Complications of blood transfusions, blood transfusion is a life saving and life threating procedure, so it's important to anticipate blood transfusion reaction

1. -1-
Evelyne Willems
CHU Liège
Complications of transfusion
BHS course of march 22 2014

2. -2-
Introduction
 Like drugs, transfusion has primary and secondary adverse
reactions.
 Immediate or delayed
 First think to do: immediately STOP the transfusion

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Transfusional reaction classification
Immune origin
 Immediate TR (min or hours)
• Hemolytic
• Febrile nonhemolytic
• Allergic
• TRALI
 Late TR (days, years)
• Hemolytic
• Allo-immunisation
• Post transfusion purpura
• GVHD
• Immune modulation
Non immune origin
 Immediate TR
• Hemolytic
• Septic
• Circulatory overload
• Air embolism
• Metabolic complication :
Hypothermie
Citrate toxicity
Hyperkalemia
 Late TR
– Infection Bacterial
Parasites
Viral
– Hemosiderosis

4. Plan
• 1. Acute Transfusion Reactions
• 2. Delayed Transfusion Reactions
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1) Acute Hemolytic reaction
2) Drug-Induced Hemolysis
3) Non immune hemolysis (mechanical)
4) Febrile Nonhemolytic Transfusion reaction (anti-HLA)
5) Allergic reaction (plasma proteins, IgA)
6) Circulatory overlaod
7) TRALI (Transfusion Related Acute Lung Injury)
8) Hypotensive reaction
9) Bacterial contamination
10) Therma effects
11) Metabolic complications
Acute transfusion reaction: etiology

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ATR : Acute hemolytic reactions (1)
 Causes :
– Immune-mediated lysis (intravascular ou extravascular) of
transfused red cells,
– Transfusion of incompatibles red cells to a recipient who has
previously performed Ab to red cell surface Ag (anti-A, anti-B)
– Patient misidentification
– Within minutes of start of Tf,
– Recipient Ab activates Complement (anti-A/anti-B, IgM) 
activation  C9  intravascular hemolysis (C5-9 component,
membrane attack complex) osmotic lysis
– Hemoglobinemia et Hemoglobinuria

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Hemolysis mecanism
Activation du Complément jusqu’au (C9)
 Complexe d’Attaque Membranaire
 hémolyse intravasculaire.
Roselyne L’Italien, Immuno-Hématologie, 2008

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 Biological diagnosis :
– Hemoglobinemia et Hemoglobinuria
– Decreased hematocrit
– Decreased Hb
– Decreased haptoglobin
– Increased LDH
– Presence of plasma hemoglobin
– Serum bilirubin increases 6 to 12 hours later
ATR : Acute Hemolytic reaction (1)

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 Clinical signs :
– Shock, Hypotension and Bronchospasm (complement
fragments, anaphylatoxins C3a et C5a and other mediators of
inflammation)
– Renal ischemia  Tubular necrosis  acute renal failure
– Cytokines network: IL1, IL6, IL8 et TNFa fever, hypotension,
leucocytes and coagulation activation
– Activation of coagulation cascade  DIC (disseminated
intravascular coagulation)
ATR : Acute Hemolytic reaction (1)

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 Severity :
– Depends of amount of blood transfused
– And the transfusion rate
– !!!!! Faster the insfusion rate, the more severe the reaction.
ATR : Acute Hemolytic reaction (1)

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Not a transfusion reaction but can be confused with HTR in the
transfused patient
–Induction of neo-antigen on red cell membrane or Formation of
immunes complex that deposit on red cell surface, rarely autoAb to
red cells  accelerated clearance
–Both autologous and transfused cells eliminated
–Positive direct antiglobin test, only in the presence of the drug
–May be severe, even fatal
–Treatment : stop drugs, transfusion, supportive care
–Drugs implicated : cephalosporin, cefotetan, ceftriaxone….
ATR: Drug-induced hemolysis (2)

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Drug-induced hemolysis
Roselyne L’Italien; Immuno-hématologie: 2008

