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

OVERVIEW OF THE CANADIAN BLOOD SYSTEM

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

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

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

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

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

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

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

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)

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

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).

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

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)

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

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

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

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.

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

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

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)

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

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

Shortness of Breath

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

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

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

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

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

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

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

Fever

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

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

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

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

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

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 20 - 24° C -- excellent growth medium for bacteria)

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.

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

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

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

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)

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)

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

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

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)

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

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

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

Health Canada Reporting tracking trending...

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)

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

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)

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

? QUESTIONS ? ? SUGGESTIONS ?