Cryopreserved platelets: a narrative review of its current role in transfusion therapy

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Introduction
Platelets, the smallest cellular fragment (since they do not
have nucleus, strictly speaking, we can not name them, cells)
in blood circulation, play an essential role in hemostasis,
tissue restoration and inammation (1,2). Their capacity to
adhere and aggregate on subendothelial structures exposed
after any injury in the blood vessel wall guarantees the
formation of a hemostatic plug that, later, will be stabilized
by the fibrin mesh, resulted from the activation of the
coagulation cascade.
This intrinsic capacity of platelets to react to many sorts
of stimuli, which is essential to their hemostatic function,
combined to their short life span in circulation (around
10 days) (3) make them very difficult to handle and store
under standard blood bank conditions. In contrast to
the other blood components for transfusion that we can
store them for weeks (red blood cells concentrates up to
7 weeks when additive solutions are used) (4) or even years
(fresh frozen plasma at temperatures below –25 ℃ up
to 3 years) (4), in the case of platelets we can store them
just days, specifically 5 days if they are stored at 22 ℃
Review Article
Cryopreserved platelets: a narrative review of its current role in
transfusion therapy
Miquel Lozano, Joan Cid
Apheresis and Cellular Therapy Unit, Department of Hemotherapy and Hemostasis, ICMHO, University Clinic Hospital, IDIBAPS, University of
Barcelona, Catalonia, Spain
Contributions: (I) Conception and design: M Lozano; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)
Collection and assembly of data: Both authors; (V) Data analysis and interpretation: Both authors; (VI) Manuscript writing: Both authors; (VII) Final
approval of manuscript: Both authors.
Correspondence to: Dr. Miquel Lozano. Department of Hemotherapy and Hemostasis, Hospital Clínic Universitari, Villarroel 170, 08036 Barcelona,
Spain. Email: mlozano@clinic.cat.
Objective: To review the current role of cryopreserved platelets (CPP) in transfusion medicine.
Background: The short shelf life of platelet concentrates (PCs) provokes logistic problems in providing
timely PC transfusions during long holiday periods when long or major transportation barriers exists (severe
weather, military operations…) or for patients highly alloimmunized by HLA/HPA antibodies. In the
European Union the only approved strategy authorized to circumvent the limited storage time of PCs is the
cryopreservation using 6% dimethyl sulfoxide (DMSO), at temperature of –80 ℃ or below.
Methods: A review of articles referenced in PubMed published in English before 2020 studying the effect
of cryopreservation on platelets in vivo and in vitro was performed.
Conclusions: Using in vitro techniques available to characterize platelets, significant changes in
the structure and function of CPP after thawing are detected. The changes detected suggest that
cryopreservation provokes an increase in the procoagulant activity of platelets. However, in vivo studies in
healthy volunteers and in patients, have shown the efcacy and safety of the transfusion of CPP in different
clinical scenarios. Nevertheless, its current use is limited to situations where liquid stored platelets is not
available mainly in military operations, for patients with complex HLA/HPA alloimmunization or for
patients with massive bleeding.
Keywords: Platelet storage; platelet cryopreservation; platelet transfusion
Received: 10 March 2021. Accepted: 24 October 2021.
doi: 10.21037/aob-21-31
View this article at: https://dx.doi.org/10.21037/aob-21-31
7

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under continuous agitation in gas permeable plastic bags
or up to 7 days if measures to prevent or detect bacterial
contamination are applied (4).
In order to extend the storage of platelet concentrates
(PCs) beyond the 7 days, the only approved alternative in
the European Union is to add a cryoprotectant and freeze
them at temperatures of –80 ℃. This paper reviews the
current methods available for freezing platelets, the impact
that such methods have on platelet structure and function
and what the main uses of this form of platelet preservation
are in the light of the most recent publications We searched
in PubMed the papers published until 2020 in English
where cryopreserved platelets (CPP) where studied.
We present this article in accordance with the Narrative
Review checklist (available at https://dx.doi.org/10.21037/
aob-21-31).
