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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

8 8

Bacterial contamination of platelets

Eder AF et al. Transfusion 2014;54:857-62

Transfusion-transmitted diseases

Donor sample testing--results

9

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

10

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

14 14

General pathogen reduction

Mundt JM et al. Photochem Photobiol 2014;90: 957-64

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

17 17

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

18

Intercept Blood System Pathogen Reduction Process

Illumination device

CAD: Compound Adsorption Device, which adsorbs residual amotosalen & free photoproducts

19 19

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

23

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

26 26

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

27 27

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

28

29

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

31 31

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

32

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

33

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

34

35

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

36

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

37

Objectives

Discuss the risk of bacterial

contamination of platelet products

Describe platelet products with a

seven-day shelf life

Describe pathogen-reduced blood

products