How I Treat

How I use platelet transfusions

Simon J. Stanworth1,3,4 and Akshay Shah2,5
1
Department of Haematology and 2 Nuffield Department of Anaesthesia, Oxford University Hospitals National Health Service (NHS) Foundation Trust, Oxford,
United Kingdom; 3 Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; 4 NHS Blood and Transplant, Oxford, United Kingdom; and
5
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom

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Platelet transfusions are commonly administered for the prevention or treatment of bleeding in patients with
acquired thrombocytopenia across a range of clinical contexts. Recent data, including randomized trials, have
highlighted uncertainties in the risk-benefit balance of this therapy, which is the subject of this review. Hemovigilance
systems report that platelets are the most frequently implicated component in transfusion reactions. There is
considerable variation in platelet count increment after platelet transfusion, and limited evidence of efficacy for
clinical outcomes, including prevention of bleeding. Bleeding events commonly occur despite the different policies for
platelet transfusion prophylaxis. The underlying mechanisms of harm reported in randomized trials may be related to
the role of platelets beyond hemostasis, including mediating inflammation. Research supports the implementation of
a restrictive platelet transfusion policy. Research is needed to better understand the impact of platelet donation
characteristics on outcomes, and to determine the optimal thresholds for platelet transfusion before invasive
procedures or major surgery (eg, laparotomy). Platelet transfusion policies should move toward a risk-adapted
approach that does not focus solely on platelet count.

• Thrombocytopenia predicts bleeding.

Introduction • Platelet transfusions consistently raise platelet counts
The purpose of this article is to provide a practical, evidence- (efficacy).
based approach for the decision to administer platelet trans- • Platelet transfusions prevent or treat clinical bleeding
fusion in patients with acquired thrombocytopenia. Platelet (clinical/cost effectiveness), without causing harm (safety).
counts remain remarkably stable during life, and reference ranges
for thrombocytopenia are typically defined by the lower limits: How are platelet transfusions
normal platelet count, 150 × 109/L; moderate thrombocytopenia,
<50 × 109/L; and severe thrombocytopenia, <20 × 109/L. manufactured and what is in the unit?
Approximately 100 billion platelets are produced daily by the The heterogeneity of the platelet component is often underap-
adult bone marrow, many of which are stored in the spleen.1,2 By preciated. Platelet units are either whole blood–derived (by the
comparison the average yield of platelets in a platelet transfusion buffy coat method in the United Kingdom and Canada or from
unit is ~3 × 1011. Platelets are essential for primary hemostasis and platelet-rich plasma in the United States; 4 to 6 donations are
maintaining vascular integrity. Therefore, treating thrombocyto- pooled for an adult dose) or by apheresis (obtained from a single
penia and reducing bleeding risk with a platelet transfusion has donor). Nearly all platelet units undergo leukocyte reduction before
biological plausibility, as first reported in a case study of a young storage. During storage in plasma or different media, platelets
man with life-threatening epistaxis in in 1910.3 Advances in undergo varying degrees of biochemical, structural, and functional
processing and storage of platelet components have underpinned changes, commonly known as the storage lesion.7,8 There is
the expansion of platelet banking.4 Annually, >2 million platelet ongoing research interest into the efficacy of cold-stored platelets
transfusions are administered in the United States5 and 300 000 by comparison with standard room temperature storage.9 There is
in the United Kingdom at considerable cost, yet there are variation in platelet count between normal individuals that will affect
concerns about security of supply, as has been apparent during yield after donation. Platelets from different donors exhibit many
the COVID-19 pandemic.6 There is a need for a better under- biological differences, for example the degree of responsiveness
standing of the role of platelet transfusions for both patients (ie, donors with highly responsive platelets have a higher level of
(recipients) and donors. activated platelets).10,11 In a proof-of-principle, semirandomized
trial, patients with nonbleeding thrombocytopenia with myelodys-
The case studies described herein review the common under- plasia were randomly allocated to receive a platelet transfusion from
lying assumptions that drive our current platelet transfusion a high- or low-response donor.12 It was hypothesized that platelets
practice, which can be summarized as follows: donated by a high responder would be cleared more quickly, but no

3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 1925

differences in platelet count increments were seen after transfusion neonates (see later section “Case 2: pediatric patients and preterm
between high- and low-responder donations, although the lack of neonates”).
change in count may reflect the study population under evaluation
and important differences may apply, for example, in patients with
acute bleeding. Transfusion reactions
Platelets are the most commonly implicated component associ-
Other important donor/donation characteristics may affect ated with transfusion reactions (Figure 1).25 Febrile nonhemolytic
affect recipient outcomes. Donor age and sex may affect transfusion reactions and allergic reactions may occur at a
platelet count, size, and function.13 Inflammatory cytokines may reported frequency of 1 in 14 and 1 in 50 per transfusion unit,
be higher in platelets from female donors.14 Because of the respectively.5 Although some of these reactions may be seen as
pressures on platelet availability and supply, substitution of minor by clinicians, recipients of platelet transfusion say that these
platelets of a different blood group may be needed for trans- episodes can be distressing, particularly when repeated. There is
fusion, such that various proportions (up to a half) of all no evidence that prophylactic antipyretics or antihistamines
administered platelet transfusions may not be fully ABO reduce the incidence of transfusion reactions,26,27 but data sug-

