ADVERSE TRANSFUSION EVENTS

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

15. 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) Why?

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

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 (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

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 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

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 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)

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 Serratiamarcescens) • leaky seals, damaged tubing, etc.

42. Commonly Implicated Bacteria Gram-negative: • Klebsiellapneumoniae • Serratiamarcescens • 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 1:20,000 - 1:47000 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 • antihistamine • corticosteroids • supportive therapy as required