Transcript Adverse Reactions to Blood Products

Adverse Reactions
to Blood Products
Medical Oncology Training Program Academic Half-Day
Friday February 20th 2009, 11:00 am – 12:00 pm
Christine Cserti-Gazdewich, MD FRCPC FASCP
Assistant Professor, University of Toronto, Faculty of Medicine
Transfusion Medicine/Hematology, University Health Network
[email protected]
UHN TGH BTL 3EC-306
14-6303
Reactions to Master….
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hemolytic transfusion reactions
FNHTRs
allergic & anaphylactic reactions
acute pain transfusion reactions
bacterial contamination
TRALI
TAGVHD
hypotensive transfusion reactions
posttransfusion purpura
stem cell reinfusion reactions
circulatory overload
IVIG adverse effects
Reporting
what
how
Our reporting obligations
• WHAT:
– all transfusion reactions (no matter how mild)
and transfusion-related errors
• TO WHOM:
– hospital transfusion service
• relays information to:
– the Transfusion Transmitted Injuries Surveillance
System (TTISS) at Public Health Agency of Canada
– CBS or Héma-Québec if related to the quality of the
product
• DEPENDS UPON:
– awareness & competence
Transfusion Hazards
Acute
Delayed
Immune
Non-Immune
Allergic
TRALI
BaCon
AHTR / IBCT
FNHTR
DHTR
HLA – PTR
PTP
TA-GVHD
TACO
Cold toxicity
Citrate toxicity
Hyperkalemia
TTD
Fe overload
Deaths Due to Transfusion
• # 1 cause of transfusion-attributed death:
TRALI
• overall risk of transfusion-related death:
1 in 200,000 chance
= risk of death from anesthesia in a fit
person
Transfusion attributable
symptoms, what they mean, &
how they happen
fever
dyspnea
allergy
cytopenias
delayed infections
Fever
HTR
BaCon
FNHTR
when is it a fever?
• T > 38ºC AND ↑ by Δ1ºC
OR
• the fever equivalent of chills or rigors
Acute Hemolytic Transfusion Reaction
• immune
– active (recipient antibodies)
– passive (donor antibodies)
• non-immune
– devices physically destroying RBCs
– thermal injury to RBCs (hot/cold storage
misadventure)
– pressurized infusions
– post-expiry infusions
Acute Hemolytic Transfusion Reaction
• active AHTR
transfused allogeneic
red blood cells
D
–recipient has, and
can keep making,
specific antibodies
against a transfused
cellular product that
bears vulnerable
antigens
 antibody-mediated
hemolysis of
transfused red cells
D
R
host
alloantibody
attacks
alloantigen
Acute Hemolytic Transfusion Reaction
high plasma-volume
containing products
(FFP, platelets)
• passive AHTR
–product carries
donor antibodies
which are specific for
a recipient’s cells
R
 antibody-mediated
hemolysis of
recipient red cells
Causes of active AHTR
• ABO mistake
– failure to avoid anticipated ABO antibody
– group O patient given non-O RBC *
• anti-A and anti-B are naturally occurring antibodies
and hemolysis is immediate
• missed or hidden non-ABO antibody
– failure to find unanticipated non-ABO antibody
– use of emergency ‘uncrossmatched’ blood
– antibody not detected on antibody screen
* : ½ of these mistakes are due to hanging the properly
labelled blood on the wrong patient, and many of the
remainder are due to the recipient being wrongly
characterized because of sampling errors
the point of the SCREEN (IAT):
preventing “minor” RBC antigen-based HTRs…
but sometimes failing
• relevant to finding recipient antibodies to non-ABO
antigens
• utilizes O red cells
ABO
Kell
Rh(D)
Duffy
plasma
Kidd
etc
1
2
AHTR: clinical facts
• presentation: fever/chills, hemoglobinuria, IV or
flank pain, ↓BP, nausea/vomiting, dyspnea, renal
failure, DIC
• case fatality rate:
<10%
• non-morbidity rate:
>50%
• + “dose-response” risk (↑ blood = ↑ risk)
• cases are usually ABO-related
• non-ABO antigens implicated in 13% of AHTRs
AHTR: How to pick it up…
look for evidence of red cell incompatibility
• clerical error search
• re-type
• direct antiglobulin test (DAT),
aka Coomb’s test
•assess plasma for hemolysis
10cc (or only 3% of a unit)
of blood is visible…!