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identical.15,16 Yet, this may not represent ideal practice, and gest that fewer reactions occur in platelet products stored in
better ABO matching, however defined, may have important platelet additive solutions, which contain less plasma.28 Sepsis
clinical benefits.17 Pathogen reduction technology has been from a bacterially contaminated platelet unit is the most frequent
applied to platelets to reduce current and future infection risks, infectious complication from transfusing any blood product.29
and research is addressing safety and efficacy in different
groups of recipients, and effects on platelet refractoriness.18
Transfusion thresholds for platelets
to prevent spontaneous bleeding
Case 1: hematological malignancy Although threshold-driven platelet transfusion forms the basis of
A 47-year-old man with myeloma received an autologous stem current practice, it is essential to recall that early investigators
cell transplant (SCT). He had experienced minor reactions to were never able to observe a threshold effect.30 Available data
platelet transfusions and minor bleeding episodes in the past, (3 RCTs, 499 participants) suggest that lower (standard thresh-
but reported no spontaneous bleeding today. His posttrans- olds) of 10 × 109/L are not associated with more bleeding
plant platelet count of 13 × 109/L yesterday was 7 × 109/L the than are higher thresholds (20 × 109/L to 30 × 109/L).31 The
next day. What are the factors to consider in this case when threshold of 10 × 109/L is now commonly recommended by
deciding on the need for a platelet transfusion? clinical guidelines (see Table 1).6 Yet, it is debatable whether
some of these trials were adequately powered, particularly
when bleeding is used as an outcome measure. A reanalysis of
Thrombocytopenia and risk of 1 trial suggested that differences may become apparent in a
larger study.32 An important issue is what constitutes clinically
spontaneous bleeding important bleeding in patients with bone marrow failure or
Clinicians often assume that a low platelet count predicts the risk of chemotherapy-induced thrombocytopenia. The WHO system for
spontaneous (or nontraumatic) bleeding, but the strength of this grading the severity of different bleeding events is often used,
relationship is unclear. In The Platelet Dose (PLADO) randomized although it was developed as a system for reporting adverse
controlled trial (RCT), there was no pattern of decreased bleeding events.33 Limitations include broad categories that may miss
with increased platelet count in the range of 6 × 109/L to 80 × 109/L small changes in bleeding and definitions, such as bleeding
in adult or pediatric patients.19-21 Even at counts <5 × 109/L, the requiring a transfusion, which, although pragmatic, may limit
increased uptick in bleeding rates was minimal. Bleeding was more standardization, as thresholds for transfusion vary. Clinically sig-
common among allograft SCT recipients and in children, suggest- nificant bleeding in RCTs has often been applied as WHO grade
ing that clinical factors other than platelet count are important ≥2, but such an outcome is a composite of different grades of
determinants of bleeding risk.22 A secondary analysis of The Trial of bleeding.34 Overall, RCTs have reported highly different baseline
Prophylactic vs No-prophylactic Platelet Transfusions in Patients rates of bleeding, raising further questions about the method-
with Hematological Malignancies (TOPPS) explored risk factors for ology and reporting of bleeding events.32,33 There are also likely
bleeding, including platelet count.23,24 The results indicated that to be differences between patients’ and clinicians’ perceptions of
a range of clinical factors are relevant to an increased number of bleeding severity. The impact of bleeding on patients’ quality of
days of bleeding, such as treatment plan (allogeneic hematopoietic life is unclear, as few studies have evaluated this aspect.35 Of
SCT/chemotherapy), female sex, and pyrexia. The number of days course, the more severe types of bleeding events (eg, intracranial
with a platelet count <10 × 109/L was associated with developing a or intracerebral) are accepted as significant to patients and cli-
World Health Organization (WHO) grade 2 to 4 bleed, perhaps nicians, but these events remain uncommon. Personal practices
suggesting that the cumulative burden of thrombocytopenia, rather and review of severe bleeding events in RCTs reveals that major
than isolated low platelet counts, alongside a history of recent bleeding events often occur at platelet counts above the
bleeding events, would be a better guide for the decision for a thresholds that would be considered indications for platelet
prophylactic platelet transfusion. The lack of a clear relationship transfusion. Finally, it is unclear whether less severe grades of
between severity of thrombocytopenia and risk of spontaneous bleeding predict more severe episodes. If there were data to
bleeding also extends to other patient populations, with a poor support this progression of bleeding, it would have important
correlation between the degree or severity of thrombocytopenia implications for how we may use prophylactic platelet trans-
and the risk of bleeding or interventricular hemorrhage (IVH) in fusions. Secondary analyses from the TOPPS RCT, found no

