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Acute adverse reactions to
transfusion: a symptomsbased approach
Kathryn E. Webert, MD, MSc, FRCPC
Assistant Professor,
Departments of Medicine and Molecular Medicine and Pathology
McMaster University, Hamilton, Ontario
Associate Medical Director, Canadian Blood Services, Hamilton
Centre
Summary of presentation
• What is a transfusion reaction ?
• Classification of transfusion reactions
• Approach to acute transfusion reactions based on
common presenting symptom:
• Fever
• Dyspnea
• Rash/allergic symptoms
**Detailed pathophysiology, management, and prevention
was covered for most of these reactions in recent
presentation**
What is a transfusion reaction?
• Any untoward event that occurs as a result of infusion of a
blood component (immediate or delayed)
• 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 Effects 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
Immediate Adverse Effects Associated with
Transfusion: risks
Complication
Acute hemolytic transfusion reaction
Febrile non-hemolytic transfusion reaction
Allergic reaction: Anaphylactic
Allergic reaction: Minor
TRALI
Transfusion-associated circulatory overload (TACO)
Risk
1:25,000
1:10 (plts)
1:40,000
1:100
1:5,000
1:700
Delayed Adverse Effects Associated with Transfusion
• Delayed hemolytic transfusion reaction
• Alloimmunization
•
•
•
•
Red Cell Antigens
HLA
Leukocytes
Platelets
• Graft versus host disease (TA-GVHD)
• Post-transfusion purpura (PTP)
• Hemosiderosis
• Viral and parasitic infections
• Transfusion-related immunomodulation (TRIM)
Signs and Symptoms of TR
• Fever/chills/rigors
• Anaphylaxis
• Pain
• Cyanosis
• Dyspnea/respiratory
• Bronchospasm
distress
• Bleeding
• Hypotension
• Hypertension
• Headache
• Nausea and vomiting
• Rash/Hives
• Angioedema
• Tachycardia
• Abdominal cramps
• Diarrhea
• Cough
• Red eye
• Anxiety
• Jaundice
Classification of reaction by predominant
symptom/sign
• This presentation will focus on 3 common
presenting symptoms and signs:
1. Fever
2. Dyspnea
3. Rash and other allergic reaction
Disclaimer: This is not easy…
• Sometimes the patient has not read the text book…
• More than one predominant presenting symptom
• More than one reaction going on
• Atypical presentation
• Underlying comorbidities unrelated to transfusion
Approach to Patients
with Transfusion
Reactions
Approach to Patient with a Transfusion Reaction
• 65 year old man develops shortness of
breath and hypoxia while receiving unit of
PRBC.
• What is the differential
diagnosis?
Approach to acute
transfusion
reactions commonly
presenting with
shortness of breath
Differential Diagnosis of TR with SOB
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload (TACO)
• Transfusion associated dyspnea (TAD)
• Anaphylaxis
• Acute hemolytic transfusion reaction
• Bacterial contamination
• Other etiology unrelated to transfusion
SOB is
usually the
predominant
symptom
Differential Diagnosis of TR with SOB:
Background
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload (TACO)
• Transfusion associated dyspnea (TAD)
• Anaphylaxis
• Acute hemolytic transfusion reaction
• Bacterial contamination
• Other etiology unrelated to transfusion
Canadian Consensus Conference Definition of TRALI
• During or within 6 hrs of
transfusion
• Acute lung injury
• Acute onset
• Hypoxemia
• PaO2/FIO2  300
• SpO2 < 90% on room air
• Bilateral infiltrates on CXR
• No evidence of circulatory
overload (PCWP18)
• No preexisting ALI or other RF
for ALI
Kleinman et al. Transfusion 2004;44:1774-89
Toy et al. Crit Care Med 2005;33:721-6
TRALI: symptoms and signs
• Virtually all patients have:
• Shortness of breath
• Hypoxia
• Bilateral lung infitrates on CXR
• May also have:
• Hypotension
• Fever
• Transient leukopenia
• Other:
• Chest findings on auscultation tend to be minimal
• No evidence of circulatory overload
Bux and Sachs. Transfusion Medicine and Hemotherapy. 2008
TRALI: Epidemiology
• 0.4 to 1.6 cases per 1,000 patients transfused
• Likely under-reported and under-recognized
• Described with all blood products
• Usually contain > 60 mL plasma
• US FDA observed TRALI to be the leading cause of transfusion
related deaths 2003-2008.