direct
Coomb’s
test
• re-screen or re-crossmatch
• review labs indicative of hemolysis
patient’s cells
Suspected HTR: What to do
Stop transfusion & run NS; check labels
Notify blood bank, send post-transfusion specimen
& remainder of product
Stat lab work:
acute renal failure work-up:
electrolytes (hyperkalemia), creatinine
DIC work-up:
PT/INR, aPTT, fibrinogen
Support BP & maintain good urine output
Manage coagulopathy and bleeding
Bacterial Contamination (BaCon)
INCIDENCE
• Risk of septic shock:
– 1 in 10,000 PPC
– 1 in 100,000 RBC
• Risk of death from septic shock:
– case fatality rate: 24-60%
– 1 in 40,000 PLT pools
– 1in 1,000,000 RBC
• Key Message –
Run transfusion slowly for 1st 15 min
BaCon
ETIOLOGY
• donor bacteremia, skin plug, processing
• most commonly:
– Yersinia enterocolitica
– Serratia marcescens/liquefaciens
– Staph aureus/epidermidis
PRESENTATION
• fever, rigors, hypotension, renal failure, DIC
• platelets more commonly implicated
• RBC more severe
FNHTR: what it is
• = Febrile Non-Hemolytic Transfusion
Reaction
• a diagnosis of exclusion
– after ruling out:
• hemolytic transfusion reaction
• bacterial contamination
• underlying illness in patient
• common
– 1/10 platelet transfusions
– 1/300 red cell transfusions
FHNTR: why it happens
•recipient “leukoagglutinins”
–patient previously
sensitized to antigens
on leukocytes
•product “pyrogens”
–residual leukocytes
secrete cytokines
–occurs more often
with:
•old transfusions
•pregnancies
–host antibodies
react with passenger
leukocytes in blood
product
D
donor leukocyte
with an HLA antigen
relevant to host
HLA alloantibody
•non-leukoreduced
products
•products under warm
storage
•products near expiry
(STORAGE
LESION)
D
donor leukocyte
secretes cytokines
in storage
FNHTR: how to manage
• acetaminophen
• meperidine (Demerol) for rigors
• PREVENTION?
– acetaminophen
• may not work
• may obscure an important febrile cue to stop
next transfusion
– fresh components
• not always available
– plasma-reduced or washed products
• risks product degradation/loss
IVIG & Immune Reactions
• immune-replacement / immune-modifying
therapy = unique immune-mediated
adverse effects, attributed to:
– cytokines, vasoactive peptides, complement
activation via Ig dimerization
• common minor effects:
– headache, fever, fatigue, chills, vomiting,
nausea, dizziness, diarrhea, flushing,
abdominal pain, chest tightness, cough,
muscle cramps, pruritis, backpan
• rarer, more serious effects:
– sucrose-induced nephropathy, aseptic
meningitis, hemolysis, anaphylaxis, vascular
thrombosis
Dyspnea
TACO
TRALI
pulmonary allergic reaction (bronchospasm)
what to do?
• assess patient (focus on cardiorespiratory
vitals & volume status)
• stop transfusion, notify blood bank
• stat CXR + ABG if hypoxic oximetry
• treat patient:
– oxygenate if hypoxic
– diurese if +evidence of volume overload
TACO
• Transfusion-Associated Circulatory
Overload
• incidence:
– 1 in 700 patients overall
– 1 in 100 elderly recipients of blood
• specific clues:
– fast infusion rate
– compensated chronic anemia (hyperdynamic
before transfusion)
– known congestive heart failure risk
– orthopnea, ↑JVP, cyanosis, ↑HR, ↑BP
TRALI: what it is
• Transfusion Related Acute Lung Injury
= NON-cardiogenic pulmonary edema
• definition:
– new acute lung injury (PaO2/FiO2 <300)
– onset during or within 6h of transfusion
– excludes:
• TACO
• underlying CHF
• other pre-transfusion pulmonary morbidities
• under-recognized & under-reported
– estimates: 1 in 1200 to 1 in 5000
TRALI: why it happens
•donor “leukoagglutinins”
D
•product toxins
–multiparous donor
sensitized to WBC
antigens
–passive antibodies
venously pumped
through lungs &
encounter host
leukocytes & react
–explains ≥ 75% of
cases
H
recipient leukocyte
with an HLA antigen
relevant to donor
HLA alloantibody
–cellular products
release biologically
active lipids
–interact with illness“primed” pulmonary
endothelium to
produce tissue
damage
donor cells
release
biologically
active lipids
TRALI: outcomes
• symptoms & signs:
– dyspnea, cough, hypoxia, fever, BP ↑ or ↓, WBC ↓
• resolves in 24-72 hours
• 72% require mechanical ventilation
• death in 5-10%
– most common cause of transfusion-attributed death
now
• supportive care is key
– diuretic utility in non-cardiogenic edema?
