hot topics in · 2020. 9. 14. · presentation of adherence molecules •as previously mentioned...

Hot Topics in Platelet Transfusions

Speaker Name

Jessica Poisson, MDDirector of Patient Blood ManagementAssociate Medical Director, TransfusionDuke Health

Objectives

▪ Platelet Physiology

▪ Platelet Transfusions

▪ Hot Topics1. Bacterial Mitigation

2. Donor Reimbursement

3. Resting Platelets

4. Cold Platelets

HEADER / PRESENTATION TITLE

Conflicts of Interest

• Cerus – grant funding - investigator

Platelets

Made in the Bone Marrow from Megakaryocytes

Life Cycle- Production: 5 days- Circulating: 7-10 days

Machlus KR, Italiano JE. J Cell Biol. 2013 Jun 10; 201(6): 785–796.Image: https://openstax.org/books/anatomy-and-physiology/pages/18-4-leukocytes-and-platelets

PlateletsPlatelets are anucleate cell fragments

https://oncohemakey.com/platelet-structure-and-function-in-hemostasis-and-thrombosis/

Alpha granules

Dense (d)granules

P-selectin ADP/ATP

Fibrinogen Calcium (Ca++)

Von WillebrandFactor (vWF)

Serotonin

Factors V & XIII

Platelet factor (PF) 4

PDGF

TGF b1

+ more

Platelets

Papa AL, Jiang A, Korin N et al. Science Translational Medicine. 2019:11 (479); eaau5898https://www.sciencedirect.com/topics/engineering/activated-platelet

Activated Platelets

Activation signal received – commonly

collagen or vWFexposure

Platelet shape changes, “flips

membrane” and rolls along endothelium –

bind fibrinogen

Granule release –activates lots of things including

WBCs and coagulation factors

Aggregation with other platelets to form platelet plug

http://what-when-how.com/acp-medicine/hemostasis-and-its-regulation-part-1/Kumar V, Abbas AK, Aster JC. Chapter 4: Hemodynamic Disorders, Thromboembolic Disease, and Shock. Robbins and Cotran pathologic basis of disease. 9th Ed. Philadelphia, PA : Elsevier/Saunders, [2015]

Platelet TransfusionTreatment of:

• Thrombocytopenia• Hypoproliferative• Consumption• Destruction

• Platelet Dysfunction• Congenital• Acquired

Murphy MF, Stanworth SJ, Estcourt. Ch 20: Hemodynamic Disorders, Thromboembolic Disease, and Shock. In Rossi’s Principles of Transfusion Medicine. 5th Ed. Chichester, West Sussex ; Hoboken, NJ : John Wiley & Sons Inc., 2016.

Platelet Transfusion

Murphy MF, Stanworth SJ, Estcourt. Ch 20: Hemodynamic Disorders, Thromboembolic Disease, and Shock. In Rossi’s Principles of Transfusion Medicine. 5th Ed. Chichester, West Sussex ; Hoboken, NJ : John Wiley & Sons Inc., 2016.

Indication Platelet Count Patient Condition

Prophylaxis <10K Stable, poor marrow fxn

<50K Invasive procedure

<75-100K CNS procedure

Bleeding <50-100K Oozing or continued non-surgical bleeding

No value Anti-platelet therapy in last 24 hours (aspirin, etc)

Platelet Components

Platelet Concentrates

• Derived from Whole Blood Collection

• 5.7 x 1010 platelets per bag minimum

• Adult dose – 4-6 units

Apheresis Platelets

• Apheresis Collection – multiple units

• 3.0 x 1011 per bag minimum

• Adult dose – 1 unit

Platelets

• Stored 20-24C in gas permeable bags with agitation

• Shelf life: 5 days in closed system

• QC: pH >=6.2 at end of storage

• Method to detect or inactivate bacteria in all platelet components (AABB BBTS standards)

