Thinking Outside the Frog - SEABB · 2013. 8. 18. · patients. DESIGN: Retrospective,...
Transcript of Thinking Outside the Frog - SEABB · 2013. 8. 18. · patients. DESIGN: Retrospective,...
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SEABB 2009
Thinking Outside the Frog
Medical and Scientific Advancements in
Blood Banking and Transfusion Medicine
Christopher D. Hillyer, MD
Professor, Departments of Pathology Hematology/Oncology and Pediatrics, Emory University School of Medicine
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Current SettingAssumptions
For many years,
specialists in blood banking and transfusion medicine focused primarily on the technical and consultative medical aspects of donor screening, blood procurement, compatibility testing, and
the proper use of common blood products, often limited to red blood cells, platelet concentrates, fresh frozen plasma (FFP), and cryoprecipitate.
More recently,
tremendous growth and diversification have occurred in the capabilities, functions, knowledge, and clinical and regulatory responsibilities of blood collection facilities and hospital-based transfusion services.
This growth has been paralleled by considerable expansion of the number of specialized processes and products available.
Cell therapies and tissue banking are new additions to our responsibilities.
Hillyer, et al. TRANSFUSION. 2008
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Cell Therapies
Thinking Outside the Ear
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Current SettingQuestions
Can we do better?
If “yes”,
What can we do better?
How can we do better?
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What Can We Do Better - 1
A next generation strategy for mitigating residual risk from bacterial contamination is needed
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BackgroundOpen Letter to the Blood Collection Community 8-16-02
Bacterial contamination of platelets represents the largest transfusion transmitted disease risk.
The current risk of bacterial contamination of platelets is approximately 1/1000-1/2000 per unit.
Bacterial detection technology is currently available and screening via bacterial culture has been shown to be practical and effective.
The authors “call for the blood collection community to immediately initiate a program for detecting the presence of bacteria in units of platelets.”
Drs. Brecher, AuBuchon, Yomtovian, Ness, and Blajchman
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5.1.5.1 - The blood bank or transfusion service shall have methods to limit and detect bacterial contamination in all platelet components.
5.1.5.2 - Standard 5.1.5.1 shall be implemented by March 1, 2004.
Date: March 3, 2003
To: AABB Members
From: Blood Bank/Transfusion Service Standards Program Unit
AABB Standards
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2005 - 2 cases of transfusion-associated sepsis reported after mandatory platelet testing
Case 1 Screening method: pH testing ; 5 unit pooled RDP received as outpatient Recipient developed symptoms consistent with sepsis; Staphylococcus
aureus from unit container and patient; confirmed identical by PFGE Recipient expired Day 21
Residual Risk Observed
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Residual Risk Observed
By 2008,
• ARC experience and all data extrapolated
• RR=1 serious reaction:60,000 screened unit
• Death risk may approximate 1:250,000 platelet doses (transfusion events)
(Compare Europe [EMEA] – no testing)
• Note opportunity cost – current bacterial testing methods challenge platelet supply and leads to use of “older”, less effective platelets
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Does it matter?
YES.
Most KOLs believe a RR of death of ~1:250,000 platelet transfusion events, or higher, is not a tolerable level of safety,
Nor are the limitations on supply, and/or platelet hemostatic effectiveness, considered to be ideal.
