Thinking Outside the Frog - SEABB · 2013. 8. 18. · patients. DESIGN: Retrospective, observational, cohort study in a Medical Intensive Care Unit. PATIENTS: Consecutive patients

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

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

Cell Therapies

Thinking Outside the Ear

Current SettingQuestions

Can we do better?

If “yes”,

What can we do better?

How can we do better?

What Can We Do Better - 1

A next generation strategy for mitigating residual risk from bacterial contamination is needed

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

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

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

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

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.


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


Enterprise Value Rank

1

3

2


A next generation strategy for mitigating TRALI cases without compromising the adequacy and availability of the blood supply is needed

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”

0

5

10

15

20

25

30

35

2003 2004 2005

Calender Year

Rep

ort

ed

Fati

lite

sSuspected TRALI Fatalities ARC (2003-2005)

72 reported Fatalities

Eder AF, et al. Transfusion 2007;47;599

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)

AABB Association Bulletin 06-07

LAPS I - REDS-II

Effect of Pregnancy on the Rate of HLA Alloimmunization

0

5

10

15

20

25

30

35

40

45

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)

%

Reduction in TRALI Through Male-Only Plasma

www.shotuk.org

0

1

2

3

4

5

6

7

8

1997 1998 1999 2000 2001 2002 2003 2004 2005

TRALI Deaths

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



N/A

2

1

3


Determine and understand the relationship between transfusion and morbidity, multi-organ failure (MOF), and mortality

Is BLOOD Bad?

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

Tinmouth et al, Transfusion 2006; 46: 2014-2027.

Substantial Data Exist

If blood is bad, then giving less blood should be better?

Carson JL et al, Transfusion Med Rev 2002; 16:187-199.

Effect of Restrictive Transfusion Triggers (less blood) on 30-day Mortality

If blood is bad, what is the mechanism, and can we fix it?

“Old Units”

O2, CO2, NO

NONONO

NONO

NONONONO

NONO

NONOHypoxic Vasodilation• Increased blood flow

• Increased O2 delivery

• Optimized cell function

• Optimized organ function

A CB

NONONO

NONO

NONONONO

NONO





A CB

NONONONO

NONO

NONONONO

NONO

NONONONO

NONO

NONONONO

NONO





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





A CB

NONONO

NONO

NONONONO

NONO





A CB

NONONONO

NONO

NONONONO

NONO

NONONONO

NONO

NONONONO

NONO





A CBA CB

NONONO

NONO

NONONONO

NONO





A CB

NONONO

NONO

NONONONO

NONO





A CB

NONONONO

NONO

NONONONO

NONO

NONONONO

NONO

NONONONO

NONO





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

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.

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.

CHEST 2008 (abstract)

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%

Seppa N. “Bad Blood? Old units might be substandard.” www.ScienceNews.org. Vol. 173. March 22, 2008, p.179.

http://www.sciencenews.org/

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


1

2

Concern

3

http://upload.wikimedia.org/wikipedia/commons/6/61/Lithobates_sylvaticus_%28wood_frog%29.jpg

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

Mortality by Level of Coagulopathy

0%

10%

20%

30%

40%

50%

60%

INR

The Ratio of Blood Products Transfused Affects Mortality in Patients

Receiving Massive Transfusions at a Combat Support Hospital

J Trauma 63: 805-813, 2007

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)

Reconstitution of “Whole Blood”Mou et al: NEJM 2004;351:1635

RCT; age


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


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


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

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

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

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

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

Donor Informed Consent

Figure 1: Must Elements on ICFs and PCFs

0%

5%

10%

15%

20%

25%

30%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% Must Elements

% C

on

sen

ts

ICF

PCF

Figure 2: Should be Elements on ICFs and PCFs

0%

10%

20%

30%

40%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% Should be Elements

% C

on

sen

ts

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

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”

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

AISD ABO-Incompatibility Stop Device

AISD

2+

+ , C

1+

+ , C

3+

+ , C

4+

+ , C

Titer: 4-8 Titer: 16-32 Titer: 32-128 Titer: 32-256

Compatible

AISD

Visual Digital

4+ Incompatible

Visual Digital

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

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

Documents

Thinking Outside the Frog - SEABB · 2013. 8. 18. · patients. DESIGN: Retrospective, observational, cohort study in a Medical Intensive Care Unit. PATIENTS: Consecutive patients