• prevention:
– defer implicated donors
– new mandates may restrict use of female plasma
Allergy
mucocutaneous vs multisystemic
IgA deficiency & other causes
The Allergic spectrum
• hives < 2/3 of body surface area
90%
– mild urticaria, pruritis, erythema, flushing
• hives > 2/3 of body surface area
• angioedema (subcutaneous rather than cutaneous)
• respiratory:
– bronchospasm
• wheezing, stridor, hoarseness, dyspnea, hypoxia, psychologic
sense of asphyxia/doom
• gastrointestinal instability:
– nausea/vomiting/abdominal cramping/diarrhea
• cardiovascular instability:
– hypotension, chest pain, tachycardia
• anaphylactoid / anaphylactic reaction
Why allergic reactions happen
•Recipient-donor
allergen-IgE interactions
–classic allergic IgE
antibodies and antigens,
with one or the other
passively infused and
interacting in host
•drugs, foods, chemicals
–likely the most common
explanation
–no routine tests or
traceback methods to
confirm
–URTICARIA to
ANAPHYLAXIS
•Recipient IgG
sensitization to normal
donor proteins
–recipient has a rare
polymorphism or
deficiency of a certain
protein compared to most
donors
•eg: IgA, haptoglobin,
complement, albumin,
α1anti-trypsin,
transferrin
–exposure to proteins =
immunizing event
–anti-protein IgG
=ANAPHYLACTOID
REACTION
a few words on IgA deficiency
• 1 in 500 are IgA deficient
• 1 in 1200 have anti-IgA IgG
(ie- proof of sensitization)
– mysteries:
• why/how IgG raised without known exposure
• why ½ don’t react if exposed later
– explains why reactions may be observed in a
1st transfusion
How often & how severely they happen
• within 1-45 min of transfusion, but up to 3 h
afterwards
• if severe:
– as little as 10cc may be anaphylactic
• dose-responsive
• relapsing
• frequencies:
– minor:
– severe allergic:
– fatal anaphylaxis:
1/100
1 in 10 000 to 40 000
1 in 1 000 000
Management of Allergic Reactions
• stop transfusion if >2/3rd BSA involved or noncutaneous (visceral) allergic symptoms
• allergic anti-histamines
– diphenhydramine (Benadryl), cetirizine (Reactine)
± H2R blockers
– ranitidine (Zantac)
• epinephrine, β2 receptor agonist bronchodilators
• corticosteriods
• ACLS: vasopressors, ventilatory support
• future transfusions:
– modify the patient:
• premedication
– modify the product:
• ± plasma depletion / washing
• obtain from donors deficient in the inciting allergen/antigen
Hypotension
HTR
BaCon
Allergy
Bradykinin
Bradykinin-mediated hypotension
• bradykinin surge from contact activation:
• for donors or recipients on ACE inhibitors:
– reduced bradykinin breakdown from crossreactive suppression of enzyme from drug
• recipients of bradykinin:
– flushing, hypotension, dyspnea, hypoxia
Cytopenias
RBC (HTR)
platelets (HLA PTR, PTP)
WBC (TRAIN)
pancytopenia (TA-GVHD)
RBC decreases after transfusion
• if immediate & not related to hemorrhage:
– investigate for acute hemolytic transfusion
reaction
• usually related to ABO antibodies (preformed) &
suspected from fever/hypotension
• if delayed (3-14 days after transfusion):
– investigate for delayed hemolytic transfusion
reaction (DHTR)
• usually non-ABO antibodies that took time to “resurge” after the offending red cell transfusion
• may not have symptoms of hemolysis (fever,
hemoglobinuria)
– 1 in 6715 transfusions
– in future: transfuse blood negative for antigen
Platelet decreases after transfusion
•HLA (human leukocyte
antige) sensitization
–recipient makes HLA
antibodies from past
exposure to WBCs
•other transfusions
•pregnancies
•transplants
–platelets express 73% of
circulating HLA class I (A &
B) antigens
–recipient can destroy
platelets bearing vulnerable
HLA antigens
–the cause of 80-90% of
platelet transfusion
refractoriness
•HPA (human platelet
alloantigen) sensitization
–recipient with a
polymorphic or missing
platelet glycoprotein makes
antibody against the
common glycoprotein type
•pregnancies
•other transfusions
–recipient can destroy
platelets bearing vulnerable
HPA antigens
–leads to PTP (posttransfusion purpura)
–fatal in 8%
–fortunately RARE!