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= mechanical
– Artificial heart valves,
– Extracorporeal circulation
– Transfusion through small-bore catheters under high pressure
– Osmotic lysis : hypotonic saline solutions, 5% dextrose in
water, distilled water, certain medication
– Heating > 42°C
– Freezing (hemolyse prior transfusion)
– Hemoglobinuria may occur but not associated with shock…
ATR: Nonimmune Hemolysis (3)

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– Fever
– Results from pyrogenes production (IL-1, IL-6, TNFa)
– FNHTR definition : > 1°C rise in the 2 hours following Tf
– 1 à 10 % of patients
– Ab directed against transfused leukocytes and platelets  Ag-Ab
reaction pyrogens from plasmocytes
– Use leucocyte-reduced blood component
ATR: Febrile Nonhemolytic
Transfusion Reaction (4)

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– 1% of transfusion recipients
– Cause: Ag-Ab reactions (infusion of plasma proteins)
– Symptoms : cutaneous (urticaria, flushing, itching) + nausea,
vomiting, diarrhea, brochospasm
– Not dose-related
– Generally mild, not recurrent and responding to antiH1
– Anaphylactic reactions rarely : Ab to IgA, haptoglobin or C4
(Chido/Rogers blood group Ag)
– Consider washed blood component, high dose CS and
antiH1
ATR: Allergic reactions (5)

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TACO: Transfusion Associated Circulatory Overload
– Patient unable to compensate for expanded blood
volume
– Signs = headache, dyspnea, pulmonary oedema,
congestive heart failure, systolic HTA
– Stop transfusion
– Prevention : rate of infusion 2 à 4 ml/Kg/h
– !!! Do not exceed 4 hours
ATR: Circulatory overload (6)

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– Non cardiogenic pulmonary oedema
– Incidence 0.08 to 15%
– Cause : Two-hit model
– First hit: underlying patient factors activation of
pulmonary endothelium  accumulation and adherence of
primed neutrophils in lungs
– Second hit: mediators in the blood transfusion  activation
of pulmonary neutrophils capillary leakage and pulmonary
oedema
– Second hit can be antibody (passive transfer af HLA or
antileukocytes Ab) or Non Ab-mediated (accumulation of
proinflammatory mediators during storage)
– Donor often multiparous woman
ATR: Transfusion-Related Acute
Lung Injury (TRALI) (7)

18. TRALI: Pathogenesis
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19. TRALI: Definition
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– TRALI = respiratory distress, hypoxia, fever, bilateral pulmonary
oedema during or within 6 hours of a transfusion
– Patients at risk: cardiac surgery, sepsis, massive transfusion,
induction chemo
– Supportive treatment. Steroids?
– Resolution within 48 to 72 hours
– But : mortality ± 10%
– Give leukocytes-reduced components
– Report to blood bank
– Diagnosis: detection of HLA and leukocytes Ab in donor plasma, HLA
Ag typing of the recipient
ATR: Transfusion-Related Acute
Lung Injury (TRALI) (7)

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– After platelets transfusion (or red cells)
– Bradykinines generation (contact of plasma with artificial surfaces
 vasodilatation  hypotension
– Stop transfusion  rapid resolution
– Rare until prestorage leukocyte reduction
– Seen in patients treated with AEC inhibitory drugs (inhibition of
kinikinase II)
ATR: Hypotensive reaction to
transfusion (8)

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– Rate of contamination 0.3%, less serious reactions
– Contamination during phlebotomy
– !!! Platelets conserved at ± 22°C
– Skin flora (Staphylococcus, Klebsiella, Escherichia)
– Clinical signs : fever, dyspnea, hypotension, shock
– Stop transfusion
– Supportive care and broad spectrum antibiotic
– Report immediately to blood bank (additional components must
be recalled)
ATR: Bacterial contamination (9)

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– Hypothermia (refrigeartor storage)  arrythmia
– Over-warming blood  hemolysis
–  Use a monitored blood warming system when needed
ATR: Thermal effects (10)

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– Citrate = Calcium chelation circumoral and fingers paresthesia
– Reversible leakage of K during storage  hyperkaliemia (rare)
– Inconsequential EXCEPT: neonates (exchange transfusion), liver
transplantation, pediatric cardiac surgery and renal failure
– Washing red blood cells, use of blood less than 7 days old
ATR: Metabolic complications (11)

