2. Concept of Patient Blood Management
• management systems to promote the rational use of blood
• limit the number of unnecessary transfusions
• development of transfusion guidelines and utilization review
• use of pharmaceuticals and blood conservation methods
• reduce transfusion risks
• save hospital resources
• requires evidence based practice (when available)
• requires multidisciplinary approach
3. Major Complications of
Transfusion Therapy
• Transfusion Transmitted Disease
• Immunologic Incompatibility
Between Donor and Recipient
• Improper Processing, Storage or
Administration
4. Donor Testing
• ABO/Rh typing and unexpected RBC antibody screening
• Antibody to Human Immunodeficiency Virus types 1 and 2 (HIV- 1/2 Ab)
• Antibody to Human T-Lymphotrophic Virus, types I and II (HTLV-I/ll Ab)
• Hepatitis B Virus Surface Antigen (HBsAg)
• Antibody to Hepatitis B Virus Core Antigen (HBcAb)
• Antibody to Hepatitis C Virus (HCVAb)
• Serologic Test for Syphilis
• Antibody to Cytomegalovirus (CMVAb)
• Nucleic acid testing (NAT) for HCV, HIV-1 and West Nile Virus (WNV)
• Antibody to T.cruzi (Chagas Disease)
• Culture for bacterial contamination (apheresis platelet components only)
• HLA antibody screen (previously pregnant platelet donor only)
5. Risk Estimates
Occurrence Probability
• HIV ~ 1:1,467,000
• Hepatitis C virus ~ 1:1,149,000
• Hepatitis B virus ~ 1:1,208,000
• HTLV ~ 1:2,678,000
• Fatal motor vehicle accidents ~ 1:10,000
• General anesthesia related death ~ 1:10-50,000
• Lee, Paling, Blajchman. Transfusion. 1998
• Dodd, et al. Transfusion Medicine Reviews, 2012
6. Vigilance for New Pathogenic
Agents
• Travel / immigration may introduce existing
agent to new geographic area
• Newly characterized agents or recognized
infections may have associated potential for
transmission via transfusion
8. Acute Transfusion Reactions and Complications
(occur during or up to 4-6 hours after transfusion)
Incidence
• Febrile non-hemolytic reactions 1:100
• Allergic reactions (uncomplicated) 1:100
• Bacterial sepsis 1:15,000-
• Transfusion Related Acute Lung Injury 1:5,000-
• Hemolytic reactions 1:38,000-70,000
• Anaphylactic reactions 1:20,000-50,000
• Circulatory overload (TACO)
9.
10. Clinical Case
• 04/19/02 61 year old male with myeloma received auto PBSCT
• 04/21/02 Fever, LLL pneumonia; Rx with Timentin and Aztreonam
• 04/24/02 Vancomycin added
• 04/24/02 Developed mild chills with 100 mL pooled plts; transfusion
d/c; developed T38.4, BP 60/30, O2 Sat 91%, HR 140 one
hour after transfusion d/c; admitted to ICU for presumptive
septic shock
• 04/26/02 Blood Bank notified of subsequent events
Gram stain of saved segment: 2+ Gram-negative rods
Culture of saved segment: 4+ Klebsiella oxytoca, sensitive to
Timentin and Aztreonam
• 05/30/02 Pt died with multiorgan failure
No post transfusion blood cultures grew Klebsiella
Final source of contaminated platelet component remains
undetermined
11. Bacterial Contamination/ Sepsis
• usually during transfusion but may occur up to 4-6 h post
transfusion
• high fever, severe chill, nausea, vomiting, hypotension,
dyspnea
• can develop shock, DIC, multiorgan system failure
12. Septic Transfusion Reaction
• Well-known risk of platelet transfusion therapy
• Most frequent infectious transfusion risk in USA
• AABB required implementation of methods to limit
and detect bacterial contamination in platelet
components (March 2004)
• Since 2004, STR have decreased but have not been
eliminated
15. Bacterial Sepsis
Determinants of Clinical
Severity
• Organism
– Gram-negative organisms elaborating endotoxins
– Virulence factors permitting bacterial growth
• Bacterial load infused
– Time of storage: >3 days for platelets
– Volume of component
• Host characteristics
– Concomitant administration of antibiotic
– Degree of immunosuppression
– Neutropenia
16. Platelet Preparation Process
• Emphasize apheresis collection
• Diversion of first 30-50 mL
• Store at standard condition for 24-36 h
• Culture in FDA approved system 18-24 h
• Estimated sensitivity for day 1 culture is only 22-40%
• Residual risk of bacterial contamination on day of transfusion
or outdate is 1:3,000 - 5,000 (clinical significance unknown)
17. Transfusion Related
Fatalities
From “Fatalities Reported to FDA Following Blood Collection and Transfusion: Annual Summary for Fiscal Year 2011”
http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/UCM300764.pdf
19. AABB Bulletin # 12-04, October 4, 2012:
“Recommendations to Address Residual Risk of
Bacterial Contamination of Platelets”
• Develop a policy to further reduce the residual risk
• Improve the recognition and monitoring of STR
• Optimize the appropriate transfusion practice
20. Bacterial Contamination of Platelet Components
Possible Future Preventive Measures
• Lower storage temperature
• Improve culture methods
• Point-of-issue testing (must be simple, rapid):
- culture platelets after the first 24 hours of storage
- retest day four or day five platelets at time of transfusion
• Limit platelet transfusion
21. Gram Staining of Apheresis Platelets
(initiated on 02/24/14)
• All platelets in available inventory on day four (4) of their shelf
life are quarantined.