1926 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 STANWORTH and SHAH

 6.0 Platelets
Red cell components

Reactions per 10,000 units issued

5.0 Cryoprecipitate
Methylene-blue FFP
4.0 Plasma components
Solvent-detergent FFP
3.0

2.0

1.0

0.0

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2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

Figure 1. Number of reactions reported per 10 000 components issued in the United Kingdom from 2011 through 2020. Although red blood cells are the most
common blood component transfused, platelets account for the highest number of reactions. Convalescent plasma is not included. Reproduced with permission from
SHOT.25 FFP, fresh frozen plasma.

evidence that minor bleeding predicted WHO grade 2 to 4 • Clinical factors other than platelet count are important
bleeding episodes,24 although an analysis of a different earlier determinants of bleeding.
data set showed different findings.36 • Certain subgroups of patients (eg, autologous SCT) may not
require prophylactic platelet transfusions, irrespective of
Coming back to our case, what would happen if we omitted a platelet count.
platelet transfusion? • A risk-adapted approach to platelet transfusions may
be more prudent in our case, rather than applying a
transfusion threshold platelet count of 10 × 109/L and
Does platelet transfusion prophylaxis this patient may not benefit from a prophylactic platelet
transfusion.
have benefit?
The PLADO trial demonstrated that a high-dose platelet policy
did not decrease rates of bleeding or the number of transfusion
episodes per participant. Put another way, there was no evi- Case 2: pediatric patients and preterm
dence of a dose effect. A higher dose was associated, unsur- neonates
prisingly, with an increase in the number of transfusion-related
A preterm female neonate, born at 27 weeks gestational age,
adverse events.19,31 This work is informing national discussions
needed minimal respiratory support at postnatal day 4. Clinical
about minimum threshold specifications for platelet content,
examination revealed minimal oozing at the umbilical cord
given ongoing concerns about supply and inventory manage-
stump. The platelet count was 35 × 109/L.
ment.37 Two later RCTs compared outcomes in patients allo-
cated to a protocol of routine prophylaxis or no prophylaxis
IVH is a catastrophic complication in preterm neonates and is
(only therapeutic).23,38 These trials were considered to challenge
associated with a high likelihood of death or disability.39 To
the dogma of the time, given that they supported a protocol of
prevent this occurrence, neonatologists have traditionally
no-platelet transfusions irrespective of platelet count. Both trials
adopted a more liberal approach toward platelet transfusion,
reached recruitment targets, perhaps indicating that any risks
with surveys suggesting that many clinicians apply prophylactic
that may have been found were more likely to be on the lower
transfusion at platelet counts >50 × 109/L.40-42 Until recently,
side. Noninferiority for rates of WHO grade 2 to 4 bleeding was
neonatologists had few data from RCTs but the Platelets for
close to being declared in the larger TOPPS trial. Moreover, in
Neonatal Transfusion Study 2 (PLaNet-2/MATISSE) trial has now
patients who underwent autologous transplantation (the largest
provided information on this question.43 Preterm neonates in
subgroup), rates of WHO grade 2 to 4 bleeding were identical.
the liberal threshold arm (<50 × 109/L) had a significantly higher
The TOPPS trial was not powered to assess differences in severe
rate of death or major bleeding within 28 days after randomi-
bleeding at WHO grade 3 or 4, but this information was
zation, when compared with restrictive transfusion (<25 × 109/
reported, as in all RCTs (6 cases in the no-prophylaxis group vs
L). A secondary analysis reported that the 25 × 109/L threshold
1 case in the prophylaxis group; see later analysis).
was associated with absolute-risk reduction of different baseline
risks across all groups. Another small trial compared a liberal
Case management (100 × 109/L) vs standard (20 × 109/L to 100 × 109/L) threshold
• Many patients who receive platelet transfusions, irrespective for platelet transfusion in preterm infants with a hemodynami-
of transfusion policy, will continue to experience bleeding, cally significant patent ductus arteriosus.44 A liberal transfusion
and the impact of platelet transfusions on bleeding on policy did not hasten closure of the patent ductus arteriosus but
subsequent days is unclear.20 resulted in a higher incidence of IVH. In summary, available data

HOW I TREAT 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 1927

Table 1. Examples of various recommendations in transfusion guidelines relevant to prophylactic platelet transfusions

Society/recommendations Strength of recommendation Quality of evidence

61
European Society of Intensive Care Medicine 2020
We suggest not using platelet transfusion to treat Conditional Very low
thrombocytopenia unless the platelet count falls below
10 × 109/L.
We make no recommendation regarding prophylactic platelet Research recommendation
transfusion before invasive procedures for platelet counts
between 10 × 109/L and 50 × 109/L.
We suggest not giving prophylactic platelet transfusion before Conditional Very low
percutaneous tracheostomy or central venous catheter insertion
for platelet counts between 50 100 × 109/L and 100 × 109/L.