Current methods for freezing platelets
As many other advances occurred in the history of
Transfusion Medicine, the cryopreservation of platelets was
developed to allow the availability of PC for transfusion in
the battlefield. And in this sense, the role of retired Navy
Capt. C. Robert Valeri, MD, of the Naval Blood Research
Laboratory at Boston University School of Medicine has
been paramount. During almost 50 years, as a Director of the
Naval Blood Research Laboratory he studied and developed
methods in the area of frozen blood components, some with
undisputable practical effects such as providing evidence for
a two-week post-thaw shelf life of deglycerolized red blood
cells or the use of dimethyl sulfoxide (DMSO) as platelet
cryoprotectant. In 2009 Dr. Valeri received the Lifetime
Achievement Award from the United States of America
Armed Services Blood Program because “Today, the entire
Department of Defense frozen blood program a vital part of
contingency operations all over the world is a direct result of
his work and the transfusion of deglycerolized red cells has
saved many lives” (5).
Dr. Valeri published the rst method for cryopreserving
platelets in 1972 (6). However, the method required
a controlled rate of temperature decrease which was
cumbersome and time consuming and storage in the gas
phase of liquid nitrogen at –150 ℃. Two years later his
group reported a simplied method where 6% DMSO was
used and the freezing was performed placing the PC after
adding DMSO, in a mechanical freezer at –80 ℃. However,
after thawing, this method required the washing of the PC
before transfusion (7).
Thirty-three years later Dr. Valeri’s group published a
modification of the second method (8). The modification
consisted in concentrating the platelets and removing the
supernatant before freezing. So the final method can be
summarized as follows: to leukoreduced [the same group had
established earlier that leukoreduction increased the recovery
after transfusion from 64% to 74% (9)], PC collected by
apheresis or prepared from whole blood donations, DMSO
is added under agitation over a 5-minute period, to reach
a final concentration of 6%. After, the unit, in a 300 mL
PVC bag, is centrifuged at 1,250 × g for 10 minutes and all
the supernatant solution is removed, leaving only about 10–
15 mL with the platelet pellet in the bag. Following, the bag
is placed at –80 ℃ in a mechanical freezer for up to 2 years (9).
The frozen bag is thawed in a water bath maintained at 37 ℃
in approximately 5 minutes then the platelets are diluted
with 0.9% saline solution and stored at room temperature
for as long as 6 hours without agitation (8). However, other
groups have shown the feasibility of resuspending the
thawed platelet in platelet additive solution (PAS), a mixture
of plasma and PAS (10) or fresh frozen plasma (11).
Impact of freezing and thawing on platelets
In spite of adding the cryoprotectant the process of freezing
and thawing has profound effects on platelets that can
be characterized using different techniques that will be
reviewed following.
Platelet count
Freezing and thawing using the no-wash Valeri’s method
provokes a decrease in the platelet count between 20%
to 30%. Interestingly, Johnson et al. reported that, when
measured 1-hour after thawing the decrease was of 31%,
however when the thawed platelet, resuspended in a mixture
of 50% plasma and 50% PAS G (SSP+, MacoPharma,
Tourcoing, France) were stored for 24 h in a platelet plastic
bag under continuous agitation, there was an increase in the
platelet count so the nal decrease was 23% (10). Slichter
et al., looked at the impact of freezing and thawing in the
platelet content of 42 units transfused to patients. They
reported a 20% to 25% decrease in the platelet content of
the units after thawing (12).
Platelet structure
One easy way to study the structure of platelets during

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platelet preparation and storage is ow cytometry combined
to fluorescein labeled monoclonal antibodies and proteins
that bind to different molecules present at the membrane
of platelets (13). Several studies have looked at the impact
of freezing-thawing on platelet structure using flow
cytometry. Our group reported changes associated with
PC cryopreservation using 6% DMSO (14). They reported
statistically significant increases in the percentage of
platelets that were positive for P-selectin (CD62P, 24%),
lysosomal integral membrane protein of 53 kDa (LIMP,
CD63, 10.6%), factor Va (FVa 29.1%) and von Willebrand
factor 12.3%). They also reported a significant decrease in
the expression of glycoprotein (GP) IV (27%) and GPIbα
(70%) with no significant changes measured in GPIIb-IIIa
expression. For reference, the changes observed after 10 days
of liquid storage at 22 ℃ under continuous agitation, in the
binding of FVa was signicantly lower (18.9%) (13).
Johnson et al. instead of using FVa to measure the
exposure of phosphatidylserine in the outer layer of platelet
membrane, used the binding of annexin A5 (10). They also
reported a significant increase in the binding of annexin
A5 to platelets 1 hour after thawing, (61%) however that
percentage decreased to 30% after 24 hours of storage.
