ADVERSE TRANSFUSION EVENTS

HEMATOLOGY ROUNDSAugust 23, 2012

D.K. Towns, MD, FRCPC (Anesthesia)Medical DirectorCanadian Blood ServicesCalgary, AB

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OVERVIEW OF THE CANADIAN BLOOD SYSTEM

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The blood system in Canada is complexRegulator

Health Canada

Blood Suppliers

Canadian Blood Services (CBS)

Hema-Quebec (H-Q)

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Government funding for CBS is approved by a provincialcommittee.

The CBS Head Office is located in Ottawa and has overallresponsibility for:

a) developing policies and standard operating procedures

b) monitoring collection facilities and regional testing laboratories

c) developing contracts with plasma fractionators to fractionate CBS plasma and obtain fractionation products

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Regional CBS staff include administrative, medical, nursing, technical, and recruitment personnel who are responsible for:

a) recruiting, assessing, and monitoring donors during blood or apheresis collections

b) processing, storing, distributing, and transporting blood components and products to area hospitals

c) performing laboratory testing or arrange for centralized laboratory testing

d) conducting quality control activities

e) maintaining lookback/traceback programs

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Partners in the Health Care system include:

1) Hospital Transfusion Laboratories

2) Clinical staff in hospitals

3) The blood recipients’ physician who orders blood transfusion

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* Source: Courtesy of Canadian Blood Services, Clinical Guide to Transfusion, pg 13.

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A few "facts”• Canadian Blood Services has 43 permanent locations

and services 732 health facilities

• We have 1.74 million donors

• Only 3.7% of eligible Canadians are blood donors (excluding Quebec)

• 21% of donors are aged 17-24

• 79% of donors are aged 25+

• 49% male/51%female

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A few more "facts”

• Last year we collected:– 910,220 units of whole blood– 54, 432 units of apheresis plasma– 54,432 units of apheresis platelets– 963 units of autologous blood– 189 units of blood for directed donation

• Each unit of whole blood can be made into up to 3 components:– red blood cells– plasma– platelets or cryoprecipitate

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Adverse Event

"An undesirable and unintended response to the administration of whole blood or a blood component that is considered to be definitely, probably, or possibly related to the administration of whole blood or blood component."

(also referred to as Adverse Transfusion Reaction, or Adverse Transfusion Event)

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Serious Adverse Event• requires in-patient hospitalization or prolongation of

hospitalization directly attributable to the event

• results in persistent or significant disability or incapacity

• necessitates medical or surgical intervention to preclude permanent damage to, or impairment of body function

• is life-threatening

• results in death

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Unexpected Adverse Event

An adverse event that is not identified in nature, severity, or frequency among the currently known adverse effects associated with the administration of blood, blood components, or blood products (plasma derivatives).

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Canadian Blood Services requires that hospitals report adverse transfusion reactions to us

We, in turn, report these reactions to Health Canada

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Why?• May result in product recall.

• May result in donor notification and/or investigation and/or deferral.

• May result in recipient notification.

• Also required for purposes of tracking and trending (?something new; ?an unexpected change in frequency)

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Timelines

Serious Adverse Event resulting in Fatality:• report immediately to MD and QAM• report immediately to Director, Regulatory Affairs

• report as soon as possible after discovery of event to MD and QAM

• report as soon as possible but no later than eight working days from the discovery of the event to Director, Regulatory Affairs

Other Serious Adverse Event (non-fatal) or Unexpected Adverse Event

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Canadian Blood Services’ Medical Director is responsible for assessing the information:• description of events preceding and following the reaction

including date, time, diagnosis, drug history, clinical symptoms, and sequelae

• identify transfused components requiring investigation within appropriate timeframes including donation numbers and dates of collection

• identify and consult with the reporting facility (if required) the feasibility of initiating additional patient/product testing

• determine ATE classification

• determine requirement for recall of companion components and/or recall of previous donations, including final disposition of recalled components

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Canadian Blood Services’ Medical Director is responsible for assessing the information (cont’d):

• determine requirement for donor deferral/notification

• determine requirement for surveillance event initiation and addition of tests pending on next donation

• review donor record(s) in PROGESA to determine if any associated donor(s) were ever associated with a previous AR type of surveillance event

• determine additional comments/actions required

• defer donors if required

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Clinical diagnosis• When any unexpected or untoward sign or

symptom occurs during or shortly after the transfusion of a blood component, a transfusion reaction must be considered as the precipitating event until proven otherwise.

• Only a high index of suspicion will allow a transfusion reaction to be diagnosed.