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Medical emergency !
– Stop transfusion
– Verify the correct unit was given to the correct patient
– Maintain iv access, blood pressure, pulse and diuresis
– Maintain adequate oxygenation
– Notify attending physician and blood bank, consult with blood
bank physician before futher transfusion
– Return unit or empty bag to blood bank
– Obtain blood/urine for analyses
– Monitor signs of hemolysis, coagulation and renal status,
monitor Hb and Ht, repeat compatibility testing (crossmatch),
anayse urine for hemoglobinuria
– If bacterial contamination suspected: blood culture of patient
and unit, initiate broad spectrum antibiotics.
ATR : Work up and Treatment

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 Analyses at the blood bank :
– Ensure correct blood component transfused to the right patient
– Plasma visually evaluated for hemoglobinemia
– Post-transfusionnel sample : Direct Coombs
– Pre-transfusionnel sample: RAI, ABO, Rh and crossmatch tests
ATR: work-up

27. Plan
• 1. Acute Transfusion Reactions
• 2. Delayed Transfusion Reactions
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Delayed transfusion reactions
• Delayed hemolytic reactions
• Posttransfusion purpura
• GVHD
• Immune modulation
• Hemosiderosis
• Air embolism
• Transfusion-transmitted diseases
– Hepatitis
– HIV
– Other viruses
– Parasites
– Prions

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DTR : Delayed hemolytic reaction (1)
 Causes :
– Induction of Ab days or weeks after a transfusion by transfused
red cells.
• Appearance days after Tf,
 anamnestic response
• Appearance weeks after Tf,
 primary response.
– For each transfusion, 1-1.6% risk of sensitizing a recipient to a red
cell Ag other than D
– Most DHR extravascular

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 Symptoms :
– Less severe than Acute HR (no complement activation)
– Clinical signs : fever, malaise, fatigue et symptoms in relation with
anemia.
– Positive DAT
– Regenerative anemia and indirect hyperbilirubinemia
– Increased LDH and decreased haptoglobin
– Rare hemoglobinemia
DTR : Delayed hemolytic reaction (1)

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Implicated Ab :
– Duffy (Fya, Fyb) et Kidd (Jka, Jkb) systems
– Less intensive complement activation, delayed reaction
– Sometimes seen in ABO incompatibility
Prevention:
High-dose IVIg (400 mg/kg)
DTR : Delayed hemolytic reaction (1)

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Intra- / extra-vascular hemolysis
Intravascular Extravascular
Serum Bilirubin +++ +++
LDH +++ +++
Haptoglobin - -
Hemoglobinemia + -
Hemoglobinuria + -
Urinary hemosiderin + -
Hemopexine-heme + -
Methemoglobinemia + -
Morphology Schistocytes, spherocytes,
agglutination
Spherocytes, elliptocytes,
ovalocytes, normal RC

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Acute versus Delayed Hemolytic
reaction
Type Signs & symptoms Usual cause Traitment Prevention
Hemolytic
Intravascular
(immune origin)
Hemoglobinemia
Hemoglobinuria
Fever, chills
Anxiety
Shock, dyspnea
Oliguria
Flank pain
ABO
incompatibility
Or other
complement-
fixing red cell
antibody
Stop transfusion,
hydrate, support
blood pressure
and respiration,
induce diuresis,
treat shock and
DIC if present
Ensure proper
sample and
recipient
identification
Hemolytic
extravascular
(immune origin)
Fever,
Malaise,
Indirect
hyperbilirubinemia,
increased LDH, urine
urobilinogen,
Falling hematocrit
IgG non-
complement
fixing Ab (anti-
Rhésus, anti-
Kell…)
Monitor Ht, renal
and hepatic fct,
coagulation
profile, no acute
treatment
generally
required
Review historical
records; ensure
proper
identification, give
Ag-negative units,
High-dosis IVIg

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DTR: Post transfusionnel Purpura (2)
– Thrombocytopenia 1 to 3 weeks after transfusion.
– Allo-Ab anti-platelets (anti-HPA1).
– Diagnostic : Ab detection.
– Spontaneous resolution after 2 to 3 weeks.
– Traitment adapted to risk of hemorrhage:
• Low risk: wait and see
• High risk : g-globulines (400-500 mg/kg), Plasmapheresis, platelet
transfusion.

