New Approaches to Preventing
Transfusion Reactions
Aaron Tobian, MD, PhD
Transfusion Medicine Division
Johns Hopkins Hospital
Transfusions in United States
16 million units of whole blood
donated annually

Plasma
Centrifuged blood…
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Cryoprecipitate
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Platelets
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Red blood cells
From: http://www.nsbri.org/HumanPhysSpace/focus3/fig2.jpg
Adverse Reactions Have Always
Accompanied Transfusions
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Ramirez (1919): Patient developed asthma to horse
dandruff within two weeks of receiving a blood
transfusion. Ramirez suggested transfer of
“anaphylactic bodies.”
Polaye and Lederer (1932): Evaluated 2500 reactions;
etiology due to ABO incompatibility, transmission of
diseases, and “allergic phenomena” in the recipients
Wiener (1940): Described febrile transfusion reactions
that were not due to ABO incompatibility or lack of
aseptic techniques; hypothesized that the reactions are
due to “extraneous factors”
National Hemovigilance Program
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The CDC and AABB in 2010 launched the
Hemovigilance Module of the National Healthcare
Safety Network.
Gives all U.S. hospitals the opportunity to
contribute data on adverse events associated with
blood transfusions.
Goal: improve patient safety by analyzing
transfusion reaction data and identifying effective
interventions.
http://www.cdc.gov/nhsn/about.html
Incidence of Transfusion Reactions
RBCs
0.18%
No Reaction
99.47%
Apheresis
platelets
0.32 %
Plasma 0.03 %
FIGURE. Percent of transfusions (N=73,766) resulting in an adverse reaction by
blood product type.
Karafin AABB 2010
How bad is it?
(selected comments from an anonymous survey)
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“Allergic transfusion reactions are usually a huge
waste of my time.”
“There’s nothing like getting called for 1 hive at
3AM.”
“I believe my negative attitude largely stems
from…”
A common frustration is that there is nothing
that can be done for common transfusion
reactions.
Savage 2011
On the other hand….
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People getting transfusions are already sick, and
additional morbidity is a burden
Result in wasted blood products
Transfusion reaction evaluations are expensive
Overutilization and expense of pre-medications
to prevent transfusion reactions
Some physicians care…
Objectives
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Be able to accurately diagnose transfusion
reactions.
Be able to advise clinicians on how to
appropriately treat and prevent transfusion
reactions.
Understand how your laboratory can manipulate
blood products to reduce transfusion reactions.
Recognize new additive solutions and products
that are being introduced to reduce transfusion
reactions.
Transfusion Reaction
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60 y.o. female with a history of MDS and follicular
lymphoma s/p autologous transplant
Three mild allergic transfusion reactions over the past
three years
Admitted for neutropenic fever, but afebrile at the time
of transfusion of 2 units of apheresis platelets
Pt received 650 mg Tylenol and 25 mg Benadryl prior
to transfusion
15 minutes into the second platelet unit pt notes chills
Temperature increased from 37.4 oC to 38.6 oC
Suspected Reaction Workup
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Assume all reactions are hemolytic
STOP the transfusion!
Required parts of work-up
Paperwork and bag check for clerical error
 Check for hemoglobinemia and hemoglobinuria
 DAT
 Repeat ABO testing for RBC transfusions