• All day four (4) and day five (5) platelets received from
suppliers are quarantined.
• Sample is sent to Microbiology for Gram stain.
• Platelets remain in quarantine until receipt of Gram stain
results.
• Through 03/31/15 Components tested: 14,193
True positive: 1
False positive: 3
22. INTERCEPT Blood System for Platelets and
Plasma
The first FDA approved pathogen reduction system for blood centers
to reduce transfusion infectious disease risk
Reduces transfusion-transmitted infectious (TTI) risk.1
– Broad spectrum inactivation with >4 log reduction for most pathogens.
– Emerging pathogens, such as Chikungunya, Plasmodium species.
– Established threats such as HIV-1, HBV,3 HCV, and 3WNV.
Plasma:
– Approved for use with whole blood derived or apheresis plasma.1
Platelets:
– Approved for use with apheresis platelets in PAS.2
– Lowers the risk of transfusion-associated graft-versus-host disease (TA-
GVHD) through reduced contaminating T-cell activity.2
1. The INTERCEPT Blood System for Plasma Package Insert, December 16, 2014. 2. The INTERCEPT Blood System for Platelet Package Insert,
December 18, 2014. Certain non-enveloped viruses (e.g., HAV, HEV, B19 and poliovirus) and Bacillus cereus spores have demonstrated
resistance to the INTERCEPT process. 2. Pathogen reduction demonstrated for DHBV and BVDV, model viruses for HBV and HCV,
respectively.
23. Robust, Broad Spectrum Inactivation
Achieve >4 logs of inactivation for most pathogens
Viruses
Log Reduction
(pfu/mL)2
HIV-1, cell-associated 5.4
DHBV (model virus for HBV) ≥4.8
BVDV (model virus for HCV) ≥4.4
HTLV-I 4.7
HTLV-II ≥5.1
West Nile Virus ≥5.7
Chikungunya virus (CHIKV) ≥5.7
Dengue virus ≥4.3
Cytomegalovirus (CMV), cell-associated ≥4.9
Influenza A virus ≥5.9
Bluetongue virus 4.4
Adenovirus 5 ≥4.9
Protozoan Parasites
Log Reduction
(pfu or cfu/mL)2
Plasmodium falciparum ≥5.6
Babesia microti ≥4.9
Trypanosoma cruzi ≥5.3
Bacteria
Log Reduction
(cfu/mL)2
Escherichia coli ≥6.3
Yersinia enterocolitica ≥5.9
Klebsiella pneumoniae 5.8
Serratia marcescens3 ≥6.7
Staphylococcus epidermidis ≥6.1
Staphylococcus aureus ≥5.4
Streptococcus pyogenes3 ≥6.8
Bacillus cereus (vegetative) ≥5.5
Clostridium perfringens (vegetative) ≥6.5
Propionibacterium acnes ≥6.5
Treponema pallidum (syphilis) ≥6.4
Borrelia burgdorferi (lyme disease) ≥6.8
Leukocytes Log Reduction
Human T-Cells 4.0
1. The INTERCEPT Blood System for Platelets Package Insert, December 18, 2014.
2. Based on input titer and post-treatment titer in 1 mL. For a full list of pathogens, see Package Insert.
3. Based on culture of full platelet unit (300 mL).
24. Mechanism of Action
Targeting DNA and RNA to prevent pathogen proliferation
1. INTERCEPT Blood System Package Insert for Plasma, December 16, 2014.
2. INTERCEPT Blood System Package Insert for Platelets, December 18, 2014.
25. INTERCEPT Blood System for Platelets
Blood Center Value Proposition
Bacterial detection replacement
– Avoid recalls/false-positives
– Mitigate sepsis cases and related costs
Potential impact of guidance
– Eliminate 24 hr. incubation / 12 hr. hold
• Testing becomes gating step for release
• Gain 12-24 hrs. dating on front end
– Alternative to POI testing (hospitals)
CMV and Gamma equivalent
Future considerations
– Extended dating
– Mitigation for emerging pathogens
26. Pathogen Inactivated Platelets: Additional
Benefits
Reduced Pathogen Load
• Discontinue 1 ͦand 2 ͦ bacterial testing
• Earlier release of platelets into inventory
• Eliminate some current testing (e.g. syphilis)
• Modify testing (large NAT pool size rather than individual donor NAT)
• Modify travel-related donor deferrals (malaria, WNV)
• May extend expiry to 7 days (eliminate outdating)
Inactivate Residual WBC
• Eliminate need to irradiate to prevent TA-GVHD
• May reduce FNHTR
• May reduce alloimmunization
27. Pathogen Inactivated Platelets
Efficacy and Safety Summary
(clinical trials and ongoing hemovigilance programs)
• ↓ CCI at 1 and 24 hours
• No ↑ in bleeding episodes, RBC or PLT utilization
• No ↑ in AE including GVHD
• No sepsis, TTI or fatalities
28. Plasma-Stored versus PAS-Stored Platelets
• The primary difference
between plasma-stored and
PAS-stored platelets is that a
fraction of the plasma volume
has been removed.