Society of Interventional Radiology 2019124

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Consider platelet transfusion if platelet count is <20 × 109/L for Weak Limited (evidence level D)
procedures with low bleeding risk (eg, central venous access,
including PICC placement, dialysis access, lumbar puncture,
paracentesis, thoracentesis, transjugular liver biopsy, or
superficial abscess drainage).
Consider platelet transfusion if platelet count is <50 × 109/L for Weak Limited (evidence level D)
procedures with high bleeding risk (eg, deep abscess drainage,
solid organ biopsies, arterial intervention <7 French sheath,
gastrostomy, urinary tract interventions [nephrostomy, stone
removal], or transjugular intrahepatic portosystemic shunt).

British Society for Haematology 201787

Consider performing the following procedures above the platelet
count threshold indicated:
Central venous lines, >20 × 109/L (using ultrasound) Strong Moderate
Major surgery, >50 × 109/L Strong Low
Lumbar puncture, ≥ 40 × 109/L Weak Low
9
Insertion/removal of epidural catheter, ≥80 × 10 /L Weak Low
Neurosurgery or posterior segment ophthalmic surgery, Strong Low
>100 × 109/L
Percutaneous liver biopsy, >50 × 109/L (consider transjugular Weak Moderate
biopsy if platelet count is lower)
Give prophylactic platelet transfusions (platelet transfusions to Strong Moderate
patients who do not have clinically significant bleeding and do not
require a procedure) to patients with reversible bone marrow
failure (eg, general critical illness, receiving intensive
chemotherapy, or undergoing hematopoietic stem cell
transplantation) at or above 10 × 109/L.
Consider increasing the threshold for prophylactic platelet Weak Low
transfusion to between 10 × 109/L and 20 × 109/L in patients
judged to have additional risk factors for bleeding (eg, sepsis).

American Association of Blood Banks (AABB) 20155

Suggest prophylactic platelet transfusion for patients having Weak Low
elective central venous catheter placement with a platelet
count <20 × 109/L.
Suggest prophylactic platelet transfusion for patients having Weak Very low
elective diagnostic lumbar puncture with a platelet count
<50 × 109/L.
Suggest prophylactic platelet transfusion for patients Weak Very low
having elective neuraxial anesthesia with a platelet
count <50 × 109/L.
Recommends against routine prophylactic platelet transfusion Weak Very low
for patients who are nonthrombocytopenic and have cardiac
surgery with cardiopulmonary bypass.
Recommends transfusing hospitalized patients with a platelet Strong Moderate
count <10 × 109/L to reduce the risk of spontaneous
bleeding.

1928 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 STANWORTH and SHAH

 Transfusion benefits Platelet transfusion Transfusion risks

Product factors Donor-recipient

factors
• Storage duration • ABO match
• Product type • Donor sex
• Microvesicles • Donor age
content

Transfusion of platelets, microvesicles and

inflammatory cytokines

Increased IL-8

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Increased platelet count
Increased sCD40L
Clinical considerations
• Setting (major hemorrhage, prophylaxis)
Increased platelet
• Patients (malignancy, neonates, critical Increased oxygen
aggregation
illness, major surgery and types of surgery) requirements and organ
• Likelihood and history of bleeding dysfunction
(including spontaneous)
Increased clot strength

Increased bleeding,
transfusion reactions,
Decreased bleeding
mortality

Figure 2. A summary of putative mechanisms underlying the potential benefits and risks of platelet transfusions. Product and donation characteristics that may
modify the efficacy and safety of platelet transfusions include ABO matching between donor and recipient, processing methods (eg, pathogen reduction technology,
and storage media), and storage duration. Platelet and leukocyte activation leads to accumulation of proinflammatory cytokines (IL-1, -6, and -8 and transforming
growth factor-β), soluble CD40 ligand, and formation of microvesicles. Platelet microvesicles become more numerous and injurious during storage and may trigger a
recipient reaction, mediated by their molecular cargo, resulting in further inflammatory cytokine release. Platelet microparticles may downregulate macrophages and
impair the reactivity of dendritic cells.

