Adverse Reactions to Blood Products

Medical Oncology Training Program Academic Half-DayFriday February 20th 2009, 11:00 am – 12:00 pm

Christine Cserti-Gazdewich, MD FRCPC FASCP

Assistant Professor, University of Toronto, Faculty of MedicineTransfusion Medicine/Hematology, University Health Network

Christine.Cserti@uhn.on.caUHN TGH BTL 3EC-306

14-6303

Reactions to Master….• 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

Reportingwhathow

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

Immune Non-Immune

Acute Allergic

TRALI

BaCon

AHTR / IBCT

FNHTR

TACO

Cold toxicity

Citrate toxicity

Hyperkalemia

Delayed DHTR

HLA – PTR

PTP

TA-GVHD

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

feverdyspneaallergy

cytopeniasdelayed infections

FeverHTR

BaConFNHTR

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

–recipient has, and can keep making, specific antibodies against a transfused cellular product that bears vulnerable antigens

antibody-mediated hemolysis of transfused red cells

R

D

transfused allogeneic red blood cells

D host allo-antibody attacks alloantigen

Acute Hemolytic Transfusion Reaction

• passive AHTR

–product carries donor antibodies which are specific for a recipient’s cells

antibody-mediated hemolysis of recipient red cells

high plasma-volume containing products (FFP, platelets)

R

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

plasma

1

2

ABO

Rh(D)

Kell

Duffy

Kidd

etc

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…

patient’s cells

directCoomb’stest

look for evidence of red cell incompatibility • clerical error search

• re-type

• direct antiglobulin test (DAT), aka Coomb’s test

•assess plasma for hemolysis10cc (or only 3% of a unit) of blood is visible…!

• re-screen or re-crossmatch

• review labs indicative of hemolysis

Suspected HTR: What to doStop 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 “leuko-agglutinins”

–patient previously sensitized to antigens on leukocytes

•old transfusions•pregnancies

–host antibodies react with passenger leukocytes in blood product

•product “pyrogens”–residual leukocytes secrete cytokines–occurs more often with:

•non-leukoreduced products•products under warm storage•products near expiry

(STORAGE

LESION)

donor leukocytewith an HLA antigenrelevant to hostHLA alloantibody

donor leukocytesecretes cytokinesin storage

D D

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

DyspneaTACOTRALI

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 “leuko-agglutinins”

–multiparous donor sensitized to WBC antigens –passive antibodies venously pumped through lungs & encounter host leukocytes & react–explains ≥ 75% of cases

•product toxins–cellular products release biologically active lipids–interact with illness-“primed” pulmonary endothelium to produce tissue damage

recipient leukocytewith an HLA antigenrelevant to donorHLA alloantibody

donor cells release biologically active lipids

D

H

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

Allergymucocutaneous vs multisystemic

IgA deficiency & other causes

The Allergic spectrum

• hives < 2/3 of body surface area– 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

90%

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: 1/100– severe allergic: 1 in 10 000 to 40 000

– fatal anaphylaxis: 1 in 1 000 000

Management of Allergic Reactions

• stop transfusion if >2/3rd BSA involved or non-cutaneous (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

HypotensionHTR

BaConAllergy

Bradykinin

Bradykinin-mediated hypotension• bradykinin surge from contact activation:

• for donors or recipients on ACE inhibitors: – reduced bradykinin breakdown from cross-

reactive suppression of enzyme from drug

• recipients of bradykinin: – flushing, hypotension, dyspnea, hypoxia

CytopeniasRBC (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 “re-

surge” 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 (post-transfusion purpura)–fatal in 8%–fortunately RARE!

Platelet-Specific Antigens in PTP

Platelet Antigen System

Protein Antigen

AllelesAntigen Frequency

HPA-1 GPIIIa

HPA-1a = PlA1

HPA-1b = PlA2

97%3%

HPA-2 GPIbHPA-2AHPA-2b

99%14%

HPA-3 GPIIbHPA-3aHPA-3b

85%66%

HPA-4 GPIIaHPA-4aHPA-4b

>99%<1%

HPA-5 GPIaHPA-5aHPA-5b

99%20%

But fortunately only 28% make the antibody if exposed

Most frequently involved polymorphism (75% of PTP cases)

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 A2B7 B9C4 C8

recipient tissue type

A2 A2B9 B9C8 C8

donor lymphocyte

Delayed onset infectionsViruses (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,screeningby donor history alone is performed in order to prevent the entry of these infections in the donor supply