Differential Diagnosis of Febrile
Reaction
Acute hemolytic transfusion reaction
 Febrile nonhemolytic transfusion
reaction
 Bacterial contamination
 TRALI
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Acute Hemolytic Reaction
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Immunologic destruction of transfused RBCs
due to preformed ABO antibodies in recipient
against donor red cell antigens.
Most often caused by a clerical error (e.g.,
incorrectly labeled sample).
The symptoms result from intravascular
hemolysis due to complement activation after
the preformed antibodies bind to the donor
red cells.
Acute Hemolytic Reaction
http://commons.wikimedia.org/wiki/File:Main_symptoms_of_acute_hemolytic_reaction.svg
Acute Hemolytic Reaction
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•
•
•
•
Lab Findings
Positive DAT
Positive eluate with alloantibody
on transfused RBCs
Hemoglobinemia
Hemoglobinuria
Tobian Transfusion 2010
•
•
•
•
Increased LDH
Elevated indirect bilirubin
Decreased haptoglobin
RBC abnormalities
• Schistocytes
• Spherocytes
Acute Hemolytic Reaction
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Treatment
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Stop transfusion
Support volume and pressure to maintain urine output
Watch for DIC
Report event
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Sentinel event and requires reporting to JCAHO.
Suspicion of death, FDA requires notification within 24
hours by phone and a written report within 7 days.
Febrile Non-hemolytic Reaction
(FNHTR)
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One of the most common reactions reported
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Up to 1% of transfusions of RBCs and 5% of
apheresis platelets.
Temperature elevation > 1 ºC
Must be distinguished from hemolytic and
septic reactions
Only 15% of pts with one febrile reaction
develop fever with subsequent transfusions
Mechanism of FNHTR
(Biological Response Modifiers – secreted prior to transfusion)
Donor’s Platelets
With leukocytes ( )
IL-1B
IL-6
TNF
Donor leukocytes produce cytokines
BRMs increase during storage
FNHTR
Plasma interacts with plastic bag
Increased C3a and C4a
Lipids prime and activate PMNs
Mechanism of FNHTR
(HLA, platelet, or granulocyte antibodies in recipients plasma
interact with transfused antigens, e.g., donor WBCs)
Donor’s Leukocytes ( )
Patient’s Antibody
FEVER
IL-1B
IL-6
TNF
Stimulates patient’s macrophage
C3
Complement
activation
Febrile Non-hemolytic Reaction
(FNHTR)
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Signs and Symptoms
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Fever ≥38oC and ≥1oC increase from pre-transfusion
Chills and Rigors
Headache, nausea, vomiting
Less frequently dyspnea
Negative culture of components and patient’s blood
sample
Patient does not have other conditions to explain fever
Leukocyte Reduction Reduces
FNHTRs
Between 1994 and 2001, all transfusion reactions associated with
RBC transfusion were retrospectively analyzed.
King Transfusion 2004
Transfusion Reaction
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65 y.o. female with AML s/p allogeneic stem cell
transplant now with relapse
No previous history of transfusion reactions
Afebrile at the time of transfusion of 2 units of
apheresis platelets
During second unit of platelets, patient became hypoxic
and temperature increased from 36.8 oC to 38.2 oC.
Patient is subsequently intubated and requires
supportive care.
Differential Diagnosis of Hypoxia
During Transfusion

Allergic/Anaphylactic reaction
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TACO (transfusion associated circulatory
overload)
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TRALI (transfusion related acute lung
injury)
Transfusion Associated Circulatory
Overload (TACO)
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Occurs when excess blood volume overwhelms
cardiovascular system and produces pulmonary edema.
Relatively common complication of transfusion with a
reported incidence ranging from 1% to up to 8% of
patients.
Patients at risk
 Elderly
 Small patients including kids
 Patients with impaired cardiac, renal, pulmonary
function
 Oncology patients
Individuals with TACO Have Positive
Fluid Balance Prior to Transfusion
35000
NT-proBNP (pg/mL)
30000
25000
20000
15000
10000
5000
0
Pre-transfusion Post-transfusion
Control
Control
Pre-transfusion Post-transfusion
TACO
TACO
Tobian Transfusion 2008
Transfusion Associated Circulatory
Overload (TACO)

Signs and Symptoms
Acute respiratory distress
(dyspnea, tachypnea)
 Elevated systolic blood
pressure
 Jugular venous distension
 Tachycardia
 Bilateral pulmonary edema on
CXR
 Symptoms responsive to
diuretics