favor a lower transfusion threshold for platelet transfusion in Case management

nonbleeding preterm neonates.45 • RCT data support a lower platelet transfusion threshold
(25 × 109/L) in nonbleeding preterm neonates.
Possible hypotheses to explain the mechanisms of harm in
participants randomly allocated to liberal transfusion groups
• Better hemovigilance reporting is needed for platelet
transfusions in children.
include the fluid shifts associated with transfusion volume and
• In this case, with the absence of any clinically significant
the proinflammatory effects of platelets, including inflam- bleeding, it would be reasonable to withhold a platelet
matory mediators that accumulate in platelets during storage transfusion.
and disruption of cerebral blood flow.39,45,46 An additional
way to understand the risks of platelet transfusions would be
to use hemovigilance systems. Unfortunately, most hemovi- Case 3: critically ill adult
gilance systems fail to clearly report pediatric and neonatal A 70-year-old man was admitted to the intensive care unit (ICU)
transfusions. Only 8% of reports submitted to SHOT (Serious with pneumococcal pneumonia. He was placed on a ventilator
Hazards of Transfusion) are pediatric cases, although these and treated with intravenous antibiotics. The platelet count was
may be more common proportionately relative to adults.47 In 17 × 109/L. The patient required insertion of a central venous
the most recent 2020 report, there was an increase in reports catheter.
related to febrile, allergic, and hypotensive reactions which
appeared to be largely related to an unexplained increase in Thrombocytopenia is common in critically ill adults, and 5% to
20% will develop severe thrombocytopenia (<50 × 109/L) at
pediatric platelet transfusions.
some point in their ICU stay.49-51 The underlying etiology is
Although there are no comparable RCT data in older children, multifactorial,52-56 but thrombocytopenia within the first
international cohort studies in critically ill children indicate that 24 hours of ICU admission appears to be associated with
most transfusions are given as prophylaxis to nonbleeding increased 28-day mortality,57 along with a dysregulated host
children, with significant variation in platelet thresholds and immune response.58 After patients with cancer, critically ill
increments after transfusion.48 Many of these children, who will patients are the second largest group of platelet users.15 In a
never develop bleeding complications, may be exposed study of 29 ICUs in the United Kingdom, 9% of all patients
unnecessarily to the risks of platelet transfusion. received a platelet transfusion at some point during their ICU

HOW I TREAT 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 1929

 A
Restrictive/none Liberal Risk ratio Risk ratio
Study or subgroup Events Total Events Total Weight M–H, Random, 95% CI M-H, Random, 95% CI
Baharoglu 2016 13 93 24 97 11.7% 0.56 [0.31, 1.04]
Curley 2019 35 330 45 328 16.5% 0.77 [0.51, 1.17]
Diedrich 2005 14 79 13 87 10.2% 1.19 [0.59, 2.37]
Heddle 2009 8 58 6 61 6.2% 1.40 [0.52, 3.80]
Lye 2017 49 182 42 187 18.1% 1.20 [0.84, 1.71]
Rebulla 1997 29 135 24 120 14.7% 1.07 [0.66, 1.74]
Slichter 2010 12 417 10 432 8.1% 1.24 [0.54, 2.85]
Stanworth 2013 6 301 1 299 1.7% 5.96 [0.72, 49.21]
Tinmouth 2004 6 56 4 55 4.6% 1.47 [0.44, 4.94]
0.34 [0.15, 0.78]

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Wandt 2012 7 194 21 197 8.0%
Total (95% CI) 1845 1863 100.0% 0.95 [0.72, 1.27]
Total events 179 190
Heterogeneity: Tau2 = 0.08; Chi2 = 16.31, df = 9 (P = 0.06); I2 = 45%
Test for overall effect: Z = 0.34 (P = 0.74) 0.01 0.1 1 10 100
Favors restrictive/none Favors liberal/standard

B
Restrictive/none Liberal Risk ratio Risk ratio
Study or subgroup Events Total Events Total Weight M–H, Random, 95% CI M–H, Random, 95% CI
Baharoglu 2016 16 93 23 97 18.1% 0.73 [0.41, 1.28]
Curley 2019 33 330 48 326 26.2% 0.68 [0.45, 1.03]
Diedrich 2005 29 79 28 87 25.9% 1.14 [0.75, 1.74]
Heddle 2009 1 58 1 61 1.2% 1.05 [0.07, 16.43]
Lye 2017 0 182 0 187 Not estimable
Rebulla 1997 18 135 9 120 12.0% 1.78 [0.83, 3.81]
Slichter 2010 9 417 4 423 5.8% 2.28 [0.71, 7.35]
Stanworth 2013 5 301 4 299 4.8% 1.24 [0.34, 4.58]
Tinmouth 2004 0 56 0 55 Not estimable
Wandt 2012 7 199 5 197 6.2% 1.39 [0.45, 4.29]
Total (95% CI) 1850 1852 100.0% 1.02 [0.76, 1.38]
Total events 118 122
Heterogeneity: Tau2 = 0.04; Chi2 = 9.40, df = 7 (P = 0.23); I2 = 25%
Test for overall effect: Z = 0.15 (P = 0.88) 0.02 0.1 1 10 50
Favors restrictive/none Favors liberal/standard