• Responsible for 16 to 65% of transfusion-related mortalities
• In Canadian TTISS Report (2004-2005):
• 2nd highest cause of transfusion-related morbidity and
mortality
Fatalities reported to FDA following blood collection and transfusion. Annual Summary for Fiscal Year 2008.
Transfusion Transmitted Injuries Surveillance System, Program Report 2004-2005, Public Health Agency of
Canada, March 2008
TRALI: Pathophysiology
Immune
• Passive transfer of donor
alloantibodies in plasma of
transfused product
• Anti-HLA (Class I)
• Anti-HLA (Class II)
• Human neutrophil antigens
(HNA)
• Antibody binding to circulating
WBC (and perhaps also
pulmonary endothelium)
causes cellular activation
Recipient
WBC
TRALI: Pathophysiology
Non-immune
• TRALI is also caused by the infusion of “biologic response modifiers”
within the blood component
• Cytokines (IL-6, IL-8, IL-1, TNF-a)
• Lipids with neutrophil-priming activity
• CD40 ligand
• These substances accumulate in cellular blood products with
prolonged storage
Silliman CC et al., Transfusion 1997
Silliman CC et al., Blood 2003
TRALI: Diagnosis
• No test with which to diagnose TRALI.
• TRALI should be suspected if a patient has appropriate
clinical findings within six hours of a transfusion
• Exclude of other causes of pulmonary edema
• Cardiac causes
• Volume overload
• Clinical diagnosis
TRALI: Treatment and Prognosis
• Ventilatory support as required
• Maintenance of hemodynamic status
• Inotropes, vasopressors
• 80% of patients show clinical improvement within
48-96 hours
• In most patients, there are no long-term
complications
• Fatal in 5-10% of cases
Differential Diagnosis of TR with SOB:
Background
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload (TACO)
• Transfusion associated dyspnea (TAD)
• Anaphylaxis
• Acute hemolytic transfusion reaction
• Bacterial contamination
• Other etiology unrelated to transfusion
TACO
• Acute pulmonary edema secondary to congestive heart
failure precipitated by transfusion of a volume of blood
greater than what the recipient’s circulatory system can
tolerate
• Respiratory distress and/or cyanosis associated with
pulmonary edema within 6 hours of transfusion
• Associated with hypertension, tachycardia, positive fluid
balance
• Many patients also complain of a dry cough, headache,
chest tightness
Bux J, Transfus Med Hemother 2008
TACO: Epidemiology
• Likely the most under-recognized and potentially serious
transfusion complication
• Studies have demonstrated incidence in orthopedic
surgery patients (hip or knee arthroplasty) to be 1-8%
Bux J, Transfus Med Hemother 2008
Popovsky MA, Transfusion and Apheresis Science, 2006
TACO: Risk Factors
• Too much blood transfused too rapidly
• Can be precipitated by even a single RBC unit
• Age <3 or >60 years
• Diminished cardiac reserve
• Chronic anemia
Bux J, Transfus Med Hemother 2008
TACO: Treatment and Prevention
Prevention
• Transfuse only when indicated
• Recognize patients at risk
• If at risk, transfuse slowly
• Consider diuretics (before and/or after)
• Watch fluid balance, monitor patient closely
Treatment
• Stop transfusion
• Position patient in upright position
• Supplementary oxygen
• Diuretics
• Cardiac and respiratory support as required
Bux J, Transfus Med Hemother 2008
Differential Diagnosis of TR with SOB:
Background
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload (TACO)
• Transfusion associated dyspnea (TAD)
• Anaphylaxis
• Acute hemolytic transfusion reaction
• Bacterial contamination
• Other etiology unrelated to transfusion
Transfusion associated dyspnea (TAD)
• European Haemovigilience Network
(EHN) introduced term to allow for
classification of respiratory distress
temporally associated with transfusion
which could not be assigned to known
pulmonary reactions
www.ihn-org.net
Differential Diagnosis of TR with SOB
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload (TACO)
• Transfusion associated dyspnea (TAD)
• Anaphylaxis
• Acute hemolytic transfusion reaction
• Bacterial contamination
• Other etiology unrelated to transfusion
• Can you narrow the diagnosis down?