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Immediate Adverse Events Associated with Transfusion

• Acute hemolytic transfusion reaction• Febrile non-hemolytic transfusion

reaction• Allergic Reactions

– urticarial– anaphylactic

• Transfusion-associated circulatory overload (TACO)

• Transfusion-associated dyspnea (TAD)

• Transfusion-related acute lung injury (TRALI)

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• Septic transfusion reaction (bacterial contamination)

• Hypotensive reactions– ACE inhibitors

• Non-immune red cell hemolysis• Metabolic disturbances

– hypothermia– hyperkalemia– acidosis

Risk of Complication

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REACTION RATE

Acute hemolytic transfusion reaction 1:25,000

Febrile non-hemolytic transfusion reaction 1:10 (platelets)

Allergic reaction: Anaphylactic 1:40,000

Allergic reaction: Minor 1:100

TRALI 1:5,000

TACO 1:700

Delayed Adverse Events Associated with Transfusion

• Delayed hemolytic transfusion reaction• Alloimmunization

– Red cell antigens– HLA– Leucocytes– Platelets

• Graft versus host disease (TA-GVHD)• Post-transfusion purpura (PTP)• Hemosiderosis• Viral and parasitic infections• Transfusion-related immunomodulation (TRIM)

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Signs and Symptoms of Transfusion Reactions

• fever/chills/rigors• pain• dyspnea/

respiratory distress• bleeding• hypotension• hypertension• headache

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• nausea and vomiting

• rash/hives• angioedema• flank pain• anaphylaxis• cyanosis• bronchospasm

• tachycardia• abdominal

cramps• diarrhea• cough• red eye• anxiety• jaundice• hematuria

Often difficult because:

• there is more than one predominant presenting symptom

• more than one reaction going on• atypical presentation

• underlying comorbidities unrelated to transfusion

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Shortness of Breath

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Differential Diagnosis of transfusion reaction with

shortness of breath:• TRALI• TACO• TAD• Anaphylaxis• AHTR• Bacterial contamination• Other etiology (unrelated to transfusion)

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TRALI

• Acute onset (within 6 hours of transfusion)• Hypoxemia• Bilateral infiltrates on CXRay• No evidence of circulatory overload• No pre-existing acute lung injury or other risk factors for ALI

May also have– hypotension– fever– transient leucopenia

Minimal findings on chest auscultation

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TRALI continued

TTISS (2004-2005) - 2nd highest cause of transfusion-related morbidity and mortality

Treatment: ventilation support

80% of patients show clinical improvement within 48-96 hours

5 - 10% fatality

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TACO• Acute pulmonary edema secondary to congestive heart failure precipitated by

transfusion of a blood volume greater than what the recipients circulatory system can tolerate

(** do not need a "sick heart" to suffer iatrogenic CHF**)

• Hypertension• Tachycardia• Positive fluid balance

Likely the most under-recognized and potentially serious transfusion complication

Risk factors:– too much blood transfused too rapidly– age <3 or > 60 years– diminished cardiac reserve– chronic (volume-compensated) anemia

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TACO continuedPrevention• transfuse only when indicated• recognize patients at risk• if at-risk, transfuse slowly• consider diuretics• watch fluid balance - invasive monitoring if at-risk patient or high-risk

transfusion (example: massive transfusion)

Treatment• stop transfusion• position patient in upright position• supplementary oxygen• diuretics• cardiac and respiratory support as required

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Transfusion Associated Dyspnea (TAD)

European Haemovigilence Network introduced the term to allow for classification of respiratory distress temporally associated with transfusion which could not be assigned

to known pulmonary reactions

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Immediate management of a transfusion reaction associated with shortness of breath:

• Stop the transfusion immediately• Notify hospital blood bank of transfusion

reaction• Maintain IV access • Monitor patient’s vital signs• Recheck patient ID and blood product

label• Chest X-ray

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Fever

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Differential diagnosis of fever associated with a transfusion reaction:

• Acute Hemolytic transfusion reaction• Febrile non-hemolytic transfusion reaction• Bacterial sepsis or contamination• TRALI• Etiology unrelated to transfusion

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AHTRAccelerated clearance of red cells in a transfusion recipient due to immunologic incompatibility between the blood donor and the recipient

Antigen-positive red cells are transfused to a recipient who has incompatible allo-antibodies

Results in intravascular hemolysis

Generally within the top 3 causes of transfusion-related mortality

Often due to the administration of ABO incompatible blood– cross-match error– wrong identification of blood specimen– blood administered to wrong patient