http://en.wikipedia.org/wiki/File:Pulmonary_oedema.jpg
Transfusion Associated Circulatory
Overload (TACO)
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Treatment
Volume reduction with diuresis
 Supportive care
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Prevention
Transfuse slowly
 Plasma reduced products
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Transfusion Related Acute Lung
Injury (TRALI)
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Leading etiology of transfusion-related fatality in
the United States.
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Frequency: 1:1000 to 1:4500 transfusions
Symptoms within 6 hours of transfusion.
Respiratory distress (tachypnea, dyspnea)
 Fever
 Hypotension
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Exclusion of other etiologies of acute lung injury
or circulatory overload.
TRALI Pathophysiology
(Two Mechanisms)
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Donor antibody hypothesis
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Two-event hypothesis
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Reaction of donor’s human leukocyte antigens (HLA) or
granulocyte specific antibodies against recipient’s
leukocytes that then aggregate in lungs
First, something stimulates recipient’s neutrophils to
aggregate in lungs.
Second, transfusion of stored blood products accumulate
lipids that activate neutrophils.
Either hypothesis leads to complement activation,
capillary damage and subsequent pulmonary edema.
Transfusion Related Acute Lung
Injury (TRALI)
Baseline and 48 hours
post transfusion
Bilateral white-out
http://en.wikipedia.org/wiki/Transfusion_related_acute_lung_injury
TRALI Management
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Treatment: aggressive respiratory support
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Immediately report suspected transfusion reactions
to the blood collection facility
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Quarantine other components associated with donor
Evaluate donor for HLA antibodies
Confirmed donor HLA antibodies do not alter
management of this reaction
TRALI and HLA Antibodies
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Antibodies to human leukocyte antigens (HLA) due to
sensitization (e.g., transfusion, transplantation, pregnancy).
HLA antibody prevalence among blood donors:
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Men: 1.7%
Women: 17.3%
Women with at least four pregnancies: 32.2%
In 2006, AABB advised blood centers to reduce plasma
components from individuals with potential HLA
antibodies.
The Red Cross began distributing male plasma and
diverting female plasma for pharmaceutical manufacturing
Triulzi Transfusion 2009 and Eder Transfusion 2010
Eder Transfusion 2010
Transfusion Reaction
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38 y.o. female with leiomyoma s/p myomectomy x 2
and hypothyroidism
Patient had TAH-BSO and small bowel resection and
transfused one unit of apheresis platelets
No previous transfusion reactions, but patient received
25 mg Benadryl and 650 mg Tylenol prior to the
transfusion.
One hour into transfusion, patient developed hives on
neck and trunk.
No changes in temperature, blood pressure or difficulty
breathing.
Allergic Transfusion Reactions (ATRs)
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A spectrum of hypersensitivity reactions to
transfused blood (particularly plasma component)
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Typically manifest <2 hours of Tx
Urticaria, pruritus, flushing
Angioedema, laryngeal edema, bronchospasm
Anaphylaxis
Most common transfusion reaction, particularly with
products containing plasma
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1-3% of all transfusions
3% of transfusion-related mortalities
Classic Hypersensitivity Reaction
Allergen
IgE
Mast cell/
Basophil
Histamines
Leukotrienes
Cytokines
Chemokines
Acute Allergic Reactions
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Signs and Symptoms
•
•
Itching
Hives, urticaria
Flushing
Tachycardia
Laryngeal stridor
Dyspnea
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Treatment
•
Antihistamines
Steroids
Epinephrine
Washed RBC (anti-IgA)
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Can pre-medication with
diphenhydramine
prevent allergic
transfusion reactions?
No Effect of Diphenhydramine
Premedication to Reduce ATRs
Study
Design
Product
Patients
Transfusions
Result
Wang
2002
Randomized,
Placebo
controlled
PLT
51
98
NS
Kennedy
2008
Randomized,
Placebo
controlled
PLT, RBC
323
323
NS
Patterson
2000
Prospective
PLT
716
3,472
NS
Sanders
2005
Retrospective
PLT, RBC
385
7,900
NS
SzeleiStevens
2006
Retrospective
PLT, RBC,
FFP
31,665
301,210
NS
Tobian Transfusion 2007
What additional methods
could prevent allergic
transfusion reactions?
Removing Plasma Reduces
Allergic Reactions
(5.5%)
(1.7%)
(0.7%)
(0.7%)
(0.4%)
Tobian Transfusion, In Press
Washing Platelets Reduces CCI
Hour
PostWash
4247
% Loss
P Value
1
PreWash
7630
44
<.0001
8
3460
1294
62
<.03
18+
2635
276
89.5
<.003
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40 patients at JHH were evaluated after being placed on a washed
protocol.
CCIs were averaged for a two day period pre- and post- transfusion
Tanz ASH 2001
Washed platelets
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Patients receiving washed platelets subsequently
received increased platelet equivalent units (8.1 vs. 10.5,
p<0.0005)
Increased frequency of platelet transfusions were
required.