An important aspect to highlight of the effect of platelet
freezing and thawing is the formation of microparticles.
Microparticles are small fragments (between 100 and
1,000 nm in diameter) originating from the cytoplasmic
membrane that are shed by platelets upon activation by
thrombin, collagen and complement (15). It has been
shown that the freezing and thawing of the platelets causes
a significant increase in the release of microparticles.
Johnson et al. reported that 6 hours after thawing the
number of microparticles in the bag increased from
just a few millions to 60,000 million. Interestingly after
24 hours of storage at 22 ℃ under agitation, the number of
microparticles decreased about 60% when the platelet had
been resuspended in plasma while in PAS G the reduction
was only around 30% (16). Raynel et al. characterized the
microparticles generated during platelet cryopreservation;
interestingly they found that in comparison to
microparticles found in fresh platelets, microparticles
generated during freeze and thawing had more expression of
GPIV, GPIIb and the GPIb-V-IX complex, and contained
more cytoskeletal proteins such as actin or lamin A (17).
Platelet function
Several approaches have been used to study the impact of
the freezing-thawing process in platelet function. Lozano
et al. reported the changes in the aggregatory response to
arachidonic acid, collagen, collagen plus epinephrine, ADP
and ristocetin before and after freezing and thawing. They
found a significant decrease in the aggregatory response
to arachidonic acid (69%), collagen (80%), collagen plus
epinephrine (66%), ADP (73%) and ristocetin (51%) (14).
The adhesive and aggregatory capacities of platelets
after freezing and thawing have been also tested under
flow conditions (18). Our group reported the results of
one study where the adhesive and aggregatory capacity
of thawed platelets under flow conditions in an in vitro
model was tested (19). In comparison to fresh whole blood
and blood reconstituted with platelets stored up to 5 days
under standard conditions, that showed a similar capacity
of adhering to the exposed subendothelium, thawed
platelets showed a 50% reduction of the surface covered by
platelets (19).
Procoagulant activity
The combination of an increased expression of
phosphatidylserine on the outer layer of the platelets and
the generation of a great number of microparticles both
with known procoagulant capacity led to the idea that
frozen-thawed platelet might have a potential thrombotic
capacity in the recipient of a transfusion. To explore this
hypothesis several techniques have been applied.
Johnson et al. studied the procoagulant capacity of
thawed platelets compared to before freezing using
thromboelastography (TEG 5000, Haemoscope Co,
Niles, IL, USA) (16). They found that freezing and
thawing was associated to a significant reduction in
the R-time, almost a 50%. R-time measures the time
taken until de appearance of the first sign of thrombus
formation. The maximum amplitude (MA), parameter
that measures the strength of the clot formed was
just slightly decreased after thawing (16). Cid et al.,
performed a similar study but using thromboelastometry
(TEM, Pentapharm GmbH, Munich, Germany)
employing two different tests EXTEM (tissue factor and
phospholipid are used as activators or the coagulation)
and FIBTEM (cytochalasin is added to inhibit platelet
cytoskeleton and contractibility) (19). TEG and TEM
use a similar technology, i.e., blood is incubated at 37 ℃
in a cup where a pin with a detector system is placed to
measure the formation of the clot. In the case of TEG the
cup is in movement while in the TEM is the pin which is

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in movement (20). In EXTEM compared to control whole
blood, thrombocytopenic blood to which frozen-thawed
platelets were added, provoked a 40% shortening of the
clotting time and also a 48% reduction in the maximum clot
firmness (MCT), i.e., an increased procoagulant capacity
and a reduced capacity of platelets to keep the strength
of the clot. That was confirmed with the measurement in
the FIBTEM test, reduction in the clotting time of 47%
without signicant changes in MCT due to the inhibition
of platelet contractibility (19).
The procoagulant capacity of the platelets generated
during the freezing and thawing can be also studied
measuring the thrombin generation. Johnson et al., found
that the supernatant from CPP was capable to increase
around 10 times the peak of thrombin generation when
compared to values observed before freezing (16).
