New Approaches to Preventing Transfusion Reactions

1
New Approaches to Preventing Transfusion Reactions

• Aaron Tobian, MD, PhD
• Transfusion Medicine Division
• Johns Hopkins Hospital

2
Transfusions in United States

• 16 million units of whole blood
• donated annually
• Plasma
• Cryoprecipitate
• Platelets
• Red blood cells

Centrifuged blood
From http//www.nsbri.org/HumanPhysSpace/focus3/f
ig2.jpg
3
Adverse Reactions Have Always Accompanied
Transfusions

• 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

4
National Hemovigilance Program

• 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

5
Incidence of Transfusion Reactions
Karafin AABB 2010
6
How bad is it?(selected comments from an
anonymous survey)

• Allergic transfusion reactions are usually a
  huge waste of my time.
• Theres 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
7
On the other hand.

• 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

8
Objectives

• 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.

9
Transfusion Reaction

• 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

10
Suspected Reaction Workup

• 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

11
Differential Diagnosis of Febrile Reaction

• Acute hemolytic transfusion reaction
• Febrile nonhemolytic transfusion reaction
• Bacterial contamination
• TRALI

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Acute Hemolytic Reaction

• 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.

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Acute Hemolytic Reaction
http//commons.wikimedia.org/wiki/FileMain_sympto
ms_of_acute_hemolytic_reaction.svg
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Acute Hemolytic Reaction

• Lab Findings

• Increased LDH
• Elevated indirect bilirubin
• Decreased haptoglobin
• RBC abnormalities
• Schistocytes
• Spherocytes

• Positive DAT
• Positive eluate with alloantibody on transfused
  RBCs
• Hemoglobinemia
• Hemoglobinuria

Tobian Transfusion 2010
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Acute Hemolytic Reaction

• Treatment
• Stop transfusion
• Support volume and pressure to maintain urine
  output
• Watch for DIC
• Report event
• 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.

16
Febrile Non-hemolytic Reaction (FNHTR)

• One of the most common reactions reported
• Up to 1 of transfusions of RBCs and 5 of
  apheresis platelets.
• Temperature elevation gt 1 ºC
• Must be distinguished from hemolytic and septic
  reactions
• Only 15 of pts with one febrile reaction develop
  fever with subsequent transfusions

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Mechanism of FNHTR(Biological Response Modifiers
secreted prior to transfusion)
Donors Platelets With leukocytes ( )
IL-1B
IL-6
TNF
Donor leukocytes produce cytokines
BRMs increase during storage
Plasma interacts with plastic bag Increased C3a
and C4a
Lipids prime and activate PMNs
FNHTR
18
Mechanism of FNHTR(HLA, platelet, or granulocyte
antibodies in recipients plasma interact with
transfused antigens, e.g., donor WBCs)
Donors Leukocytes ( )
Patients Antibody
Complement activation
FEVER
C3
IL-1B
IL-6
TNF
Stimulates patients macrophage
19
Febrile Non-hemolytic Reaction (FNHTR)

• Signs and Symptoms
• Fever 38oC and 1oC increase from
  pre-transfusion
• Chills and Rigors
• Headache, nausea, vomiting
• Less frequently dyspnea
• Negative culture of components and patients
  blood sample
• Patient does not have other conditions to explain
  fever

20
Leukocyte Reduction Reduces FNHTRs

• Between 1994 and 2001, all transfusion reactions
  associated with RBC transfusion were
  retrospectively analyzed.

King Transfusion 2004
21
Transfusion Reaction

• 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.

22
Differential Diagnosis of Hypoxia During
Transfusion

• Allergic/Anaphylactic reaction
• TACO (transfusion associated circulatory
  overload)
• TRALI (transfusion related acute lung injury)

23
Transfusion Associated Circulatory Overload (TACO)

• 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

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Individuals with TACO Have Positive Fluid Balance
Prior to Transfusion
Tobian Transfusion 2008
25
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/FilePulmonary_oedema
.jpg
26
Transfusion Associated Circulatory Overload (TACO)

• Treatment
• Volume reduction with diuresis
• Supportive care
• Prevention
• Transfuse slowly
• Plasma reduced products

27
Transfusion Related Acute Lung Injury (TRALI)

• Leading etiology of transfusion-related fatality
  in the United States.
• Frequency 11000 to 14500 transfusions
• Symptoms within 6 hours of transfusion.
• Respiratory distress (tachypnea, dyspnea)
• Fever
• Hypotension
• Exclusion of other etiologies of acute lung
  injury or circulatory overload.