Topic 1:Platelet Bacteria Management

Platelet Contamination

• Estimated 1 in 2500-3000 room temperature platelet units contain bacteria

• Mitigation has included• Reduction of unit life from 7 days to 5 days

• Requiring bacterial culture 24 hours after collection

• Risk of Septic Transfusion reaction from platelets still significant• 1 in 10,000 by active surveillance

Hong H, et al, Blood, 2016; 127(4): 496-502


Staphylococcus aureus contamination – day 4 unit

From: Siddon AJ, Snyder EL, TormeyCA. Visualization of bacterial contamination in an apheresis platelet unit. J Clin Apher. 2018 Dec;33(6):671-672.

Platelet Fatalities

https://www.fda.gov/media/136907/downloadhttps://www.fda.gov/vaccines-blood-biologics/report-problem-center-biologics-evaluation-research/transfusiondonation-fatalities

Platelet contaminants 2014-2018

Gram Pos 9

Gram Neg 4

Other 1 (WNV)

Most Common Staph aureus

Published September 2019

FDA Guidance on Bacterial Control

• Implementation 18 months from publication• March 2021

• Requires additional steps to mitigate for potential bacteria in the product• Treat the Product – Pathogen Reduction

• More testing – numerous strategies• Recommendations divided into Apheresis/Pre-pooled platelets and Whole Blood

Derived (WBD) platelets

• Also provides strategies for 7 day platelets

Treatment/Testing OptionsPathogen Reduction - Inactivates cells/pathogens containing nucleic

acids- Will also serve as Irradiation modification- Only for Apheresis platelets

Bacterial Culture - Standard FDA approved bacterial culture technique

- Volumes differ between apheresis/pre-pool and WBD single units

Large Volume, Delayed Sampling (LVDS) - Larger volume taken for bacterial sample – 16 mL- Delayed means the sample collection happen >24

hours (usu 36 or 48 H) post unit collection- Only Apheresis/Pre-pool platelets

Rapid bacterial testing - Small sampling with one hour test time

Apheresis/Pre-Pooled Strategies

Current bacterial culture will only be good for 3 days

Requires strict

platelet unit qualification

Single Unit WBD Platelets

Would still require secondary testing to take it

from 3 day to 5 day life

Strategy Considerations

• Life of Product: Do you want 7 day platelets?• Platelet must be in a bag approved for 7 day storage

• May require relabeling and additional product codes

• Hands-On Time: Do you have staffing to perform the testing?• Some methods can be batched or performed once

• Rapid test could be time of issue

• Cost: How much is the test with new equipment?• Repeat testing may be required and significant staff time is a cost consideration

Financial Analysis

JHH Analysis

Found Secondary Bacterial testing to be cheapest strategy

• Caveat: Not included in analysis –cost to set up testing platform

Method 2018 $

Baseline $651.45

Pathogen Reduced PLTs $827.82

Point of Release test (rapid test) $686.33

Secondary Bacterial Test $668.50

Platelet Bacterial Mitigation

• No “One Size Fits All” Solution

• Option deployed should consider:• Utilization and wastage rates

• Type of unit (including bag type) produced by supplier

• Costs of supplier testing versus in-house testing

• Internal staffing and space

Topic 2:Platelet Supply: Reimbursed Donors


• Platelet inventory management is challenging because of their short shelf life

• Seasonal supply and demand imbalances are particularly stressful• Outdate rates ~20% in 2015 and 2017 NBCUS data

Platelet Donor Demographics

TRANSFUSION Volume 58, Issue S2: Abstract Presentations from the AABB Annual Meeting, Boston MA, October 13-16, 2018.

Will we run out of donors using current donor recruitment strategies?