Differential Diagnosis—TR with SOB
Other Symptoms
Timing of Symptoms
TACO
Elevated JVP, hypertension,
pulmonary edema (crackles,
rales, S3 gallop)
Within several hours of
transfusion
TRALI
SOB, hypoxemia, hypotension, Within 6 hours of
pulmonary edema (crackles,
transfusion (usually
relatively quiet chest), fever
during)
TAD
All other pulmonary reactions
ruled out
Within 6 hours of
transfusion
Anaphylaxis
Generalized rash, flushing,
wheezing, angioedema
Usually early in
transfusion
AHTR
Flank pain, DIC, hypotension,
fever
Usually within first 15
minutes
Bacterial
sepsis
Fever, hypotension
Usually within first 15
minutes
Immediate Management: TR with SOB
• Stop transfusion immediately
• Notify hospital blood bank of transfusion reaction
• Sample sent: screen for hemolysis, DAT
• Maintain IV access (0.9% saline)
• Monitor patient’s vital signs
• Recheck identification of patient (wrist band) and label of blood
product for discrepancy
• CXR
Serious Reaction
• What symptoms/signs would suggest a serious reaction?
• Hypotension/shock
• Shortness of breath
• Hypoxemia
• Hemoglobinuria
• Nausea and vomiting
• Bleeding from IV sites
• Back pain
• Chest pain
• Temperature >39oC
Initial management of a serious reaction
with SOB
• Suspect TRALI, TACO
• Do not restart transfusion
• Notify blood bank and hematologist on call
• Maintain IV access
• CXR
• Assess patient
•  JVP, pulmonary edema: suspect TACO
• Diuresis, supportive therapy
• Normal JVP, fever, CXR suspicious for ALI: suspect TRALI
• Supportive therapy
Approach to Patient with a Transfusion Reaction
• 65 year old man develops fever (temp 38oC) with rigors
and chills while receiving unit of PRBC.
• What is the differential diagnosis?
Approach to acute
transfusion
reactions commonly
presenting with
fever
Differential diagnosis: TR with Fever
• Acute hemolytic transfusion reactions
(AHTR)
• Febrile non-hemolytic transfusion
reactions (FNHTR)
• Bacterial sepsis or contamination
• Transfusion-related acute lung injury
• Etiology unrelated to transfusion
Fever is
usually the
predominant
symptom
Differential diagnosis: TR with Fever
• Acute hemolytic transfusion reactions
(AHTR)
• Febrile non-hemolytic transfusion
reactions (FNHTR)
• Bacterial sepsis or contamination
• Transfusion-related acute lung injury
• Etiology unrelated to transfusion
AHTR
• Lysis or 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 alloantibodies
• Results in intravascular hemolysis
Epidemiology
• Generally within the top 3 causes of transfusion-related
mortality
• 10.8% of all fatalities reported to the US FDA in 2005-2008
AHTR—Etiology
• 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
• Other causes of hemolysis include:
•
•
•
•
•
•
Overheating of RBC
Freezing of RBC
Outdated RBC
Transfusion under pressure with small bore needle
Transfusion with hypotonic solution
Causes unrelated to transfusion
AHTR-- Pathophysiology
• Red cell alloantibody (IgM) in recipient
binds to antigen on transfused red cell
membrane
• Development of immune complexes
and activation of complement
• Results in formation of membrane
attack complex (C5b-9) on the red cell
surface which leads to lysis of cells
• Release of C3a and C5a
• Hypotension
• Production of IL-1 from
macrophages
• Fever
• Activation of coagulation cascade
• Disseminated intravascular coagulation
(DIC)
AHTR--Clinical Presentation
• Acute onset, often within first 15 minutes of starting
transfusion
• Transfusion of as little as 20-30 mL of red cells may result in an
acute hemolytic transfusion reaction
• Initial clinical presentation:
• Fever and/or chills, anxiety, nausea or vomiting, pain (flank, back,
abdomen, chest, head, infusion site), dyspnea, hypotension, brown
urine, bleeding
• Complications:
• Renal failure, disseminated intravascular coagulation (DIC), death
AHTR—Treatment
• STOP the transfusion immediately
• Begin infusion with normal saline
• Alert the blood bank, check for clerical error, send entire
transfusion set-up to blood bank for testing
• Supportive care
• Monitor vital signs closely
• Maintain blood pressure and urine output
• Monitor for hyperkalemia
• Administer FFP, cryoprecipitate and platelets as required for
coagulopathy
AHTR—Investigation