Figure 3. Exploratory forest plots of the effect of 2 strategies. Restrictive or no prophylaxis strategy (as defined by the study authors) vs a liberal strategy (as defined by the
study authors) on major bleeding (A) and all-cause mortality (B) from randomized trials of platelet transfusions recruiting ~100 patients or >100 patients. Study definitions vary
and analysis included all settings although more commonly hematological cancers. No prophylaxis strategies for platelet transfusion were applied unless there was evidence
of clinically significant bleeding. Restrictive transfusion strategies advocated platelet transfusions at thresholds ranging from 10 × 109/L to 25 × 109/L. Slichter et al19 compared
3 different doses of platelets; for the purposes of this analysis, we selected the low- and high-dose arms.

stay, many as prophylaxis. The range of platelet counts over in case 1. However, critically ill patients may also have
which platelet transfusions are given to critically ill patients is acquired platelet dysfunction related to accompanying con-
wide,50,59,60 usually within 10 × 109/L to 50 × 109/L; the ditions (renal failure, trauma, and antiplatelet drugs), and
variation most likely reflects a lack of supporting evidence bleeding may occur even with platelet counts >50 × 109/L.62
for best practice. Clinical guidelines have made inconsistent Given the routine use of ultrasound to guide insertion of
recommendations, often based on low-quality evidence central venous catheters, the incidence of major procedure-
(Table 1). Recent European Society of Intensive Care Medicine related bleeding is very low at ~0.05% to 1%,63 which has
transfusion guidelines did not have enough evidence to make a implications for sample sizes for future studies.64 A substudy
recommendation regarding prophylactic platelet transfusion of a large RCT found that prophylactic platelet transfusions
before an invasive procedure for platelet counts between given to critically ill patients with thrombocytopenia were not
10 × 109/L and 50 × 109/L, and trials are urgently needed.61 associated with a reduction in the risk of major bleeding
compared with that in patients without transfusion.65 One
Other guidelines5 have recommended transfusion thresholds observational study found that preprocedural platelet trans-
of 10 × 109/L to 20 × 109/L, largely based on studies in fusion in patients with thrombocytopenia (<100 × 109/L)
patients with a hypoproliferative bone marrow as described scheduled to undergo interventional radiology procedures

1930 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 STANWORTH and SHAH

was not associated with a reduced risk of bleeding compli- correlate better with bleeding than platelet count.88,89 A
cations (defined as a requirement for a periprocedural red systematic review of the use of TEG/ROTEM in patients with
cell transfusion).66 sepsis found that these tests may be useful for diagnosing
alterations in coagulation in sepsis, such as impaired fibri-
The expected increase in platelet count from 1 platelet trans- nolysis, when compared with standard laboratory tests.90
fusion is between 12 × 109/L and 20 × 109/L,15,67 but this is Larger studies are needed to answer whether correcting
highly variable in critically illness.48 Patients with underlying abnormal TEG/ROTEM values is associated with improve-
bone marrow failure may experience smaller increments in ments in clinical outcomes in critically ill patients, including
platelet count when compared with those without marrow use of platelets.
failure.68 Although the absolute count may increase, it is unclear
whether these transfused platelets function effectively, and Case management
there are few data on critically ill patients.69 • Platelet transfusions may be associated with increased
morbidity and mortality in critically ill patients, with limited
Platelet transfusions in critically ill patients are associated evidence of benefit, and RCTs are needed.