What is old is new again…

• One way to motivate a steady donor pool is compensation• Apheresis platelet donation requires ~2 hours to complete

• In the 1980s, it was not uncommon to provide monetary compensation for platelets• Mayo donor center open through 2002

• Then the AIDS crisis hit and integrity of the blood supply became critical

Reimbursed Donors

Pros

• Encourages repeat donation

• Treat it like a job

• Steady supply

Cons

• Potential lying on DHQ for to meet criteria

• Could compromise volunteer donation of other blood products

Paid plasma donation

• There is a subset of compensated donors already – source plasma donors

• Difference: Source plasma is pooled and pathogen reduced prior to manufacturing

• Still perform standard donor testing

Source Plasma Donors

Infectious Disease Testing Results

Data: Crowder LA et al. Transfusion 2017:57(S3);47A (abstract)PPTA Presentation Plasma Product Biotechnology Meeting, May ‘17

Major infectious disease testing rates similar between volunteer and paid donor populations

New Technology

• Pathogen Reduction Technology for Apheresis Platelets• INTERCEPT (Cerus, ) FDA approved in 2017

Viruses inactivated

HIV-1

HIV-2

HBV

HCV

CMV

WNV

Chikungunya virus

Dengue virus (DENV)

Transfusion 2005;45:580-590 INTERCEPT package insert: https://intercept-usa.com/images/resources/Package_Inserts/INTERCEPT_Blood_System_LV_Platelets_Package_Insert_May-2019.pdf

Bacteria Inactivated

Gram Positive Gram Negative Others

Staphylococcus epidermidis

Klebsiella pneumonia Treponema pallidum

Staphylococcus aureus Escherichia coli Borrelia burgdorferi

Listeria monocytogenes

Serretia marcescens Clostridium perfringens(vegetative)

Corynebacteriumminutissimum

Pseudomonas aeruginosa

Streptococcus pyogenes

Enterobacter cloacae

TRANSFUSION 2020;60;S134–S137

In conclusion, a potential blood sustainability strategy would be to reimburse blood donors to ensure a safe and adequate supply while protecting the donors and meeting the patientsʼ needs. Additionally, we will need to understand the cost and bene ts, the targeted populations (all or only for certain products), and societyʼs acceptance. However, with many changes in blood safety, population demographics, social norms, and economics, it is time we embrace remunerated donors.

Topic 3:Platelet Function – Non-Activated Platelet Products


• 70-75% of platelet transfusions are prophylactic in non-bleeding cancer patients• Goal of transfusion is to raise the platelet count, not stop bleeding

• Older platelet units with higher activation markers have shown poorer count recoveries

Delaflor-Weiss E, Mintz, P. Transfus Med Rev. 2000 Apr;14(2):180-96.

Platelet Recovery

• Not dissimilar to RBCs, platelets have been shown to have a storage lesion

• Features of platelets that will not be effective post transfusion- Increased P-selectin expression

- Increase in morphologic complexity

- Decreased response to agonists

- Increased microparticles

Mauer-Spurej E, Chipperfield K. Transfus Med Rev. 2007 Oct;21(4):295-306.

Platelet Swirl is the only quality measure performed routinely- But no objective

grading

- More informative tests not easily automated

Mauer-Spurej E, Chipperfield K. Transfus Med Rev. 2007 Oct;21(4):295-306.

Platelet Microparticles

• Microparticles have been correlated with inflammation• Linked to SLE, RA, atherosclerosis,

diabetic nephropathy

• Shed when platelets are activated

• What does their presence mean in a platelet unit?

Goubran HA, Burnouf T, Stakiw J, Seghatchian J. Transfus Apher Sci. 2015 Feb;52(1):12-8.Labrie A et al. Transfus Med Hemother 2013;40:93–100

How can you Make or Keep Platelets Non-Activated?

• Patient Factors

• Age of Unit

• Manufacturing

• Activation is typically irreversible

TRANSFUSION 2009;49:2276-2284.