28
TRALI Pathophysiology (Two Mechanisms)

• Donor antibody hypothesis
• Reaction of donors human leukocyte antigens
  (HLA) or granulocyte specific antibodies against
  recipients leukocytes that then aggregate in
  lungs
• Two-event hypothesis
• First, something stimulates recipients
  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.

29
Transfusion Related Acute Lung Injury (TRALI)

• Bilateral white-out

• Baseline and 48 hours post transfusion

http//en.wikipedia.org/wiki/Transfusion_related_a
cute_lung_injury
30
TRALI Management

• Treatment aggressive respiratory support
• Immediately report suspected transfusion
  reactions to the blood collection facility
• Quarantine other components associated with donor
• Evaluate donor for HLA antibodies
• Confirmed donor HLA antibodies do not alter
  management of this reaction

31
TRALI and HLA Antibodies

• Antibodies to human leukocyte antigens (HLA) due
  to sensitization (e.g., transfusion,
  transplantation, pregnancy).
• HLA antibody prevalence among blood donors
• 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
32
Eder Transfusion 2010
33
Transfusion Reaction

• 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.

34
Allergic Transfusion Reactions (ATRs)

• A spectrum of hypersensitivity reactions to
  transfused blood (particularly plasma component)
• Typically manifest lt2 hours of Tx
• Urticaria, pruritus, flushing
• Angioedema, laryngeal edema, bronchospasm
• Anaphylaxis
• Most common transfusion reaction, particularly
  with products containing plasma
• 1-3 of all transfusions
• 3 of transfusion-related mortalities

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Classic Hypersensitivity Reaction
Allergen IgE Mast cell/ Basophil Histamines Leu
kotrienes Cytokines Chemokines
36
Acute Allergic Reactions

• Signs and Symptoms
• Itching
• Hives, urticaria
• Flushing
• Tachycardia
• Laryngeal stridor
• Dyspnea
• Treatment
• Antihistamines
• Steroids
• Epinephrine
• Washed RBC (anti-IgA)

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Can pre-medication with diphenhydramine prevent
allergic transfusion reactions?
38
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
Szelei-Stevens 2006 Retrospective PLT, RBC, FFP 31,665 301,210 NS
Tobian Transfusion 2007
39
What additional methods could prevent allergic
transfusion reactions?
40
Removing Plasma Reduces Allergic Reactions

(5.5)
(1.7)
(0.7)
(0.4)
(0.7)
41
Washing Platelets Reduces CCI
Hour Pre-Wash Post-Wash Loss P Value
1 7630 4247 44 lt.0001
8 3460 1294 62 lt.03
18 2635 276 89.5 lt.003

• 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
42
Washed platelets

• Patients receiving washed platelets subsequently
  received increased platelet equivalent units (8.1
  vs. 10.5, plt0.0005)
• Increased frequency of platelet transfusions were
  required.
• No. of days between transfusions
• 1.47 days vs. 0.89 days (plt0.005)
• However, there was still an overall decrease in
  bleeding score indicating no change in in vivo
  efficacy of washed platelets

Tanz ASH 2001
43
Workload Implications

• 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

44
Transfusion Reactions Associated with Plasma

• Allergic Hypersensitivity
• Febrile Non Hemolytic
• TRALI
• Transfusion Transmitted Infections
• ABO Mismatched Hemolysis
• Additional methods to reduce
• transfusion reactions are needed.

45
Plasma Additive Solution (PAS)

• 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
• (PAS-C InterSol, Fenwal/Baxter, Lake Zurich,
  IL).

46
Transfusion Reactions Reduced with PAS Platelets

• Multicenter, randomized trial of 84 patients in
  each arm who received ABO matched products

Plasma PAS II p
of Transfusions 354 411 -
Reactions () 17 (5.5) 9 (2.4) 0.04
Patients 84 84 -
Patients w/Reactions () 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)

47
Comparison of PAS Platelets vs. Platelets Stored
in Plasma

• Prospective, open-label, randomized
• Hematology/oncology patients
• Buffy coat (pools of 5) ABO-matched
• Three arms
• Control (platelets in plasma)
• PAS III (65/35)
• PAS III plus PR (Intercept)

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Bleeding after Receiving PAS Platelets
Plasma PAS III (InterSol)
Patients 99 94
Transfusions 357 381
Patients with Any Grade of Bleeding () 19 (19) 14 (15)
Number of Bleeding Episodes 19 16
Patients with Transfusion Rxns () 11 (11) 8(9)
Number of Transfusion Reactions 13 8
49
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)
Time to next transfusion (hr) 81 77
Red cell transfusions 43 53
Off-protocol platelets were suspended in T-Sol
50
Transfusion Service Questions

• 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
51
Summary

• 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.

52
ConclusionsWhat is best for the current patients
with transfusion reactions?

• 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.