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with risks, including acute respiratory distress syndrome, • The role of TEG/ROTEM in stable, nonbleeding, critically ill
nosocomial infection, worsening organ failure, venous and patients requires further investigation.
arterial thrombosis, longer ICU stays, and increased mortal- • It would be reasonable to withhold a platelet transfusion in
ity70-73 although there may be residual confounding by this case. The procedure should be performed by an
indication (sicker patients receive more platelet transfusions). experienced operator, using ultrasound guidance, to mini-
The rates and mechanisms of harm need further investigation mize the risk of bleeding.
in critical illness but may result from proinflammatory
mediators contained in platelet transfusions, including
platelet-derived microvesicles and inflammatory cytokine
release7,74-77 (Figure 2). Worsening oxygenation may also be
Cases 4 and 5: traumatic hemorrhage
associated with the mostly platelet-derived soluble form of and intracranial bleeding
CD40 ligand.73,78,79 In case 4, a 25-year-old man was admitted to the emergency
department after a serious traffic accident. The massive
The effects of platelet transfusion on inflammation and hemo- hemorrhage protocol (MHP) was activated. Despite an initial
stasis in critically ill patients may be further modified by dona- normal platelet count of 140 × 109/L and an intraoperative
tion characteristics of the platelet unit, but this has been poorly transfusion of 1 dose of platelets, the repeated platelet count
studied in critical illness. In the setting of prophylaxis in hema- was 49 × 109/L.
tological cancers, a secondary analysis of the PLADO trial
showed that platelet source, ABO compatibility, and duration of Trauma-induced coagulopathy is an overall failure of the coagu-
storage did not affect bleeding rates, although platelet incre- lation system mediated by protein C activation, hyperfibrinolysis
ments were generally higher with transfusions of apheresis secondary to release of tissue plasminogen activator, and rapid
platelets, ABO-identical platelets, and platelets stored 3 days vs depletion of fibrinogen.91-93 Platelet dysfunction is common after
4 to 5 days.80 In other studies, ABO-incompatible transfusions major trauma and may be associated with increased mortality,
have been associated with poor platelet recovery and increased even when the platelet count is within the normal reference
mortality.80-82 Data support possible associations between range.94 Significant thrombocytopenia is considered a late event
donation characteristics and outcomes and this reiterates the in major hemorrhage. The cornerstones of management include
importance for further study of how donation characteristics timely and balanced administration of blood components with
impact on outcomes including in settings such as critical control of bleeding (either surgical or radiological).91 As a prag-
illness.83-86 matic approach, guidelines often recommend that platelet trans-
fusions be given to maintain the platelet count at >50 × 109/L
in trauma bleeding.95,96 MHPs may have improved outcomes
in many observational studies, including mortality, but these
Are there alternatives or better tests studies did have significant survivorship or immortal time bias
than a platelet count to predict (ie, participants must be alive long enough to receive the
intervention).91,97,98
bleeding?
Viscoelastic hemostatic assays (VHAs) such as thromboelas-
The Pragmatic, Randomized Optimal Platelet and Plasma Ratios
tography (TEG) and rotational thromboelastometry (ROTEM)
are increasingly being used to guide transfusion therapy in (PROPPR) trial randomly allocated 680 patients with traumatic
critical care, liver disease, cardiac surgery, and obstetrics.87 bleeding to receive either high or low ratios of plasma and
Such tests provide a global assessment of coagulation at platelets to red blood cells (1:1:1 vs 1:1:2). There was no dif-
the bedside to deliver targeted transfusion of blood prod- ference in all-cause mortality between the groups, but in sec-
ucts. Limited evidence suggests that VHA-guided therapy ondary analyses, patients in the high-plasma and platelet ratio
may reduce transfusion requirements in patients who group (1:1:1) had a reduced risk of dying from exsanguination in
undergo cardiac or liver surgery or have obstetric hemor- the first 24 hours, although not a prespecified outcome.99 A
rhage.87 In a small number of patients with thrombocytopenia post hoc analysis suggested that early platelet administration
and hematological malignancy, ROTEM-measured clot firm- was associated with improved hemostasis and reduced
ness and TEG-measured α angle have been shown to mortality.100

HOW I TREAT 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 1931

TEG/ROTEM-directed transfusion algorithms have been used across all randomized trials, recruiting 100 patients or more,
to guide a more individualized approach for blood components irrespective of clinical setting. The results of this analysis are
and platelets in major traumatic bleeding. These have been hypothesis generating, but the pooled estimates of effect
widely reported, and the most common abnormality observed suggest no consistent impact of platelet transfusions in
is a reduction in clot strength.101 Two small, single-center RCTs reducing bleeding or mortality, although the confidence inter-
have reported reductions in mortality and clinically relevant vals are wide and may encompass potentially important clinical
bleeding using TEG102 and ROTEM.103 However, the recent differences. Platelets clearly have many biological roles beyond
Implementing Treatment Algorithms for the Correction of hemostasis, and we need a better understanding of the clinical
Trauma-Induced Coagulopathy (ITACTIC)104 multicenter RCT consequences of these immune effects.109,110 Given the
compared standard MHPs, using conventional coagulation tests uncertainties regarding the role of platelet transfusions, there is
vs VHA guided algorithms, but found no difference in the interest in alternatives to platelet transfusion111,112 that may
number of patients who were alive and free of massive trans- include drugs and factors that stimulate endogenous produc-
fusion at 24 hours.104 tion of platelets or von Willebrand factor (eg, thrombopoietin,
desmopressin),113 target fibrinolysis (eg, tranexamic acid),114 or