Developed an instrument that measures platelet product features and software that combined platelet shape, temperature response and microparticle content into a quality score

DLS score and platelet recovery

• Platelet unit sampled, tested and scored

• Recipient of unit then reviewed for pre and post transfusion platelet counts (1 hour and 24 hour post)

• 49 patients received 96 analyzed units

Platelet Transfusion Outcomes

• Platelet Activation Affects Transfusion Outcomes in Hematology-Oncology Patients: Meta-Analysis of Data From Four North American Hospitals (AABB 2019 Abstract)

• Maurer E, Noland DK, Kniep JN, Ye Z, Chipperfield K, Labrie A, Szefer E, Thompson D

• 432 patients, 2139 transfusions

• Activation measured using dynamic light scattering

• Found receipt of an activated platelet decreased count increment significantly

Non-activated Activated P value

1 hour count increment 32.2 x 109/L 26.7 x 109/L <0.0001

24 hour count increment 19.8 x 109/L 15 x 109/L 0.0008

Platelet Transfusion Outcomes• Activated Platelet Transfusions in Hematology-Oncology Patients are Associated

with Lower Post-Transfusion Count Increments and Shorter Interval Between Transfusions(AABB 2019 Abstract)

• Mettman D , Brown L , Hogan K , Labrie A , Maurer-Spurej E , Ye Z

• 119 patients• Activation measured using dynamic light scattering

• Found receipt of an activated platelet decreased count increment significantly from mean 22.88 to 17.95

• Also days between transfusion decrease 32% after activated transfusion from 3.88 days to 2.63 days

Non-Activated Platelets• Platelets that are not activated will circulate longer in the blood

stream• Good for prophylactic transfusions

• Currently platelet swirl is only measure of quality• Not quantitative

• Microparticle content is a marker of inflammation/activation• New rapid assay gives activation score based on MP content

• Non-activated platelet transfusion have better count recoveries• May reduce utilization by allowing more time between transfusions

Topic 4:Platelet Function – Activated Cold Platelets

Why do we keep platelets room temp?

• Discovered in the 1970s that platelets stored cold (1-6C) result in poor count recoveries

• Refrigerator temperatures lead to platelet shape change and presentation of adherence molecules• As previously mentioned – signs of platelet activation

Murphy S, Gardner FH. N Engl J Med 1969;280: 1094-1098Slichter SJ, Harker LA. Br J Haematol, 1976;34: 403-419

Cold Platelets vs RT-Platelets

Reddoch KM, Pidcoke HF, Montgomery RK, et al. Hemostatic function of apheresis platelets stored at 4C and 22C. Shock 2014;41:54-61.

Platelet Aggregation StudiesCold Platelet results in blue circle

Thromboelastogram (TEG) StudiesCold Platelet results in blue circle

TRANSFUSION 2017;57;2836–2844

Cold Platelet Experience at Mayo Clinic

• FDA variance approve for 3 day cold stored (CS) platelets in 2015• Also required AABB Standards exception as no bacterial testing

performed

• Plasma suspended platelets have high clot rate – 24% were discarded

• Next Steps:• PAS suspended cold platelets to decrease clotting

• Pathogen reduction with a goal of extending product life to 10 days

Extended Storage of Cold PLTS

Braathen H, Sivertsen J, Lunde THF, et al. In vitro quality and platelet function of cold and delayed cold storage of apheresis platelet concentrates in platelet additive solution for 21 days. Transfusion. 2019 Aug;59(8):2652-2661

In summary

More bacteria mitigation for platelets is coming – you have options

We can look at changing the platelet donation process by paying donors to stabilize the supply – pathogen reduction is the key

Prophylactic platelet transfusions may be optimized by checking quality markers – non-activated platelets stick around

Bleeding patients may benefit from activated platelets – and keeping them cold (1-6C) gets them ready to clot

Cold Platelets

• Storing platelets at 1-6C activates the platelets• Not good for count recoveries

• Good for rapid hemostasis

• Allows for prolonged storage – slows cell metabolism• Keeps platelets from dying

• Reduces bacterial growth

• Increasing use in bleeding patients• Military and trauma most common

hot topics in · 2020. 9. 14. · presentation of adherence molecules •as previously mentioned...

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