• Clerical check (labels, records in blood bank,
review of blood typing results, antibody tests)
• Repeat ABO type
• Post-reaction blood specimen
• Visual check for free hemoglobin
• DAT
• ABO type
• Antibody screen
• Evidence of hemolysis
• free serum hemoglobin, haptoglobin, LDH, urine free
hemoglobin
Transfusion Reactions with Fever: Background
• Acute hemolytic transfusion reactions (AHTR)
• Febrile non-hemolytic transfusion reactions (FNHTR)
• Bacterial sepsis or contamination
• Transfusion-related acute lung injury
• Etiology unrelated to transfusion
FNHTR—Epidemiology
• Common adverse event
• 1 in 10 transfusions of pooled random donor platelets
• 1 in 3000 units of RBC
• Frequency varies with:
• Type of blood product
• Age of blood product
• WBC content of blood product
• Recipient characteristics
• Use of pre-medications
• Variability in recording of symptoms
Callum J, Pinkerton P. Bloody Easy, 2nd edition, 2005
FNHTR—Etiology
Reactions mediated by antibodies
• Recipient alloantibody reactive to antigens expressed on
WBCs in component
• Antigen-antibody interaction causes the release of
endotoxins
• 1o mechanism causing FNHTR after transfusion of RBC
Reactions mediated by biologic response molecules
• Accumulation of leukocyte and/or platelet-derived cytokines
in the bag during storage
• IL-1b, IL-6, IL-8, TNF-a
• Accounts for >90% of reactions to platelet transfusions
Heddle et al., 1994; Brittingham and Chaplin, 1957; deRie et al., 1985; Perkins et al., 1966; Heddle et al., 1994;
Muylle and Peeterman, 1994; Stack and Snyder, 1994; Aye et al.,1995; Kluter et al., 1995; Flegel et al., 1995 .
FNHTR—Clinical Presentation
• Fever (>1oC rise) during or soon after transfusion
• Usually associated with chills and rigors
• May be associated with nausea and vomiting
• Symptoms typically appear toward the end of the
transfusion
• 5-10% of reactions present 1-2 hours after the
transfusion
AABB Technical Manual, 14th Edition, 2002;
Heddle et al., 2002; Heddle et al., 1993.
Slide 48
FNHTR—Treatment
• Stop the transfusion while assessing patient
• Determine that an acute hemolytic transfusion
reaction or reaction secondary to bacterial
contamination is not occurring
• Acetaminophen +/- merperidine may help
patients with severe chills and rigors
• Continue transfusion cautiously
Transfusion Reactions with Fever: Background
• Acute hemolytic transfusion reactions (AHTR)
• Febrile non-hemolytic transfusion reactions (FNHTR)
• Bacterial sepsis or contamination
• Transfusion-related acute lung injury
• Etiology unrelated to transfusion
Bacterial Contamination—Epidemiology
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
• Most frequent infectious risk associated with transfusion
• Accounts for ~11% of deaths due to blood components
• Occurs most frequently with platelets
• Stored at 20-24oC
• Excellent growth medium for bacteria
Slide 51
Callum and Pinkerton, Bloody Easy 2, 2005
Bacterial Contamination: Etiology
• Blood components may be contaminated by
• Unrecognized bacteremia in the donor
• e.g., Yersinia enterocolitica
• Skin organisms from the donor
• Difficult to totally decontaminate surface of human skin
• Small core of skin may enter phlebotomy needle at time of donation
(~65% of donations)
• Bacterial present in deep layers of skin
• e.g., Staphylococcus epidermidis
• Contamination from the environment or handling of the product
• Leaky seals, damaged tubing, etc.
• e.g., Serratia marcescens
Bacterial Contamination—Commonly implicated bacteria
Gram-negative
Gram-positive
• Klebsiella pneumoniae
• Staphylococcus aureus
• Serratia marcescens
• Staphylococcus epidermidis
• Pseudomonas species
• Bacillus cereus
• Yersinia enterocolitica
Clinical Presentation
• Depends on bacterial load of product, species of
implicated bacteria
• Rigours, fever, chills
• Hypotension
• Tachycardia
• Nausea and vomiting
• Dyspnea
• Disseminated intravascular coagulation
• Usually occurs during transfusion of 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 antibiotic therapy
Differential Diagnosis: TR with fever
• Febrile non-hemolytic transfusion reaction
• Bacterial contamination
• Acute hemolytic transfusion reaction
• TRALI
• Can you narrow down the diagnoses
further?