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Case management increase fibrin and fibrinogen (eg, fibrinogen concentration,
• Trauma-induced coagulopathy can lead to platelet loss and recombinant factor VIIa) or use of artificial platelets or platelet
consumption. membranes (eg, nanoparticles).115 Of note, a recent trial
• The impact of TEG/ROTEM on clinical outcomes is unclear. reported no evidence of an effect of tranexamic acid in
• In our case, priority should be given to identifying and reducing WHO grade 2+ bleeding in adult patients with
controlling the source of bleeding, either radiologically or thrombocytopenia who undergo therapy for hematological
surgically. The platelet count should (pragmatically) be malignancy116; results of an ongoing trial are awaited.117
maintained at 50 × 109/L with platelet transfusions.
There are gaps in research and development for the platelet
In case 5, a 78-year-old woman was admitted to the emergency product, including the role of cryopreserved and cold-storage
department with increasing confusion. She was taking clopi- platelets, particularly in military settings or remote hospitals
dogrel. A computed tomography scan revealed an acute sub- where the ability to provide standard platelets is challenging
dural hematoma but neurosurgery is not currently planned. Her because of their short shelf life. Recent research has highlighted the
platelet count was 271 × 109/L. uncertain clinical impact of the transfusion of platelets with quali-
tative defects in donations.118 Cryopreserved platelets have been
Approximately 2 million nontraumatic (spontaneous) intracere- approved for general civilian use and for military use in some
bral hemorrhages (ICHs) occur worldwide each year,105 and in countries.91 Small pilot RCTs of cryopreserved119 or cold-stored
high-income countries more than a quarter of patients who platelets120 in patients who undergo major cardiac surgery have
experience an ICH will be taking antiplatelet therapy.106 shown no signs of harm and may have added hemostatic benefits.
Platelet transfusions have been commonly used (and continue A large confirmatory trial of cold-stored platelets is ongoing
to be) in those patients to reduce ICH volume. However, the (registered on https://clinicaltrials.gov as #NCT04834414).
results of the Platelet Transfusion in Cerebral Hemorrhage
Work on larger data sets, using advanced statistical techniques,
(PATCH) RCT have challenged this indication.107 Patients with a
would enable us to identify the patient at lower or greater risk of
supratentorial ICH, use of antiplatelet medication for at least 7
bleeding, allowing us to target interventions like platelet
days prior, and Glasgow Coma Scale >8 were randomly allo-
transfusions. Sufficient platelets would be administered to
cated to receive standard care or standard care with platelet
optimize vascular integrity and improve hemostasis and
transfusion within 90 minutes of diagnostic brain imaging.
improve patient outcomes, while avoiding unnecessary routine
Platelet transfusion was associated with an increased the risk of
transfusions of platelets with associated risks and costs.121,122
death or dependence in patients receiving antiplatelet therapy
A high platelet count unit containing platelets that are more
and presenting with an acute ICH. It is unclear whether the
primed for activation and aggregation (hyperreactive) may be
findings are generalizable to an increasing number of patients
preferentially allocated for major bleeding. In contrast, a low
who are now taking agents such as clopidogrel, and various
platelet count unit may be indicated in the setting of non-
methodological limitations have been described,108 but this
bleeding prophylaxis, where these platelets support and
trial again shows the potential harm of platelet transfusions.
maintain endothelial function, without adding to prothrombotic
and proinflammatory risks.123
Case management
• Despite its limitations, PATCH is the best available RCT evi- We must design more cost-efficient adaptive trials, rather than
dence on this topic, and a platelet transfusion is not indicated. those based on comparisons between only 2 arguably arbitrarily
• Further studies are needed on patients prescribed anti-
defined thresholds, which may not identify the actual “sweet
platelet medication and the underlying mechanisms spot” or optimal threshold where platelet transfusions have
between platelet transfusions and clinical outcomes. maximal benefit in a specific patient subgroup. The future offers
opportunities for a precision-medicine–based approach for
Discussion platelet transfusions with optimized donor-recipient matching.

This review has highlighted the uncertainty about the perceived

benefits of platelet transfusions alongside risks. To further Acknowledgments
illustrate this uncertainty, we undertook an exploratory meta- The authors thank Darrell Triulzi, Rebecca Cardigan, and Peter Watkinson
analysis of major bleeding (grade ≥3) and mortality (Figure 3) for constructive feedback and discussions that refined the manuscript.

1932 3 NOVEMBER 2022 | VOLUME 140, NUMBER 18 STANWORTH and SHAH

 Correspondence: Simon J. Stanworth, Radcliffe Department of Medi-
Authorship cine, University of Oxford, Oxford, United Kingdom and NHS Blood and
Contribution: Both authors designed, reviewed, and approved the final
submission. Transplant, Level 2, John Radcliffe Hospital, Headley Way, Headington,
Oxford OX3 9BQ, United Kingdom; email: simon.stanworth@nhsbt.
Conflict-of-interest disclosure: S.J.S. reports receiving funds from gov- nhs.uk.
ernment sources (National Institutes of Health Research and NHS Blood
and Transplant) for research in the field of platelet transfusion. S.J.S. and
A.S. are co-investigators on the NIHR-funded Threshold for Platelet
(T4P) trial (NIHR 131822).
Footnote
Submitted 4 April 2022; accepted 1 August 2022; prepublished
ORCID profiles: S.J.S., 0000-0002-7414-4950; A.S., 0000-0002-1869- online on Blood First Edition 4 August 2022. https://doi.org/10.1182/
2231. blood.2022016558.

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