May rarely be due to recipient allo-antibodies to other red cell antigens

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AHTR continuedAcute onset : often within first 15 minute of starting transfusion (as little as 20-30 ml)

Initial presentation: fever, chills, anxiety, nausea, vomiting, pain (flank, abdomen), dyspnea, hypotension, brown urine, bleeding

Complications: renal failure, DIC, death

Treatment:– stop transfusion immediately– begin infusion with normal saline– alert blood bank, c heck for clerical error, sent entire transfusion set-up

for testing

Supportive care: monitor vital signs, maintain BP and urine output, monitor for hyperkalemia, treat any resulting coagulopathy

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Febrile Non-hemolytic Transfusion Reaction

Common adverse event– 1 in 10 transfusions of pooled random donor platelets– 1 in 3000 units of RBCs

Frequency varies with:– type of blood product– age of blood product– WBC content of blood product– recipient characteristics– ? pre-medication– variability in recording of symptoms

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FNHTR - continuedEtiology:• reactions mediated by antibodies (recipient alloantibody reactive to antigens

on WBCs in component)• reactions mediated by biologic response molecules

Clinical Presentation:• Fever (>1°C rise) during or soon after transfusion (5 - 10% present 1-2

hours after transfusion)• Chills and rigors• Nausea and vomiting

Treatment:• Stop the transfusion and assess patient• Rule out other more serious causes (AHTR, bacterial contamination)• Tylenol +/- Demerol• continue transfusion cautiously

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Bacterial ContaminationComponent Bacterial

ContaminationSymptomatic

Septic Reactions

Fatal Bacterial Sepsis

Platelet Pool 1 in 1,000 1 in 10,000 1 in 40,000

RBC (1 unit) 1 in 50,000 1 in 100,000 1 in 500,000

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This is the most frequent infectious risk associated with transfusion

Accounts for about 11% of deaths due to blood components

Occurs most frequently with platelets

(Stored at 20 - 24° C -- excellent growth medium for bacteria)

EtiologyBlood components may be contaminated by:

• unrecognized bacteremia in the donor (ex Yersinia enterocolitica)

• skin organisms from the donor (ex staphylococcus epidermidis)– difficult to totally decontaminate surface of skin– small core of skin may enter phlebotomy needle at

time of donation

• contamination from the environment or handling of the product (ex Serratia marcescens)– leaky seals, damaged tubing, etc.

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Commonly Implicated Bacteria

Gram-positive:

• Staphylococcus aureus

• Staphylococcus epidermidis

• Bacillus cereus

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Gram-negative:

• Klebsiella pneumoniae

• Serratia marcescens

• Pseudomonas species

• Yersinia enterocolitica

Clinical PresentationDepends on bacterial load and species of bacteria

• rigors, fever, chills• hypotension• tachycardia• nausea and vomiting• dyspnea• DIC

Usually occurs during transfusion of the implicated product

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Management and Investigation• Stop the transfusion immediately

• Notify the hospital blood bank

• Return residual product and tubing to blood bank

• Collect peripheral blood samples for culture

• Aggressive supportive therapy

• Broad spectrum therapy

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Differential Diagnosis of a Transfusion Reaction with Fever

Febrile non-hemolytic transfusion reaction– usually temp < 39° C– during transfusion; usually towards the end

Bacterial contamination– hypotension, shock, DIC– usually within first 15 minutes of a transfusion

AHTR• flank pain, DIC, hypotension• usually within first 15 minutes of transfusion

TRALI– SOB, hypoxemia, hypotension– within 6 hours of transfusion (usually during)

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Allergic ReactionUsually due to soluble allergenic substances in the plasma of donated blood

– react with pre-existing IgE antibodies in the recipient– causes release of histamine from mast cells and basophils

Possible mechanisms– pre-existing anti-IgA in IgA-deficient patient– pre-existing antibodies to other serum protein that patient is

lacking (IgG, Albumin, haptoglobin, alpha1-antitrypsin, transferrin, C3, C4, etc.)