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What Can We Do Better - 1
Possible Answers
Testing at the hospital transfusion service
Colorimetric; Flow cytometric; other methods
Sensitivity matters; Trial and claims
Platelet storage solutions
Business case and FDA issues
Pathogen inactivation technologies
Many see this as the primary driver for FDA approval in the US
Business case and FDA issues
Enterprise Value Rank
1
3
2
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What Can We Do Better - 2
A next generation strategy for mitigating TRALI cases without compromising the adequacy and availability of the blood supply is needed
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TRALIHistorical and Current Definitions
“Respiratory distress, acute pulmonary edema, usually with hypotension and sometimes fever that occurred within a few hours of transfusion of a blood component”
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Calender Year
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sSuspected TRALI Fatalities ARC (2003-2005)
72 reported Fatalities
Eder AF, et al. Transfusion 2007;47;599
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ARC study of fatalities due to probable TRALI from surveillance reports: 2003-2005
72 fatalities: 38 TRALI, 34 non-TRALI
Plasma (odds ratio of 12.5) and apheresis platelets (odds ratio of 7.9) were disproportionately associated with TRALI fatalities in the ARC system
70-75% of TRALI fatalities were associated with a leukocyte antibodies from female donors
Prudent measures to reduce patient exposure to female plasma may prevent 6 fatalities each year in the ARC system ARC moves to predominantly male-only plasma (FP24)
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AABB Association Bulletin 06-07
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LAPS I - REDS-II
Effect of Pregnancy on the Rate of HLA Alloimmunization
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No preg
n=1744
1 preg
n=642
2 preg
n=1313
3 preg
n=1061
>3 preg
n=999
Any HLA Ab (2.2)
Any HLA Ab (10.0)
%
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Reduction in TRALI Through Male-Only Plasma
www.shotuk.org
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1997 1998 1999 2000 2001 2002 2003 2004 2005
TRALI Deaths
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What Can We Do Better – 2 - TRALI
Possible Answers
Male-only plasma
Limits supply; not easy for platelets,pheresis
Donor screening
for pregnancy history
Limits supply; male – transfused and nontransfused
for HLA, HNA antibodies
Several methods under evaluation by REDS-II
Platelet storage solutions
Business case and FDA issues; cost is less
Pathogen inactivation technologies
Business case and FDA issues
Enterprise Value Rank
N/A
2
1
3
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What Can We Do Better - 3
Determine and understand the relationship between transfusion and morbidity, multi-organ failure (MOF), and mortality
Is BLOOD Bad?
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Blood Transfusions and Mortality
Multiple studies over the past 10 years have examined the relationship between blood transfusions and morbidity/mortality (typically in ICU settings)
CAVEAT: Given the many factors leading to transfusion and the patient co-morbidities, results may be difficult to interpret
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Tinmouth et al, Transfusion 2006; 46: 2014-2027.
Substantial Data Exist
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If blood is bad, then giving less blood should be better?
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Carson JL et al, Transfusion Med Rev 2002; 16:187-199.
Effect of Restrictive Transfusion Triggers (less blood) on 30-day Mortality
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If blood is bad, what is the mechanism, and can we fix it?
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“Old Units”
O2, CO2, NO
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NONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CB
NONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CB
NONONONO
NONO
NONONONO
NONO
NONONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CBA CB
A - the effect of a variety of elements related to NO and related species, Hgb and the RBC, etc
in normal versus stored RBCs are not well understood;
B - the release and functional capabilities of normal versus stored, transfused RBCs are not
well understood; and
C – the ability of normal versus stored, transfused RBCs to affect hypoxic vasodilation are not
well understood.
Hillyer CD and Roback JD. Unpublished 4-08
NONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CB
NONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CB
NONONONO
NONO
NONONONO
NONO
NONONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CBA CB
NONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CB
NONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CB
NONONONO
NONO
NONONONO
NONO
NONONONO
NONO
NONONONO
NONO
NONOHypoxic Vasodilation• Increased blood flow
• Increased O2 delivery
• Optimized cell function
• Optimized organ function
A CBA CB
A - the effect of a variety of elements related to NO and related species, Hgb and the RBC, etc
in normal versus stored RBCs are not well understood;
B - the release and functional capabilities of normal versus stored, transfused RBCs are not
well understood; and
C – the ability of normal versus stored, transfused RBCs to affect hypoxic vasodilation are not
well understood.
Hillyer CD and Roback JD. Unpublished 4-08
The INOBA Hypothesis (Roback and Hillyer)Inadequate Nitric Oxide Bio-Availability
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Duration of Red-Cell Storage and Complications after Cardiac Surgery
Koch CG, Liang L, Sessler DI, et al. New England Journal of Medicine 2008;358:1229-39.
HYPOTHESIS
Serious complications and mortality after cardiac surgery are increased
when transfused red cells are stored for more than 2 weeks.
