Seven-Day Platelets and Blood Component … need is constant. The gratification is instant. Give...
Transcript of Seven-Day Platelets and Blood Component … need is constant. The gratification is instant. Give...
The need is constant.
The gratification is instant.
Give blood. TM
Seven-Day Platelets and Blood Component Pathogen Reduction
Barry Siegfried, MD
2
Objectives
Discuss the risk of bacterial
contamination of platelet products
Describe platelet products with a
seven-day shelf life
Describe pathogen-reduced blood
products
Storage temperatures for blood components
Frozen plasma (FFP, PF24, PF24RT24)-- -18 C or colder
Red blood cells--1 to 6 C
Platelets--20 to 24 C
Methods to reduce bacterial risk
Skin disinfection
Diversion of first blood drawn
Blood center quality control
testing for bacteria in platelets
— BacT/ALERT (bioMérieux)
— eBDS System
(Haemonetics)
Transfusion service (point of
issue) testing for bacteria in
platelets
— Platelet PGD Test System
(Verax)
— BacTx (Immunetics)
Sample diversion pouch
http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/UCM459461.pdf
Decrease in US fatalities due to bacterial contamination of platelets
6 6
Bacterial contamination of platelets • After early screening for bacteria,
about 1/2000 to 1/3000 platelet transfusions are still contaminated with bacteria, primarily coagulase-negative Staphylococcus species (AABB Association Bulletin 14-04)
• Residual risk of septic transfusion reaction
• 1/6000 to 1/80,000 (Tomasulo P et al. Transfusion 2011;51:2527-33)
• 1/94,000 (Eder AF et al. Transfusion 2014;54:857-62)
Aggregates of Staphylococcus epidermidis & activated platelets from an experimentally contaminated whole-blood platelet unit (Transfusion 2007 Jul;47:[cover])
7 7
Bacterial contamination of platelets
Gibson T et al. Skin fragments removed by injection needles. Lancet 1958;2:983-5
Transfusion-transmitted diseases
Donor sample testing--results
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Organism Residual risk of infection
(components/infection)
Window period
(d)
HIV 1,500,000 9
Hepatitis C
virus
1,100,000 7
Hepatitis B
virus
1,000,000 22
HTLV 2,700,000 51
Syphilis Millions (not since 1966) 30
Emerging agents
Babesia species, mostly B microti in the US
— most frequently reported transfusion-transmitted
infectious agent in the US
Dengue virus
— Spread to the Americas in 1980s and 1990s
Chikungunya virus
— Spread to the Americas (the Caribbean) in Dec 2013
Ebola virus
Zika virus
Etc
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Solvent-detergent treatment of plasma
Octaplas (Octapharma)
— Method
Treated with tri(n-butyl) phosphate (TNBP) and
polyoxyethylene-p-t-octylphenol (Triton X-100)
» TNBP remove lipids from pathogen membranes
» Triton X-100 is a detergent that both stabilizes
TNBP and disrupts lipid bilayers
These compounds are removed by first oil and
then solid phase extraction procedures
— Ineffective against nonenveloped viruses--
hepatitis A, hepatitis E, parvovirus B19
Prion reduction
Pall Leukotrap Affinity Plus Prion and Leukocyte
Reduction Filter System
— can be applied to RBCs
P-Capt Prion Reduction Filter (ProMetic,
Macopharma)
— can be applied to RBCs
Ligand gel chromatography used in production of
solvent-detergent plasma (octaplasLG
(Octapharma))
General pathogen reduction System Photosensitizer Treatment Components Availability
Theraflex None UVC Platelets Outside US
Theraflex MB Methylene blue Visible light
Plasma In development
Intercept Amotosalen (S-59)
UVA Platelets, plasma
US, outside US
Mirasol Riboflavin (vitamin B2)
UV Platelets, plasma. RBCs & whole blood in development
Outside US
Frangible anchor linker effector (FRALE) compound S-303
None None Red blood cells, whole blood
In development
15 15
Pathogen reduction
• A pathogen reduction system for platelets and plasma, the Intercept Blood System (Cerus Corp), was licensed by FDA in December 2014
• Inactivates a broad range of pathogens such as viruses, bacteria, and parasites
• White blood cells, which might cause immunologically based adverse reactions, are also inactivated
16 16
Intercept Blood System
• Applied to apheresis platelets in platelet additive solution 3 (PAS 3 (InterSol (Fenwal division of Fresenius Kabi))) • Medium is 35% plasma,
65% PAS 3 • PASs are crystalloid,
isotonic, saline-based nutrient media
• Only approved collection device is Amicus Separator (Fenwal)
https://www.fenwalinc.com/Pages/ Amicus.aspx
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Intercept Blood System
