New Approaches to Preventing Transfusion

Reactions

Aaron Tobian, MD, PhDTransfusion Medicine

DivisionJohns Hopkins Hospital

Transfusions in United States

16 million units of whole blood

donated annually PlasmaPlasma

CryoprecipitateCryoprecipitate

PlateletsPlatelets

Red blood cellsRed blood cellsFrom: http://www.nsbri.org/HumanPhysSpace/focus3/fig2.jpg

Centrifuged blood…

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”

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

Incidence of Transfusion Reactions

Karafin AABB 2010

FIGURE. Percent of transfusions (N=73,766) resulting in an adverse reaction by blood product type.

How bad is it?(selected comments from an anonymous

survey)

“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….

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

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

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

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

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.

Acute Hemolytic Reaction

http://commons.wikimedia.org/wiki/File:Main_symptoms_of_acute_hemolytic_reaction.svg

Acute Hemolytic Reaction

Lab Findings• Positive DAT• Positive eluate with alloantibody on transfused RBCs

• Hemoglobinemia• Hemoglobinuria

• Increased LDH• Elevated indirect bilirubin

• Decreased haptoglobin

• RBC abnormalities• Schistocytes• Spherocytes

Tobian Transfusion 2010

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.

One of the most common reactions reported 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

Febrile Non-hemolytic Reaction (FNHTR)

Mechanism of FNHTR(Biological Response Modifiers – secreted

prior to transfusion)

BRMs increase during storage

Donor’s PlateletsWith leukocytes ( )

IL-1B

IL-6

TNF

FNHTR

Donor leukocytes produce cytokines

Plasma interacts with plastic bagIncreased C3a and C4a

Lipids prime and activate PMNs

C3

Mechanism of FNHTR(HLA, platelet, or granulocyte antibodies in recipients plasma interact with transfused

antigens, e.g., donor WBCs)Patient’s Antibody Donor’s Leukocytes ( )

IL-1B

IL-6

TNF

FEVER

Stimulates patient’s macrophage

Complementactivation

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 patient’s blood sample

Patient does not have other conditions to explain fever

Febrile Non-hemolytic Reaction (FNHTR)

Leukocyte Reduction Reduces FNHTRs

King Transfusion 2004

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

analyzed.

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.

Differential Diagnosis of Hypoxia During Transfusion

Allergic/Anaphylactic reaction

TACO (transfusion associated circulatory overload)

TRALI (transfusion related acute lung injury)

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

Individuals with TACO Have Positive Fluid Balance Prior

to Transfusion

0

5000

10000

15000

20000

25000

30000

35000

Pre-transfusionControl

Post-transfusionControl

Pre-transfusionTACO

Post-transfusionTACO

NT-proBNP (pg/mL)

Tobian Transfusion 2008

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

Transfusion Associated Circulatory Overload (TACO)

http://en.wikipedia.org/wiki/File:Pulmonary_oedema.jpg

Treatment Volume reduction with diuresis Supportive care

Prevention Transfuse slowly Plasma reduced products

Transfusion Associated Circulatory Overload (TACO)

Leading etiology of transfusion-related fatality in the United States. Frequency: 1:1000 to 1:4500 transfusions

Symptoms within 6 hours of transfusion. Respiratory distress (tachypnea, dyspnea) Fever Hypotension

Exclusion of other etiologies of acute lung injury or circulatory overload.

Transfusion Related Acute Lung Injury (TRALI)

TRALI Pathophysiology (Two Mechanisms)

Donor antibody hypothesis Reaction of donor’s human leukocyte antigens (HLA) or granulocyte specific antibodies against recipient’s leukocytes that then aggregate in lungs

Two-event hypothesis 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)

Bilateral white-outBaseline and 48 hours post transfusion

http://en.wikipedia.org/wiki/Transfusion_related_acute_lung_injury

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

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

Eder Transfusion 2010

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.

Allergic Transfusion Reactions (ATRs)

A spectrum of hypersensitivity reactions to transfused blood (particularly plasma component) Typically manifest <2 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

Classic Hypersensitivity Reaction

Allergen

IgE

Mast cell/Basophil

HistaminesLeukotrienesCytokinesChemokines

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

Acute Allergic Reactions

Can pre-medication with diphenhydramine prevent allergic

transfusion reactions?

No Effect of Diphenhydramine Premedication to Reduce ATRsStudy 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

What additional What additional methods could methods could

prevent allergic prevent allergic transfusion transfusion reactions?reactions?

Removing Plasma Reduces Allergic Reactions

Tobian Transfusion, In Press

(5.5%)

(1.7%) (0.7%)

(0.4%)(0.7%)

Hour Pre-Wash

Post-Wash

% Loss P Value

1 7630 4247 44 <.0001

8 3460 1294 62 <.03

18+ 2635 276 89.5 <.003

Washing Platelets Reduces CCI

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

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) 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

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

Allergic Hypersensitivity Febrile Non Hemolytic TRALI Transfusion Transmitted Infections ABO Mismatched Hemolysis

Additional methods to reduce transfusion reactions are needed.

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).

AABB Bulletin #10-06

Transfusion Reactions Reduced with PAS Platelets

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

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

Kerkhoffs Blood 2006

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)

Comparison of PAS Platelets vs. Platelets

Stored in Plasma

Kerkhoffs Br J Hematol 2010

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)

Bleeding after Receiving PAS

Platelets

PlasmaPAS 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 8Kerkhoffs Br J Hematol

2010

CCI and PAS Platelets

PlasmaPAS 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 4±3 5±3

* Off-protocol platelets were suspended in T-Sol Kerkhoffs Br J Hematol

2010

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

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.

Summary

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.

ConclusionsWhat is best for the current patients with transfusion reactions?