs. no

PLT transfusion vs. no

Treatment/patients with TTP-HUS

Treatment/patients with ITP

All-cause mortality, 1 (108)41

All-cause mortality, 1 (121)42

All-cause mortality, 1 (66)43

All-cause mortality, 1 (88)44

All-cause mortality, 15 (466)45,46

Major bleeding, 1 (608)48

All-cause mortality, 1 (4536)

All-cause mortality, 1 (187)

In-hospital mortality, 1 (3399

0/1536 (0/6440 procedures)

Major bleeding, 7 (1536)

All-cause mortality, 1 (105)25

Major bleeding, 1 (105)25

Outcome, number of studies