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DTR : GvHD (Graft versus Host Disease)(3)
– Transfusion of immuno-competent lymphocytes to immunodeficient
recipient
– Or transfusion of blood products from HLA-homozygous donor to
immunodeficient HLA-heterozygous recipients(familial donor).
– Donor lymphocytes engraft and recognize host histocompatibility Ag and
attack host tissues.
– 10-12 days after transfusion,
– Clinical signs : fever, cutaneous rash, diarrhea, hepatitis, marrow aplasia.
– Fatal in most cases.
– Prevention : IRRADIATION of blood and cellular components (2500cGy).

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DTR : Immune modulation (4)
– Alteration in the recipient immune system after transfusion.
– sometimes :
• Beneficial (ex: prolongation of renal allograft survival or
prevention of spontaneous abortion)
• Deleterious : increased risk of tumor recurrence and post-
operative bacterial infections
– Relationship unproven.

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DTR : Hemosiderosis (5)
– 1 mL of red cells contain 1 mg of Iron.
– A unit of RBC: 150-250 mg of Iron.
– Iron accumulation  organ damage (heart, liver pancreatic islets)
–  Phlebotomy (after HSCT)
– parenteral (deferoxamine) or enteral (exjade) chelation

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DTR : Air embolism (6)
– Rare with conventional transfusion techiques.
– May occur with blood pomps and apheresis machines
– Fatal risk of 1/30000 after readministration of recovered blood. In
cardiac surgery
– Complication : acute cardio-pulmonary failure, cyanosis, dolor,
cough, arythmia, shock, cardiac arrest.
– Traitment : place the patient head-down on the left side

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DTR : Transfusion transmitted-disease (7)
– Allogeneic blood donation tested for : HBsAg, HBcAb, HCV-Ab,
HIV-Ab (1+2), HIV-Agp24, HTLV, syphilis.
– Methods : serologic + NAT.
– Residual risk: the « window period »
– 12 days for VIH
– 10 days for HCV
– 51 days for HTLV
– 38 days for HbS Ag

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Residual risk France (2009)

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Residual risk in France

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Prions Variant Creutzfeldt-Jakob
Chronic Wasting Disease (CWD)
Arbovirose West Nile virus
Dengue
Chikungunya
Other arbovirus
Other emergent virus in
transfusion
Humen herpes virus 8 (HHV-8)
Erythrovirus B-19
HAV – HEV
Influenza A/H5N1
Retrovirus simiens
Other
Emergent virus
for transfusion
in 2011

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Risk 10 -2 10 -3 10 -4 10 -5 10 -6 10 -7
10 -8 0
High
HIV Paludism
HCV Variant MCJ
Bacteral contam GVHD
ABO Incompat Anaphylact. shock
Acute H. ABO
Middle
CMV Other bacterial
Delayed H PPT HPA-Ab Other parasites
HBV HTLV
Moderate
Febrile R Other virus Syphilis
allergic R
Low
Imm. Erythroc. anti-HPA Ab
anti-HLA Ab
10 -2 10 -3 10 -4 10 -5 10 -6 10 -7 10 -8 0
Immunological Risk Infectious risk
Transfusionnel risk per infused red unit
J-Y Py, Réanimation 12 (2003) 564-574

45. Microparticles
• Submicron-sized fragments of cells’ plasma membranes
released in the supernatant during storage
• Procoagulant and proinflammatory activities
• Risk associated with age of the red blood cells
• Interaction with complement system, white blood cells
and potential mediator for TRALI
• Procoagulant activity via expression of anionic
phospholipid  activation of coagulation cascade
• Increasing risk of TVP with older blood and involvement in
ischemic brain disease
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46. -46-
- SHOT (Serious Hasard of Transfusion)
http:www.shotuk.org
- Alexander PJ Vlaar, Transfusion-related acute lung injury: a clinical
review. Lancet 2013; 382: 984-94
- Wenche Jy et al., Microparticles in stored red blood cells as
potential mediators of transfusion complication, Transfusion 2011;
51: 886-893
- Aysola A, et al. Blood Transfusion Therapy; 109-135, AABB 2002
References