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Evelyne WillemsCHU Liège

Complications of transfusion

BHS course of march 22 2014

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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

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 NonhemolyticTransfusion 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)

TRALI: Pathogenesis

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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

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

HemolyticIntravascular

(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

ModerateFebrile R Other virus Syphilis

allergic R

LowImm. 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

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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- SHOT (Serious Hasard of Transfusion)http:\\www.shotuk.org

- Alexander PJ Vlaar, Transfusion-related acute lung injury: a clinicalreview. 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