METHODS
Retrospective, 6.5-year clinical database study ; June 1998-January 2006)
Data sources: Cleveland Clinic’s cardiac anesthesia and cardiovascular information registries and its blood
bank database (IRB-approved for use without patient consent)
•Subjects: Patients ≥ 18 yo who received RBC transfusions during CABG, heart-valve surgery, or both
•Total patients studied: 11,002
•Total units RBCs received: 19,584
Major Variable: age of stored blood received*
2872 patients: 8802 RBC units ≤ 14 days (“newer blood”)
3130 patients: 3130 RBC units < 14 days (“older blood”)
* All pts included in the data analysis received exclusively newer or older blood; pts who received a mixture
of newer and older blood were excluded from the study to reduce confounding factors.
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RESULTS
Patients who received older RBC units had significantly higher rates of:
In-hospital mortality
Intubation beyond 72 hours
Renal failure
Sepsis or septicemia
Composite of these complications
Effect of newer blood on long-term patient survival:
At 1 year, those patients who had received newer blood had a significantly lower mortality rate than those patients who received older blood (P 2 week old RBCs was associated with:
1. significantly higher risk of post-operative complications
2. reduced short-term and long-term survival
Duration of Red-Cell Storage and Complications after Cardiac Surgery
Koch CG, Liang L, Sessler DI, et al. New England Journal of Medicine 2008;358:1229-39.
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CHEST 2008 (abstract)
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OBJECTIVE: Few studies have shown that aged packed red blood cells (RBC) transfusion negatively influenced the outcome of ICU patients, probably related to storage lesions which could be decreased by leukodepletion of RBC. The purpose of this study was to evaluate the impact of aged leukodepleted-RBC pack, on the outcome of ICU patients. DESIGN: Retrospective, observational, cohort study in a Medical Intensive Care Unit.
PATIENTS: Consecutive patients admitted during the years 2005 and 2006, and requiring a transfusion. We recorded patient's demographic data, number of RBC unit and age of each RBC, length of ICU, mortality during ICU stay.
RESULTS: Five hundred and thirty-four patients were included with global mortality was 26.6%, length of stay in ICU six days (3-14) and SAPS II 48 (35-62). RBC equaling to 5.9 were transfused per patients (22.7%
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Seppa N. “Bad Blood? Old units might be substandard.” www.ScienceNews.org. Vol. 173. March 22, 2008, p.179.
http://www.sciencenews.org/
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What Can We Do Better – 3A
Understand the relationship between
storage age of RBCs and morbidity and
mortality
Understand the cause of MOF; these studies will challenge efficacy; see also NIH REO
Possible Answers Investigate the problem (RFA 08-005; REO)
Make 14d pRBCs the universal standard
Make a better storage solution (100d AS) May be able to follow on PI
Enterprise Value Rank
1
2
Concern
3
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http://upload.wikimedia.org/wikipedia/commons/6/61/Lithobates_sylvaticus_%28wood_frog%29.jpg
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CENTER for TRANSFUSION and CELLULAR THERAPIES
Adult Transfusion Medicine – CD Hillyer, JD Roback, BH Shaz, LE Logdberg
Pediatric Transfusion Medicine – CD Josephson, JE Hendrickson
Blood Center Operations – KL Hillyer, CS Sheppard, CK Hopkins
Advanced Laboratory Coagulation – JC Zimring, A Duncan
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Mortality by Level of Coagulopathy
0%
10%
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60%
INR
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The Ratio of Blood Products Transfused Affects Mortality in Patients
Receiving Massive Transfusions at a Combat Support Hospital
J Trauma 63: 805-813, 2007
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Comparison of pre-MTP to MTP cohorts
Data point
Pre-MTP
n=84
ave (+/- std)
MTP
n=57
ave (+/- std) p value
Injury severity score 29 (+/-15) 28 (+/-12) 0.94
Penetrating trauma 42% 45% 0.64
RBC 24 hr (products) 23 (+/-13) 24 (+/-10) 0.50
PL 24 hr (products) 8 (+/-6) 13 (+/-10)
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Reconstitution of “Whole Blood”Mou et al: NEJM 2004;351:1635
RCT; age
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What Can We Do Better - 4
Data are starting to suggest that: recapitulation of whole blood may improve survival,
and increased early transfusion may decrease overall
transfusion;
Thus, Massive Transfusion Protocols (MTPs) are changing
drastically and quickly
Recapitulation vs reconstitution
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What Can We Do Better - 4
Consider recapitulation of whole blood for MTPs in the civilian setting
Expect some facilities to start (increase) to request “new products” and/or technical specifications Regular bank of thawed plasma
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What Can We Do Better - 5
Change in blood collection methods may significantly impact the marketplace
Per capita blood use variation in developed countries is considerable
The whole blood market is likely to change substantially
Automated (apheresis) collections may have advantages (recruitment, comfort, safety); dial in component combinations (replaces in-lab manufacturing in part?)