Platelet-Specific Antigens in PTP
Most
frequently
involved
polymorphism
(75% of PTP
cases)
But fortunately
only 28% make
the antibody if
exposed
Platelet
Antigen
System
Protein
Antigen
Alleles
Antigen
Frequency
HPA-1
GPIIIa
HPA-1a =
PlA1
HPA-1b =
PlA2
97%
3%
HPA-2
GPIb
HPA-2A
HPA-2b
99%
14%
HPA-3
GPIIb
HPA-3a
HPA-3b
85%
66%
HPA-4
GPIIa
HPA-4a
HPA-4b
>99%
<1%
HPA-5
GPIa
HPA-5a
HPA-5b
99%
20%
Post transfusion neutropenia
•donor anti-granulocyte antibodies
–although usually implicated in TRALI, may also
(or instead) cause neutropenia of host’s
neutrophils
–passive alloimmune reaction
TA-GVHD
• Transfusion-Associated Graft Versus Host
Disease
• passenger lymphocytes “engraft” in
recipient
– who:
• immune compromised
• immune recognition failure
– what happens:
• bone marrow aplasia (empyting from attack) =
pancytopenia (all counts down)
• fever, rash
• liver dysfunction, diarrhea
• death in 90%
Vulnerable recipients
•immune compromised
–congenital
immunodeficiency
–fetuses, premature
neonates
–hematologic malignancies
(eg lymphoma)
–stem cell transplants
–high dose chemotherapies
with immune-ablation
potential
–nucleoside analogue drugs
(eg fludarabine for chronic
lymphocytic leukemia)
•immune “oblivious”
–host’s HLA type is
foreign to transfused
lymphocytes, which
resemble the host enough
to be tolerated
•eg. donor is HLA
“homozygous
haploidentical” with
respect to recipient
•related donors
•1 in 18 000 – 39 000 of
strangers
A1 A2
B7 B9
C4 C8
recipient
tissue
type
A2 A2
B9 B9
C8 C8
donor
lymphocyte
Delayed onset infections
Viruses (H A/B/C V, HIV, CMV, HTLV, WNV, PVB19, HHV8)
Prions (vCJD)
Others (protozoal, helminthic, spirochetal, rickettsial)
Viral testing of each donation
• all donors:
–
–
–
–
–
–
HIV Ab, HIV NAT
HCV Ab, HCV NAT
HBsAg, HBcAb
Syphilis
HTLV-1/2 Ab
WNV NAT
• selected cases/products:
– CMV Ab
– bacterial culture (pre-pooled/high volume
platelets only)
– Parvovirus B19 (fractionated products only)
Residual risk (window period misses)
Virus
Risk per donor
exposure
Outcome of
exposure
HIV
1 in 4.7 million
50% risk of HIV in 7y,
shorter latency in elderly
HCV
1 in 3.1 million
50-70% chronic hepatitis
HBV
1 in 82 000
60% hepatitis with <5%
chronicity
HTLV
1 in 3 million
unknown
WNV
<1 in 1 million
at least 20%
Other transfusion transmissible infections
•Malaria
•Toxoplasmosis
•Leishmaniasis
•Filariasis
•Ehrlichiosis
•Babesiosis
•Trypanasoma cruzi (Chagas)
•Borrelia burgdorferi
•Rocky mountain spotted fever
(rickettsial group)
•Q fever (Coxiella burnetti)
•variant CJD
at this time,
screening
by donor
history alone
is performed
in order to
prevent the
entry of these
infections in
the donor
supply