• Also applied to apheresis platelets in 100% plasma
• Only approved collection device is Trima (Terumo BCT)
https://www.terumobct.com/location/north-america/products-and-services/Pages/trima-accel-collection-system.aspx
The Intercept Blood System for Platelets
Step 2 Illumination
Step 3 CAD
Process Complete Storage
Step 1 Amotosalen
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Intercept Blood System Pathogen Reduction Process
Illumination device
CAD: Compound Adsorption Device, which adsorbs residual amotosalen & free photoproducts
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Description of Intercept
• Amotosalen is added to plasma or platelets
• The product is illuminated causing the agent to crosslink any nucleic acid (DNA or RNA) thereby inactivating cells and viruses
Intercept efficacy
Inactivates:
— Enveloped viruses
HIV-1 and -2
HTLV-I and -II
Cytomegalovirus (CMV)
» No transfusion-transmitted infections reported
Chikungunya virus
Flaviviridae
» Dengue
» West Nile virus (WNV)
» Zika virus--inactivated in plasma
Others
— Non-enveloped viruses
Adenovirus--common causes of respiratory illness 20
Intercept efficacy Inactivates:
— Gram-negative bacteria
— Gram-positive bacteria
— Anaerobic Gram-positive bacteria--eg,
Propionibacterium acnes
— Spirochete bacteria--eg, Treponema pallidum
— Protozoa
Plasmodium falciparum
Babesia microti
No septic transfusion reactions attributed to Intercept-
treated products
Likely to inactivate unknown pathogens and those for
which a test has not been developed (eg, Ebola virus)
21
Intercept efficacy Resistant to inactivation
— Non-enveloped viruses
hepatitis A virus
parvovirus B19
hepatitis E virus
» Report of 2
transfusion-transmitted
infections by plasma
from 1 donor (Hauser L
et al. Blood
2014;123:796-7)
poliovirus
— Bacillus cereus spores
— High concentrations of
Klebsiella pneumoniae 22
Parvovirus B19 infection
(http://www.fifthdisease.org/general.
html)
Intercept efficacy
T cells in the product are
inactivated, reducing the
likelihood of transfusion-
associated graft-vs-host
disease
— Animal model showed TA-
GVHD reduction
— No TA-GVHD attributed to
Intercept-treated products
— AABB standards allow
pathogen reduction to prevent
TA-GVHD if it inactivates
leukocytes, effective 4/1/2016
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Skin changes in TA-GVHD
24 24
Intercept efficacy • Platelets in PAS 3 are associated with reduction
in adverse transfusion reactions
• Allergic reactions reduced about 45-65%
• Inconsistent reduction in febrile, non-
hemolytic reactions
• Too little data to determine effect on other
transfusion reactions
• Treated platelets have a potentially longer
storage time of 7 days
• May partially offset increased cost (Girona-
Llobera E et al. Transfusion 2014;54:158-68)
Intercept safety
Platelet yield (dose)
— Sandgren P et al. Vox Sang 2015;108:340-9
6% less than untreated units after 5 days of storage
7% less after 7 days
— 8% less than untreated units after 5 days (Intercept
Blood System for Platelets--Dual Storage (DS)
Processing Set, package insert, 12/18/2014)
Intercept-treated plasma & platelets are
contraindicated for neonates treated with low-
wavelength phototherapy
— may develop erythema from interaction between UV
& amotosalen
— US phototherapy is high-wavelength 25
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Intercept safety
• SPRINT clinical trial of platelets showed possible increase
in ARDS--1.6% in Intercept platelet recipients vs 0% in
controls (Snyder E et al. Transfusion 2005;45:1864-75)
• Cerus contested this
• Reanalysis showed that after reclassification of
pulmonary complications, there was no difference
between Intercept & control
• Reanalysis + other data showed that Intercept
platelet recipients had better lung status than
controls
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Intercept safety
• Clinical trial of platelets showed possible increase in
ARDS (continued)
• Nonetheless, Cerus must complete a phase 4 clinical
trial
• Evaluates the incidence of acute lung injury, with an
emphasis on ARDS
• Primary outcome measure is proportion of patients
requiring treatment-emergent assisted mechanical
ventilation
Safety of pathogen-inactivated (PI) platelets Butler C et al. Cochrane Database Syst Rev
2013 Mar 28;3:CD009072 Analysis of 10 trials, 9 of which were studies of Intercept
"We found no evidence of a difference in mortality, ’clinically
significant’ or ’severe bleeding’, transfusion reactions or
adverse events between pathogen-reduced and standard
platelets."