No. of days between transfusions:
 1.47 days vs. 0.89 days (p<0.005)
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However, there was still an overall decrease in bleeding
score indicating no change in in vivo efficacy of washed
platelets
Tanz ASH 2001
Workload Implications
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Greater than 20,000 platelet transfusion annually
at Johns Hopkins
70% for oncology and hematologic malignancies
1600 (7.95%) require concentration and/or
resuspension
400 (1.99%) require platelet washing
Platelet manipulations are costly, reduce shelf
life, and reduce in vivo effectiveness
Transfusion Reactions Associated
with Plasma
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Allergic Hypersensitivity
Febrile Non Hemolytic
TRALI
Transfusion Transmitted Infections
ABO Mismatched Hemolysis
Additional methods to reduce
transfusion reactions are needed.
Plasma Additive Solution (PAS)
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RBC crystalloid additive solution has extended shelf life and
viability of RBCs.
PAS replaces ~65% of the plasma used when storing platelets.
Long history of use in Europe to increase plasma supplies for
transfusion and fractionation.
There are numerous different compositions of platelet additive
solutions (variable glucose, acetate, MgCl2, NaCl)
FDA approved the first platelet additive solution on July 30,
2010
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(PAS-C; InterSol, Fenwal/Baxter, Lake Zurich, IL).
AABB Bulletin #10-06
Transfusion Reactions Reduced with
PAS Platelets
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Multicenter, randomized trial of 84 patients in
each arm who received ABO matched products
# of Transfusions
# Reactions (%)
# Patients
# Patients w/Reactions (%)
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Plasma
PAS II
p
354
411
-
17 (5.5)
9 (2.4)
0.04
84
84
-
13 (15.4)
8 (9.5)
0.35
Azuma et al., showed a 42% reduction in allergic TR and FNHTRs
among patients who received PAS platelets (Transfusion 2009)
Wildt-Eggen showed a 66% reduction in transfusion reactions
(Transfusion 2000)
Kerkhoffs Blood 2006
Comparison of PAS Platelets vs.
Platelets Stored in Plasma
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Prospective, open-label, randomized
Hematology/oncology patients
Buffy coat (pools of 5); ABO-matched
Three arms
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Control (platelets in plasma)
PAS III (65/35)
PAS III plus PR (Intercept)
Kerkhoffs Br J Hematol 2010
Bleeding after Receiving PAS
Platelets
Plasma
PAS III (InterSol)
Patients
99
94
Transfusions
357
381
19 (19)
14 (15)
19
16
Patients with Transfusion Rxns (%)
11 (11)
8(9)
Number of Transfusion Reactions
13
8
Patients with Any Grade of Bleeding (%)
Number of Bleeding Episodes
Kerkhoffs Br J Hematol 2010
CCI and PAS Platelets
Plasma
PAS III (InterSol)
Patients
99
94
Transfusions
357
381
Transfusions on protocol (%)*
82
73
Platelet storage age (days)
4
3.8
Platelet Product Content (x 1011)
3.9
3.6
1-hr CCI
17.1
15.3 (-9%)
24-hr CCI
12.8
11.6 (-7%)
81
77
4±3
5±3
Time to next transfusion (hr)
Red cell transfusions
* Off-protocol platelets were suspended in T-Sol
Kerkhoffs Br J Hematol 2010
Transfusion Service Questions
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PAS platelets have medical advantages for oncology
users but potential disadvantages for surgical patients.
Usage of FFP may increase.
Will neonatologists accept PAS in platelets?
Will ABO matching requirements for plasma in
platelets be reduced?
What is the in vivo survival of PAS platelets?
Will platelet costs go up, and if so, will they be balanced
by workload reductions at the transfusion service?
How will PAS platelets be implemented into the blood
supply chain?
Ness 2011
Summary
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Although the incidence of transfusion reactions
nationally is unknown, they are common.
The majority of transfusion reactions are due to
the plasma component.
Several methods are currently available to reduce
transfusion reactions and other methods are
being investigated.
Conclusions
What is best for the current patients
with transfusion reactions?

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Pre-storage leukocyte reduction substantially
decreases febrile non-hemolytic reactions.
Distribution of male only plasma reduces TRALI.
If pre-medications are used, clinicians should be
aware of toxicity and that they are not necessarily
effective.
Product manipulation (e.g., concentrating, washing)
is effective and should be employed for more
severe reactions.