In vivo studies of CPP in healthy volunteers
Slichter et al. reviewed the studies published looking at
the effect of platelet cryopreservation on post-transfusion
platelet recovery and survival using radiolabeling in healthy
volunteers (21). If only the studies performed using the
second method described by Dr. Valeri (no-wash) were
considered, 3 studies in 32 healthy volunteers have been
reported. In those studies, the mean recovery of CPP after
transfusion was 33%±10% (mean ± standard deviation)
in comparison to fresh platelet that was 63%±9%, i.e.,
a reduction of 48%. Regarding platelet survival, fresh
platelets were found to have a mean survival of 8.6±1.1 days
in the circulation, while CPP had 7.5±1.2 days, i.e., the
survival was an 89%±15% of that of the fresh. Those studies
suggest that the cryopreservation of platelets provokes a
loss of about 50% of the CPP and that the other 50% can
circulate in vivo during a time similar to that of the fresh.
In 4 of the studies, involving 32 healthy volunteers who
received CPP, no adverse effects were reported (21).
In vivo Studies of CPP in Patients
Since the 70s of the last century 27 papers have reported
the clinical efficacy and safety of platelet transfusions
cryopreserved in DMSO (12,21-24).
In the already mentioned review that Slichter et al.,
published in 2014 (21), they reported that in 18 studies,
where the platelet loss associated with the freezing and
thawing in DMSO was analyzed, the mean of platelet loss
was 28%±12% with a range of 13% to 55%. About the
post-transfusion response in general the recovery of CPP
was about 48% of fresh platelet while the 1 h corrected
count increment (CCI) was 52% of fresh. The reported
24 h-CCI of the CPP varied from 27% to 64% of fresh.
Slichter concluded that the responses to CPP, both
autologous and allogeneic were similar to that observed to
platelets stored from 5 to 7 days at 22 ℃ under continuous
agitation transfused to thrombocytopenic patients (21).
Regarding adverse events, 6 studies reported 101 patients
who received 181 cryopreserved units, and no adverse effects
were reported. In 4 studies including 72 patients, receiving
181 cryopreserved PCs bad odor or bad taste (metallic) was
noted that was likely related to residual DMSO, however the
frequency of these events was not reported (21).
Slichter et al. reported a study where CPP using no-
wash Valeri’s method were transfused to bleeding hemato-
oncology patients with thrombocytopenia (12). Patients
with a World Health Organization (WHO) bleeding score
of 2 or more were randomized to receive 0.5 units, 1 unit,
3 units of cryopreserved PCs or 1 apheresis unit stored
under standard conditions. WHO grade 2 bleeding is any
gross organ system bleeding, WHO grade 3 bleeding is
severe enough to require a red blood cell transfusion(s) and
WHO grade 4 is a life/organ function-threatening bleeding.
Twenty-four patients were included in the study.
Fifty-eight percent of the patients transfused with a
CPP product showed an improvement in the bleeding
in comparison to a 50% in the patients who received
the standard product. There were no thrombotic events
considered related to any of the study platelet transfusions.
There were 11 serious adverse events reported in five
patients who received CPPs but all of them were considered
related to their underlying clinical condition (12).
In 1999 a randomized controlled clinical trial, where the
effect of CPP was compared to liquid preserved platelets
after cardiopulmonary bypass was published. Seventy-
three patients undergoing cardiopulmonary bypass were
randomized to receive transfusions of cryopreserved
(stored up to 2 years) or liquid preserved platelets, although
finally, data of only 53 patients (24 receiving CPP and 29
receiving liquid preserved platelets) was analyzed. Platelet
cryopreservation was performed using the “old” Valeri
method, i.e., washing the platelet after thawing. In both
groups no adverse effects of the transfusion were observed.
The patients in the group of CPP received lower dose of
platelets per patient (4.5±2.1)×1011 compared to the group
receiving standard platelets, (6.9±3.9)×1011, P=0.008. Also,
the median postoperative blood loss per patient was lower:

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1,721 mL in the cryopreserved group vs. 2,299 mL in
the standard platelets group, P=0.007. The volume of
blood products transfused to the patients receiving CPP
was significantly lower, 1,933±1,042 mL compared to the
group of patients receiving standard platelets, 3,426±1,963,
P=0.012 (25).
In 2019, another randomized controlled trial was
published that had investigated the role of CPP in cardiac
surgery, but this time cryopreservation was performed using
the Valeri “no-wash” method. The study was a double-blind,
pilot, multicenter randomized controlled trial involving
high-risk cardiothoracic surgical patients. The primary
outcome was feasibility and safety of the protocol. In the
study 23 patients received CPP and 18 received standard
platelets. Although the blood loss was similar in both
groups, significant postoperative hemorrhage composite
bleeding endpoint occurred in nearly twice as many patients
in the standard group compared to the group receiving
CPP [55.6% vs. 30.4, P=0.10). The group receiving CPP
received more platelet units (median 2, P=0.012)] and less
red blood cell transfusion (median 3, P=0.23) compared to
the group receiving standard platelets (platelets median 1,
red cells median 4). There were no differences in adverse
effects in both groups. The authors concluded that the
transfusion of CPP was associated with no evidence of harm
and that a study testing safety and hemostatic effectiveness
was warranted (23).
