novel platelet storage strategies to improve supply and
TRANSCRIPT
AM21-75 Strategies to address critical
stresses on the platelet inventory
Novel platelet storage strategies to
improve supply and minimise
wastage
Denese C Marks
Australian Red Cross Lifeblood
Faculty Disclosure
Research funding from:
• Macopharma
• Cryogenics Holdings Pty Ltd
Member of Scientific Advisory Board for Vitrafy Life Sciences
In compliance with ACCME policy,
AABB requires the following
disclosures to the session audience
Objectives
• Describe characteristics of cold stored and cryopreserved platelets
• Advantages of these storage modes
• Ways they can be implemented to manage platelet inventory
• Gaps in knowledge and important considerations
• Clinical evidence for use
• Regulatory status
Storage at room temperature (20-24 °C) with agitation
• Maximises platelet recovery and survival in transfusion recipients1
Disadvantages of RT storage
• Short shelf-life (5-7 days)
Platelet storage lesion
Bacterial proliferation
• Inventory management challenges – remote and rural hospitals
Conventional storage of platelets
1. Murphy & Gardner. N Engl J Med 1969;280:1094-8
Cold-stored platelets
Simplicity - storage in refrigerator (2-6 °C) without
agitation
Cold-stored platelets are not new!!
• Historical platelet storage method
• Reduced platelet survival in transfused recipients1
• RT-storage adopted to maximise outcomes of prophylactic
transfusions
1. Murphy & Gardner. N Engl J Med 1969
From Murphy and Gardner, 19691
Reduced metabolism ► longer shelf-life
Apheresis platelets in 100% plasma Apheresis platelets in 40% plasma/60% SSP+
Advantages: cold storage slows metabolism
1 2 5 9 14 21
0
2
4
6
8
Storage time (days)
Glu
co
se (
mm
ol/L
)
RT
Cold-stored
1 2 5 7 9 14 21
0
5
10
15
20
25
Storage time (days)
Glu
co
se (
mm
ol/L
)
RT
Cold-stored
Adapted from Johnson et al., Transfusion 2021
Procoagulant platelets
• Surface for assembly of coagulation factors
• Generation of thrombin burst
• Fibrin formation and clot stability
• Link between unstable aggregate and stable clot
Cold-stored platelets are more procoagulant
1 2 5 7 10 14 21
0
10
20
30
40
50
Storage time (days)
An
nex
in-V
(%
po
sit
ive)
*
1 2 5 7 10 14 21
0
5000
10000
15000
Storage time (days)
Mic
rop
art
icle
s (
x10
6/u
nit
)
*
Increased procoagulant capacity ► better able to stem bleeding?
FDA approval
• 21 CFR 606.65(e) & 610.53(c) To store apheresis platelet products at 1-6 °C for up
to 14 days without agitation. The cold stored platelet products will be used to treat
actively bleeding patients when conventional platelet products are not available, or
their use is not practical 1
• South Texas Blood and Tissue Centre received FDA approval April 2020 – platelets must
be refrigerated within 2 hours of collection2
• Mayo clinic received approval for use of cold-stored platelets during COVID-19 pandemic
(April 2020)2
Regulatory status- are they available now?
1. US FDA Exceptions and Alternative Procedures Approved Under 21 CFR 640.120; 2. Warner et al., Transfusion 2020
Implementation?
Johnson et al., Transfusion 2021; Wagner et al., Transfusion 2020
Transfer day 1 post-collection
Transfer 8 hours post-collection
South Texas Blood and Tissue Centre – Transfer 2 hours post collection
Delayed cold-storage: minimising wastage
Wood et al, Vox Sanguinis 2018; Braathen et al, Transfusion 2019; Warner et al, Transfusion 2020
Transfer on day 4 post-collection
Transfer on day 7 post-collection
Transfer on day 5 post-collection
- 40 patients transfused
- haemostasis/no adverse effects
Knowledge gaps: bacterial proliferation
Reduced bacterial proliferation… but not eliminated
Should cold-stored platelets still be screened for bacterial contamination?
Ramirez-Arcos et al., Vox Sanguinis 2021 (ISBT abstract)
• Do cold-stored platelets still need to be screened for bacterial contamination? If they are transferred from RT storage at or near expiry, then yes!
• Alternatively, can cold-stored platelets be PI treated?
Knowledge gaps – pathogen inactivation
1 2 5 7 9
500
600
700
800
900
1000
Storage time (days)
Pla
tele
t co
un
t (x
10
9/L
) RT untreated
RT UVC-PI
Cold untreated
Cold UVC-PI
Johnson et al., Transfusion 2018
Knowledge gaps: the optimum shelf-life?