Automated component manufacturing is likely
At time of collection (dial a component)
In the blood center lab
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Belgium 60 units per 1,000 population per year
United States 50 units per 1,000 population per year
United Kingdom 40 units per 1,000 population per year
France 30 units per 1,000 population per year
Canada 20 units per 1,000 population per year
Sub-Saharan Africa 1-5 units per 1,000 population per year
Variation in per capita blood use in developed countries is considerable
As transfusion-related risk decreases, per capita transfusion is likely to increase
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The whole blood market is likely to change substantially
Current Whole Blood Collections:
~15M units – US
~40M units – Developed World
~75M units – Worldwide
GROWTH DRIVERS:
Increasing sophistication of healthcare in the developing world will require increased transfusions per capita (surgery, trauma care, obstetrics, cancer therapy, etc.)
Increasing age demographics likely to affect growth (e.g. France)
Automated collections – adoption drivers? - 5 to 40% in some US locations
Development drivers – China, India, Brazil – the next superpowers
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GROWTH: Future Markets
China (Lancet 2002; 360: 1770–75) >400 provincial, regional, and county blood centers (2000) >10,000 hospital blood banks (2000) WB units: 5.9M (1996), 7.0M (1998), 8.2M (2000) >90% of WB are 200 mL units (2000)
Population (2008) 1.3B ~40M units/yr to reach 30 units/1,000 people/yr
Unit definition varies
Would almost double the current developed world market
Will the world import blood? The UK experience
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Eder AF, Hillyer CD, Dy BA, et al. JAMA 2008;299:2279-2286.
Complication Rates of Loss of Consciousness and Major Systemic (Syncopal-Type) Complications by Donor Age
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Donor Informed Consent
Figure 1: Must Elements on ICFs and PCFs
0%
5%
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15%
20%
25%
30%
10%
20%
30%
40%
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% Must Elements
% C
on
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ICF
PCF
Figure 2: Should be Elements on ICFs and PCFs
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% C
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ICF
PCF
Critical Evaluation of Informed Consent Forms for Adult and Minor Aged Whole Blood
Donation Used by United States Blood Centers
Shaz BH, Demmons DG, Hillyer CD
TRANSFUSION 2009
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Prevention of ABO incompatible transfusion will become a major priority
Mistransfusion (ICBT)
BVN will add increased focus
Technologies Improved tracking –
RFID and computer systems
Vending machine model
“Locks, Clocks and Stops”
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MISTRANSFUSION
Wrong patient receives the wrong blood Considered by many authorities to be the leading
cause of transfusion-related mortality Estimated incidence approaching 1 in 14,000 units (US) Fatalities
1:500,000 - 1:800,000 equals 30 deaths per year US high on list of “Never Events”
Why? improper identification of the intended recipient during initial sample
collection for blood typing (“wrong blood in tube”; WBIT) incorrect typing of the blood component or recipient by transfusion
service misidentification of the patient recipient and/or the blood unit at the
time of initiation of the blood transfusion
ALL OF THESE INCLUDE/REQUIRE HUMAN ERROR
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AISD ABO-Incompatibility Stop Device
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AISD
2+
+ , C
1+
+ , C
3+
+ , C
4+
+ , C
Titer: 4-8 Titer: 16-32 Titer: 32-128 Titer: 32-256
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Compatible
AISD
Visual Digital
4+ Incompatible
Visual Digital
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Genotyping will become the major method for blood collection establishments and transfusion services by 2015
Drivers Sickle cell anemia patients
A more effective Rh strategy
Multichannel, cost
Improved blood center/hospital relationship
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Infectious Diseases – Watch List
(New and emerging) infections will continue to play a dominant role in the US TM system
List of 70 key TTDs to be published
Babesia – 70 deaths to date
Dengue fever
Malaria returns to the US (testing strategies)
Discontinuation of Chagas testing
Mad ungulates scare US population vCJD testing in the US