Bohonek et al. reported also in 2019, an observational
study performed in the Military University Hospital of
Prague where CPP are indicated for polytrauma and
conditions with heavy bleeding. The aim of the study was
to determine whether the results of treatment with fresh
of frozen platelets were clinically comparable in a group of
patients with massive, life threatening bleeding (of trauma,
gastrointestinal, and other origins) (24) Twenty-ve patients
received a total of 81 units of CPP while 21 patients in the
control group, received al total of 67 liquid stored platelets.
The 30-day survival rate in both groups of patients was
similar (76% in the group receiving CPP and 81% in the
group receiving liquid stored platelets). There were no
statistically significant differences in the number of blood
components transfused between the two groups. Only the
median platelet count after transfusion was statistically
signicant higher in the groups of patients receiving liquid
stored platelets in comparison to the group receiving CPP
(97.0×109/L vs. 41.5×109/L, P=0.02) among the laboratory
parameters measured (24).
Current uses of CPP in routine
In 2017, a Vox Sanguinis International Forum investigated
the current use of CPP in routine in 12 different countries
(26,27). Only in 7 of them, the product was being used
(Australia, Belgium, Czech Republic, the Netherlands,
Poland, Spain, Switzerland) in a variety of settings. Among
those settings, highly alloimmunized patients in need
of HLA/HPA matched units (autologous or allogeneic
units), armed forces and heavily bleeding patients. The
Netherlands Armed Forces, during the past 16 years, have
frozen 2,554 apheresis platelets units of which 1,152 were
transfused to 350 patients in several conicts (26). In Poland
cryopreserved units are used for neonatal and intrauterine
transfusions, immune refractory patients and the stem cell
transplant population but only when liquid-stored units
are not available (26). A publication reviewing recent mass
shootings events, identied some trauma centers transfusing
up to 42 therapeutical platelet units in the day of the
event (28) suggesting the potential role of CPP to assure
that the needs are covered in those consumption peaks.
Summary
Since the development of the cryopreservation method
by Valeri, CPP have been available for almost 50 years.
However, its use in routine has been limited probably by
the technical complications associated with its freezing and
thawing and for the impact that the procedure provokes in
the platelets. For these reasons currently its use is limited
to some scenarios. One is armed forces in order to assure
platelet transfusion therapy to combat casualties in locations
where liquid platelets are not easily available. Another use
is to assure that highly HLA and or HPA alloimmunized
patients with hematology-oncology disorders will have
products available for transfusion during the aplasia period
associated to chemotherapy treatment. Other potential uses
of CPP is for covering supply shortages in remote areas or in
situations of increased demand such as mass casualties events.
Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned

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by the Guest Editor (Pilar Solves) for the series “Platelet
Transfusion” published in Annals of Blood. The article has
undergone external peer review.
Reporting Checklist: The authors have completed the
Narrative Review reporting checklist. Available at https://
dx.doi.org/10.21037/aob-21-31
Peer Review File: Available at https://dx.doi.org/10.21037/
aob-21-31
Conflicts of Interest: Both authors have completed the
ICMJE uniform disclosure form (available at https://dx.doi.
org/10.21037/aob-21-31). The series “Platelet Transfusion”
was commissioned by the editorial office without any
funding or sponsorship. Dr. ML reports research support
from Terumo BCT, consulting fees from Grifols and
speaker fees from Grifols. Dr.ML serves as Editor-in-
Chief of Vox Sanguinis and President of European Society
for Hemapheresis. The authors have no other conicts of
interest to declare.
Ethical Statement: The authors are accountable for all
aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Open Access Statement: This is an Open Access article
distributed in accordance with the Creative Commons
Attribution-NonCommercial-NoDerivs 4.0 International
License (CC BY-NC-ND 4.0), which permits the non-
commercial replication and distribution of the article with
the strict proviso that no changes or edits are made and the
original work is properly cited (including links to both the
formal publication through the relevant DOI and the license).
See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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