57
Differential Diagnosis: TR with Fever
Febrile non-hemolytic
transfusion reaction
Other
Symptoms
Usually temp <
39oC
Timing of Symptoms
Bacterial
contamination
Hypotension,
shock, DIC
Acute hemolytic
transfusion reaction
Flank pain, DIC, Usually within first
hypotension
15 minutes
TRALI
SOB,
hypoxemia,
hypotension
During transfusion;
usually towards the
end
Usually within first
15 minutes
Within 6 hours of
transfusion (usually
during)
Immediate Management
• Stop transfusion immediately
• Notify hospital blood bank of transfusion reaction
• Maintain IV access (0.9% saline)
• Monitor patient’s vital signs
• Recheck identification of patient (wrist band) and label of
blood product for discrepancy
Serious Reaction
• What symptoms/signs would suggest a serious reaction?
• Hypotension/shock
• Shortness of breath with hypoxemia
• Hemoglobinuria
• Nausea and vomiting
• Bleeding from IV sites
• Back pain
• Chest pain
• Temperature >39oC
Initial management of non-serious reaction with
fever
• No serious symptoms
• Possible FNHTR
• Treat with acetaminophen (+/- Demerol)
• Restart transfusion with caution
• Observe patient closely
• Stop transfusion immediately if patient develops any
serious signs or symptoms
Initial management of serious reaction with
fever
• Suspect: hemolytic transfusion reaction or bacterial
sepsis
• Do not restart transfusion
• Notify blood bank and hematologist on call
• Continue IV fluids
• Send blood product and set-up (IV tubing) to blood bank
• Arrange for unit to be cultured and a gram stain
performed
Initial management of serious reaction with
fever
• Order “transfusion reaction” investigations, post-
transfusion sample for
•
•
•
•
Group and screen
Direct antiglobulin test (DAT)
Antibody screen
Blood culture of product
• Check for hemolysis: free hemoglobin, decreased
haptoglobin, hyperbilirubinemia
• Blood culture of patient
• Urinalysis (free hemoglobin)
• +/- CXR
Approach to Patient with a Transfusion Reaction
• 65 year old man develops
diffuse, pruretic body rash with
throat tightness and wheezing
while receiving unit of plasma.
• What is the differential
diagnosis?
Approach to
transfusion
reactions commonly
presenting with rash
Differential diagnosis: rash
• Mild allergic reactions
• Serious allergic reactions
• Anaphylaxis
• Anaphylactoid reactions
• Reactions unrelated to transfusion
Allergic Transfusion
Reactions
Allergic Reactions
• 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, a1-antitrypsin, transferrin, C3, C4, etc.)
• Passive transfer of IgE antibodies
• Transfusion of allergen to which patient is sensitized (e.g. drugs,
chemicals)
Vamvakas and Pineda, Transfusion Reactions, AABB Press 2001
Allergic reactions
Incidence:
•Mild: 1:33-100 (1% - 3%)
•Severe: 1:20,000-47,000
Timing
•During transfusion; up to 3 hours from the start of
transfusion
Vamvakas and Pineda, Transfusion Reactions, AABB Press 2001
Allergic Reactions—Clinical Presentation
Signs and Symptoms
• Skin lesions (hives)
• May also have
• Pruritis
• angioedema
• Cough and wheezing
• Nausea and vomiting
• Abdominal pain
• Diarrhea
• Hypotension
• Cyanosis
• Tachycardia
Allergic reactions: Serious
• What symptoms/signs would suggest a serious
reaction?
• Hypotension/shock
• Shortness of breath, hypoxemia
• Cough
• Tachycardia
• Nausea and vomiting
• Generalized flushing or anxiety
• Widespread rash (covering more than 2/3 of body)
Callum and Pinkerton, Bloody Easy 2, 2005
Management of non-serious reaction with
rash
• Antihistamine
• Diphenhydramine 25-50 mg IV/PO
• Continue transfusion with caution
• Stop transfusion if any “serious” symptoms
Management of serious reaction with rash
• Stop the transfusion and do not restart
• Notify hospital transfusion service
• Epinephrine
• Antihistamine
• 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
Summary
• May be able to classify reaction by predominant
presenting symptom
• Shortness of breath
• TRALI, TACO, TAD
• AHTR, allergic reaction, bacterial contamination
• Fever
• FNHTR, bacterial contamination, AHTR, TRALI
• Rash
• Mild allergic reaction, anaphylaxis
The End!!!