PI platelets posed about a 3 times higher risk of platelet
refractoriness--146/1000 v 53/1000
Patients receiving PI platelets needed 7% more platelet
transfusions
Corrected count increments were generally lower for PI
platelets
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Intercept-treated plasma
Cinqualbre J et al. Comparative effectiveness of plasma prepared
with amotosalen-UVA pathogen inactivation and conventional
plasma for support of liver transplantation. Transfusion
2015;55;1710-20
— Retrospective study
— Same volumes of plasma transfused
— Same numbers of RBC units transfused
— Same numbers of platelets transfused
— Same frequency of hepatic artery thrombosis, indicator of "balance
between the procoagulant and antithrombotic function of plasma in
patients with chronic liver disease"
— Same mortality
Cost-effectiveness of Intercept platelets
McCullough J et al.
Transfusion
2015;55;2312–2320
— Nonquantified benefits
Fewer donor deferrals
» Recent tattoos or
piercings
» Travel to malaria-
endemic areas
Fewer weekend collections,
which cost more
30
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Intercept--current status
• Several blood centers have signed agreements with
Cerus for purchase of Intercept
• Centers for Medicare and Medicaid Services has created
codes for pathogen-reduced platelets and plasma
• Interim payment rates for apheresis platelets are same
as for irradiated products
• FDA approved collection of plasma & platelets in areas
with active Zika virus transmission if
• FDA-approved pathogen reduction is used, or
• donations are tested with an FDA-licensed blood donor
screening test for Zika virus
TReatment UsE (TRUE) study
A Prospective, Open Label, Treatment Use
Study of Patient Safety Following Transfusion of
INTERCEPT Platelet Components
(https://clinicaltrials.gov/ct2/show/study/NCT023
05732)
Platelet component traits — Apheresis-derived (any platform)
— 5-day shelf life
— PAS 3 or 100% plasma
— leukocyte-reduced
— no gamma irradiation
— no bacterial detection
— no CMV serology testing
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TReatment UsE (TRUE) study
Locations: 4 hospitals in Puerto Rico
Primary outcome measures
— Proportion of patients/transfusions with any adverse event or
transfusion reaction
— Proportion of Intercept platelet components containing platelet doses ≥ 3.0 ×1011
— Proportion of patients with a transfusion-transmitted chikungunya virus
or dengue infection
Estimated study completion date: August 2017
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Barriers to adoption of pathogen reduction For Intercept, currently only single and double
platelets can be collected
Not available for RBCs
No mandate from FDA or anyone else
Blood centers won't implement unless they can
recover costs from hospitals
Accrediting organizations face resistance from
hospitals to new safety measures
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Seven-day platelets
In the United States, blood centers that wish to store Platelets
Apheresis Leukocytes Reduced in 100% plasma for 7 days must
label every product with a statement that the product must be tested
with a bacterial detection device cleared by FDA and labeled as a
"safety measure".--addition to indications for use, Amicus Separator
System (Fresenius Kabi), approved by FDA on 7/22/2015
Additionally, for storage up to 7 days, every product must be tested
with a bacterial detection device cleared by FDA and labeled as a
“safety measure.”--addition to indications for use, Trima Accel
System (Terumo BCT), approved by FDA on 8/6/2015
In US, Intercept-treated platelets may be stored only for the usual 5
days
— In Europe, 7 days
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Seven-day platelets Currently, only Platelet PGD Test System (Verax) is approved as a
"safety measure"
— only for apheresis platelets and pools of whole-blood-derived platelets
— ~$40/test, including labor
— Labor-intensive
— Most positives are false positives--94% or more
— Test must be done within 24 hours before transfusion
http://www.veraxbiomedical.com/products/platelet-pgd-test.asp