• Platelet product yield, final
product concentration, and
final volume are the same.
30. Platelet Additive Solution (PAS) Platelets
• equivalent efficacy regarding bleeding outcomes
• substantially reduced risk of allergic transfusion reactions
• may be used interchangeably with standard component
• may replace saline-washed platelets in certain circumstances
• may replace plasma-reduced platelets
• may reduce FNHTR and TRALI
31. Next Generation PAS
• Includes glucose for energy metabolism and
bicarbonate as a pH stabilizer
• 90 – 95% plasma removal
• may further reduce transfusion reactions
• May eliminate need for HLA screening of previously
pregnant female donors
34. Considerations for Risk Reduction in
Transfusion
• Transfusion has never undergone prospective randomized
testing in the manner expected of a new drug
• Repletion of elements of hemostasis effective in bleeding
patient
• Prophylaxis to prevent bleeding in setting of mild-moderate
abnormal test result often lacks evidence-based support
• Associated with unfavorable risk-to-benefit ratio
35. Prophylactic Platelet Transfusion
most common use of platelet transfusion
previous research focused on optimal dose and threshold
effectiveness is uncertain/unproven compared to
therapeutic strategy
two recent RCT of therapeutic vs. prophylactic transfusion
- increase in WHO grade ≥ 2 bleed (> 90% grade 2)
- no increase in RBC transfusion
- no change in hospital days, SAE or survival
- significant decrease in platelet transfusion
Stanworth, et al. NEngl J Med 368 (19): 1771 – 1780, 2013
Wandt, et al. Lancet 380: 1309 – 1316, 2012
36. MSKCC
Platelet Transfusion Guidelines
1) PLT CT < 10,000/mcL
2) PLT CT < 20,000/mcL for outpatient
3) PLT CT < 20,000/mcL for recent hemorrhage (within 5 days)
4) PLT CT < 50,000/mcL for DIC
5) PLT CT < 50,000/mcL for existing CNS lesion
6) PLT CT < 50,000/mcL for invasive procedure (except bone marrow biopsy)
7) PLT CT < 50,000/mcL for active bleeding not controlled by local measures
8) PLT CT < 100,000/mcL for CNS or pulmonary invasive procedure (except
lumbar puncture) or bleeding
9) PLT CT < 100,000/mcL for active bleeding requiring RBC transfusion
10) other
37. Platelet Transfusion: A Clinical Practice Guideline From the AABB
Ann Intern Med. doi: 10.7326/M14-1589
*The article was published online first at www.annals.org on 11 November 2014.
1.PLT CT < 10,000/mcL in non-bleeding hospitalized patient
2.PLT CT < 20,000/mcL for elective CVC placement
3.PLT CT < 50,000/mcL for elective diagnostic LP
4.PLT CT < 50,000/mcL for elective nonneuraxial surgery
5.CPB with perioperative bleeding, thrombocytopenia and/or
evidence of platelet dysfunction
6. No recommendation regarding ICH and current antiplatelet
therapy
38. Future Platelet Transfusion Criteria Changes
1) PLT CT < 20,000/mcL for elective CVC placement
2) Reinforce:
- PLT CT < 10,000/mcL for non-bleeding inpatient
- PLT CT < 20,000/mcL for non-bleeding outpatient
3) Therapeutic transfusion only in otherwise stable autologous HSCT
4) Utilize half dose (low dose) platelet components for inpatient
prophylactic transfusion not associated with performance of an
invasive procedure
5) Develop criteria for end-of-life utilization
39. Platelet Transfusion References
1. Therapeutic Platelet Transfusion Versus Routine Prophylactic Transfusion in
Patients with Haematological Malignancies: An Open-Label, Multicentre
Randomised Study. Lancet. 2012; 380: 1309 – 16
2. A No-Prophylaxis Platelet-Transfusion Strategy for Hematologic Cancers. N
Engl J Med. 2013; 368: 1771 - 80
3. Impact of Prophylactic Platelet Transfusion on Bleeding Events in Patents
with Hematologic Malignancies: A Subgroup Analysis of a Randomized Trial.
Transfusion 2014; 54: 2385 – 2393
4. They Took a Mulligan and Mostly Got It Right…The Issue of Prophylactic
Platelet Transfusion for Patients Receiving Autologous Stem Cell
Transplantation. Transfusion 2014; 54: 2372 – 2374
