1. ADVERSE TRANSFUSION EVENTS
HEMATOLOGY ROUNDS
August 23, 2012
D.K. Towns, MD, FRCPC (Anesthesia)
Medical Director
Canadian Blood Services
Calgary, AB

2. OVERVIEW OF THE CANADIAN BLOOD SYSTEM

3. The blood system in Canada is complex
Regulator
Health Canada
Blood Suppliers
Canadian Blood Services (CBS)
Hema-Quebec (H-Q)

4. Government funding for CBS is approved by a provincial
committee.
The CBS Head Office is located in Ottawa and has overall
responsibility for:
developing policies and standard operating procedures
b) monitoring collection facilities and regional testing laboratories
developing contracts with plasma fractionators to fractionate CBS plasma and obtain fractionation products

5. Regional CBS staff include administrative, medical, nursing, technical, and recruitment personnel who are responsible for:
recruiting, assessing, and monitoring donors during blood or apheresis collections
b) processing, storing, distributing, and transporting blood components and products to area hospitals
performing laboratory testing or arrange for centralized laboratory testing
conducting quality control activities
e) maintaining lookback/traceback programs

6. 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

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

8. 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

9. 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

11. 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)

12. 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

13. 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).

14. We, in turn, report these reactions
Canadian Blood Services requires that hospitals report adverse transfusion reactions to us
We, in turn, report these reactions
to Health Canada

15. 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)

16. Timelines Serious Adverse Event resulting in Fatality:
report immediately to MD and QAM
report immediately to Director, Regulatory Affairs
Other Serious Adverse Event (non-fatal) or Unexpected Adverse Event
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

17. 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

18. 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

20. 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.

21. 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)
Septic transfusion reaction (bacterial contamination)
Hypotensive reactions
ACE inhibitors
Non-immune red cell hemolysis
Metabolic disturbances
hypothermia
hyperkalemia
acidosis

22. Risk of Complication 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

23. 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)

24. Signs and Symptoms of Transfusion Reactions
fever/chills/rigors
pain
dyspnea/ respiratory distress
bleeding
hypotension
hypertension
headache
nausea and vomiting
rash/hives
angioedema
flank pain
anaphylaxis
cyanosis
bronchospasm
tachycardia
abdominal cramps
diarrhea
cough
red eye
anxiety
jaundice
hematuria

25. Often difficult because:
there is more than one predominant presenting symptom
more than one reaction going on
atypical presentation
underlying comorbidities unrelated to transfusion

26. Shortness of Breath

27. Differential Diagnosis of transfusion reaction with shortness of breath:
TRALI
TACO
TAD
Anaphylaxis
AHTR
Bacterial contamination
Other etiology (unrelated to transfusion)

28. 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

29. TRALI continued
TTISS ( ) - 2nd highest cause of transfusion-related morbidity and mortality
Treatment: ventilation support
80% of patients show clinical improvement within hours
5 - 10% fatality

30. 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

31. TACO continued Prevention 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

32. 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

33. 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

34. Fever

35. 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

36. AHTR
Accelerated 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

37. AHTR continued
Acute onset : often within first 15 minute of starting transfusion (as little as 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

38. 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

39. FNHTR - continued Etiology:
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

40. Bacterial Contamination
Component
Bacterial Contamination
Symptomatic 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
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 ° C -- excellent growth medium for bacteria)

41. Etiology Blood 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.

42. Commonly Implicated Bacteria
Gram-negative:
Klebsiella pneumoniae
Serratia marcescens
Pseudomonas species
Yersinia enterocolitica
Gram-positive:
Staphylococcus aureus
Staphylococcus epidermidis
Bacillus cereus

43. Clinical Presentation
Depends 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

44. 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

45. 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)

46. Allergic Reaction
Usually 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)

47. Incidence:
mild 1:33 – 1:100 (1-3%)
severe 1:20, :47000
Timing
during transfusion, or up to 3 hours from the start of presentation

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

49. 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)

50. Management Non-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
corticosteroids
supportive therapy as required

51. 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

52. 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

53. Health Canada Reporting
tracking trending...

54. 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)

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

56. 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)

57. 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)

58. 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 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

67. ? QUESTIONS ? ? SUGGESTIONS ?