– passive transfer of IgE antibodies– transfusion of allergen to which patient is sensitized to (drugs,

chemicals)

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Incidence:• mild 1:33 – 1:100 (1-3%)• severe 1:20,000 - 1:47000

Timing• during transfusion, or up to 3 hours from

the start of presentation

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Signs and Symptoms• hives• pruritis• angioedema• cough and wheezing• nausea and vomiting• abdominal pain• diarrhea• hypotension• cyanosis• tachycardia

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Signs & Symptoms of Serious Reactions

• hypotension/shock• shortness of breath, hypoxemia• cough• tachycardia• nausea and vomiting• generalized flushing or aniety• widespread rash (>2/3 of body)

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ManagementNon-serious:• antihistamine

- diphenhydramine 25-50 mg PO/IV• continue transfusion with caution• stop transfusion if any "serious" symptoms

Serious:• stop transfusion and do not restart• notify hospital transfusion service• epinephrine• antihistamine• corticosteroids• supportive therapy as required

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Summary

Initial management of transfusion reaction– stop transfusion immediately– notify blood bank– maintain IV access– monitor patient's vital signs– recheck identification of patient

Assess for symptoms of "serious" reaction

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What actions does Canadian Blood Services take when

these are reported?Immediate:• assess need for companion component recall• assess need for in-date component recall from same donor• assess need for hospital notification about potential component

problem

Next step:• assess need for additional product testing• assess need for lot number investigation

Possibly:• assess need for donor notification, testing, deferral

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Health Canada Reporting

• tracking trending...

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TACO

This is an iatrogenic clinical issue, and not a product problem.

However, we continue to receive these reports. (frequently because there is an uncertainty as to whether or not it is TRALI)

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ABO incompatibility

Health Canada does not require this information from CBS. (Provided labelling is correct!)

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TTISS(Transfusion Transmission

Injuries Surveillance System)

• Public Health Agency of Canada

• Electronic reporting from hospitals directly to PHAC

• Most, but not all hospitals, are providing this information

• DOES include reports of "wrong unit to wrong patient"

• Reconciliation of reports with CBS and Héma-Québec

• Last annual Program Report printed 2004/2005 (is available on-line)

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Plasma Protein Products

• Direct reporting from hospitals to Health Canada (CBS may, or may not be in the loop)

• This includes both patient reactions, as well as product complaints

• The manufacturer investigates, and sends CBS the report (… I send a copy to the relevant hospital).

• Also extremely useful for trending. (example - hemolysis associated with IVIg)

What about current infectious disease risk?

O’Brien SF, Yi Q-L, Fan W, Scalia V, Fearon MA, Allain J-P. Current incidence and residual risk of HIV, HBV and HCV at Canadian Blood Services. Vox Sang. 2012;103:83-6.

Incident rates estimated for allogeneic whole blood donations 2006-2009 . Based on transmissible disease conversions of repeat donations with a 3-year period.

Residual risk of:

HIV 1 per 8 million donations

HCV 1 per 6.7 million donations

HBV 1 per 1.7 million donations

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Adverse Reactions

ARs by Category

0

5

10

15

20

Sep-

09

Oct-09

Nov-09

Dec-09

Jan-1

0

Feb-

10

Mar-1

0

Apr-1

0

May-1

0

Jun-1

0Ju

l-10

Aug-

10

Sep-

10

Potential product problem Known complication

Analysis:• There were 130 ARs reported from September 2009 to September 2010; none were related to an error by

CBS.• There were 10 ARs reported in September 2010, within the statistical range of 4 to 16.

Results:The column chart to the left, ARs by Category, illustrates the ARs as categories based on the type of reaction. The 5 most prevalent/noteworthy are bar graphed.

1. Known Complication of transfusion (e.g. allergic, anaphylactic, febrile, PTP, acute/delayed hemolytic). 7 of these were reported to HC in September 2010.

• 2 Allergic• 1 TACO• 1 PTP• 1 Febrile• 2 Miscellaneous

2. Potential Product Problem of transfusion (e.g. TRALI, bacterial sepsis, transfusion transmitted WNV). There were 2 suspected TRALI reactions and 1 suspected Bacterial reaction reported to HC in September 2010.

TRALI suspected• 1 RBC (male)• 1 FFPA (male)

Bacterial Suspected• Patient and 1 unit positive for gram negative bacilli

ARs, Cumulative 13 months: n = 130

2%

13%

5%

5%

2%

6%

6%15% 17%

29%

Suspected TRALI (39)

Febrile (23)

TACO (19)

Suspected Bacterial (8)

Allergic (8)

Anaphylactic (6)

Delayed Hemolytic (6)

Acute Hemolytic (2)

PTP (2)

Miscellaneous (17)

Most prevelant ARs reported to Health Canada

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1

2

3

4

5

6

7

Suspected TRALI Allergic Febrile TACO Suspected Bacterial

Sep-09

Oct-09

Nov-09

Dec-09

Jan-10

Feb-10

Mar-10

Apr-10

May-10

Jun-10

Jul-10

Aug-10

Sep-10

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? QUESTIONS ?

? SUGGESTIONS ?