Taken from Stolla et al., Transfusion 2019
Maximum shelf-life?
Platelet count vs. haemostatic activity
Clinical trials still needed
Clinical evidence
1. Becker et al., Transfusion 1973; 2. Strandenes et al., Anesthesiology 2020; 3. Warner et al., Transfusion 2020; 4. Krachey et al., J Trauma Acute
Care Surg. 2018; 5. clinicaltrials.gov (NCT04834414)
• Cold-stored platelets superior to RT platelets for treatment of bleeding thrombocytopaenic
patients1
• Norway - Pilot trial in bleeding cardiac surgery patients
Cold stored platelets prevented bleeding following 7 and 14 days of cold-storage
No adverse events 2
• Cold-stored platelets (delayed transfer to cold) used at Mayo Clinic during COVID-19
safe and provided effective haemostatis3
• The CHIPS RCT will recruit 1000 adult and paediatric cardiac surgery patients receiving
conventional or cold-stored platelets4,5
Advantages
• Extended shelf-life, possibly to 21 days
• Reduced bacterial proliferation
• Increased haemostatic potential
Implementation options for blood banks
• Immediate cold-storage
• Delayed cold-storage
Considerations
• Bacterial contamination screening or PI?
• Plasma or PAS
In summary…
Cryopreserved platelets: an unmet clinical need
5-6% DMSO
-80 °C storage
2-4 year shelf-life1
1. Lelkens et al., 2006
Frozen platelets are not new either
• US Navy 1970s technology – Dr Robert Valeri1,2
• Later adopted and used extensively by Dutch military3,4
• Now also used in civilian or military settings in Australia,
Czech Republic, France, Singapore, Switzerland and
others6,7
1. Valeri et al., Blood 1974; 2. Valeri et al., Tranfusion 2005; 3.; 4. Lelkens et al., 2006; 5. Noorman et al., Plos ONE 2016; 6. Bondar et al., Transfusion
2014 (AABB abstract); 7. Cohn et al., Vox Sanguinis 2017
1 2 5 7 9 14 21 0 240
20
40
60
80
An
ne
xin
-V (
%)
Post-thaw(hours)
Liquid storage(days)
1 2 5 7 9 14 21 0 240
40000
80000
500000
Mic
rop
art
icle
s (
x10
6/L
)
Post-thaw(hours)
Liquid storage(days)
RTCold
Frozen
Increased haemostatic potential
Multiple changes due to freeze-thaw damage
Adapted from Wood et al., Transfusion 2016; Johnson et al, Transfusion 2018; Tohidi-Esfahani et al., Vox Sanguinis 2017 (ISBT abstract)
Clinical evidence
Cryopreservation reduces in vivo recovery and survival
Dumont et al., Transfusion 2013
University of Maryland: program established to address shortages of HLA-matched platelets1
• > 1600 autologous cryopreserved platelet units to support chemotherapy patients
• Platelet increments achieved
• An effective way to create an inventory of frozen platelets
After introduction of a massive transfusion protocol, more patients received frozen platelets
and fewer died2
Clinical evidence – in practice
1. Schiffer et al., Prog Clin Biol Res; 2. Noorman et al., Plos ONE 2016
1043 units transfused in Afghanistan with no adverse effect
Dutch military – platelets prepared in advance to meet future transfusion needs
Randomised clinical trials
Shlicter et al., Transfusion 2018
Cryopreserved platelets effective for bleeding thrombocytopaenic patients
Randomised clinical trials
Reade et al., Transfusion 2018
• Pilot RCT, 41 patients
• CLIP: Cryopreserved vs. conventional platelets in bleeding cardiac surgery patients
• Typically frozen within 48-50 hours of collection, with bacterial screening1,2
• Can also be frozen at expiry with no loss in platelet quality post-thaw3,
minimise wastage
• Post-thaw shelf-life 4-6 hours1,2 but combined with cold storage (post-thaw) it could be
longer4
How can they be used – minimising wastage?
1. Noorman et al., Plos ONE 2016; 2. Reade et al., Transfusion 2018; 3. Johnson et al., Transfusion March 2020; 4. Johnson et al., Transfusion Jul 2020
In summary
• Cryopreservation can extend platelet shelf-life to at least 2 years
• RCT and retrospective data show safety, efficacy and practicality
• Further trials under way
• Not approved in US; approved and used in other countries
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