The ABCs of Transfusion Reactions

1
The ABCs of Transfusion Reactions

• Laura Cooling MD, MS
• Associate Professor, Pathology
• Associate Medical Director, Blood Bank
• University of Michigan, Ann Arbor, MI
• 2009 BBANY Annual Meeting

2
Suspected Reaction Occurs within minutes-hours
Hemolytic Immune (Antibody-mediated) Non-immune
Nonhemolytic Febrile Allergic Hypotensive TRALI V
olume O/L (TACO) Bacteria
No Reaction Patient diagnosis Infection Medicatio
n
3
Acute Transfusion Reactions - overlapping
signs/symptoms - laboratory clinical
correlations
Reaction
Fever /or chills/rigors
Cardiovascular Respiratory
Hemolysis Febrile Bacterial Other
TRALI Hypotensive AHTR Bacterial
Allergic Volume Overload Other
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Case 1

• G2P2 45 yo woman admitted with a subarachnoid
  hemorrhage due to right carotid bifurcated
  aneurysm. Four days after surgical repair, she
  was transfused 2u RBC for Hgb7.0 mg/dL. Two
  weeks later she was transfused two additional
  units (Hgb7.1 mg/dL). Early in the 2nd unit,
  the patient became febrile (38.1?40.1?C),
  tachycardic (99?106), hypertensive
  (128/72?153/76). The nurse also noted new
  cranberry colored urine in her catheter bag.

5
Acute Hemolytic Transfusion Reaction (AHTR)

• Intravascular hemolysis of RBC
• Transfused RBC
• Patient RBC
• Significant morbidity mortality

6
Acute Hemolysis Causes

• ABO Incompatibility
• Bedside errors (99)
• Patient identification
• Mislabeled sample wrong blood in tube
• Transfusion
• transcriptional errors
• improper identification of patient
• FDA reportable if blood bank error or patient
  death

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Acute HTR Causes

• ABO Incompatibility
• Transfusion errors
• Other
• Out-of-group platelets (grp O, apheresis)
• IV immune globulin
• Factor concentrates
• Transplantation-donor lymphocyte
• RBC alloantibodies

8
Non-immune Hemolysis

• Infusion of hemolyzed RBCs
• Frozen/thawed RBC
• Cryopreserved marrow/cord RBC
• Malfunctioning refrigerators
• Mechanical
• Small bore needles (eg. NICU)
• Infusion pumps
• Cell salvage
• Osmotic
• Hypotonic solutions
• Eg. dilution 25 albumin with water

9
Acute HTR Signs/Symptoms

• Fever
• Chills/Rigors
• Hypotension
• Pain
• IV site
• flank pain
• Chest pain

• Renal
• Hemoglobinuria
• Oliguria
• Acute renal failure
• DIC
• GI complaints
• nausea/vomiting

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Evaluation of Acute HTR

• Blood Bank Evaluation
• Post-transfusion Reaction Sample
• /- Urine sample (institution-specific)
• First Tier Evaluation
• Clerical Check
• ABO/Rh type pre post-transfusion samples
• DAT (direct Coombs)
• Visual check for hemolysis

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Blood Bank Evaluation

• Clerical Check
• Match between unit, patient, sample
• Match between product order
• Repeat ABO/Rh
• Verify post-transfusion Blood type
• Pre-transfusion blood type
• Historical blood type

12
Direct Antiglobin Test (DAT)

• DAT (direct Coombs)
• Test for bound antibody or complement on RBCs
• Caveats
• Not-specific for HTR
• DAT pre-transfusion
• Negative DAT-AHTR
• Lysis of transfused RBC

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Visual Check for Hemolysis

• Manually compare color
• of patient plasma/serum
• pre- transfusion (TS)
• 2) post-transfusion

Post Pre Post
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Additional Blood Bank Test

• RBC eluate
• Repeat antibody screen
• Pre Post-transfusion samples
• /- Enhanced techniques (ficin, PEG,..)
• Repeat crossmatch
• /- Extended antigen typing

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Ancillary Tests HTR

• Complete Blood Count
• Pre Post Hct/Hgb
• 1 gm Hgb/unit RBC
• Blood smear
• RBC morphology
• /- Reticulocyte Count
• E.g. Sickle cell disease

16
Peripheral Blood SmearSpherocytes with immune
hemolysis
Peter Maslak MD. ASH Image Bank 20088-00103
17
Laboratory Studies for HTR

• Acute Hemolysis
• Plasma free (serum) hemoglobin
• Haptoglobin
• Hemoglobinuria
• Lactate dehydrogenase (LDH)
• Bilirubin
• Indirect Bilirubin gt Direct

Interpreted relative overall liver function
18
Urinalysis in HTR

• Urine Dipstick
• Blood /-
• Urobilinogen
• Evidence UTI?
• Nitrate, WBC
• Hematuria vs Hemoglobinuria
• Spun urine
• Microscopic exam

Hematuria
Hemoglobinuria
Images from www.goldbamboo.com/pictures
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Intravascular Hemolysis
Free Hgb
? Plasma Hgb
Hgb-Haptoglobin Release RBC Enzymes
? Haptoglobin
? LDH (LD1 gt LD2)
Kidney
Hemoglobinuria
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INTRAVASCULAR (ACUTE) HEMOLYSIS
Free Hgb
Duvall et al. Hemoglobin catabolism following
anHTR in SS anemia. Transfusion 197414382-387.
Hemoglobinuria
Haptoglobin
24 hr
1-6 hr
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Free Hgb
Heme ? Bilivirdin ? Indirect Bilirubin
Spleen
Hgb-Haptoglobin
Kidney
Hemoglobinuria
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Free Hgb
Heme ? Bilivirdin ? Indirect Bilirubin
Spleen
Hgb-Haptoglobin
Kidney
Liver
Direct Bilirubin
Hemoglobinuria Bilirubinuria
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Renal Ancillary Testing

• Urinalysis
• Monitor renal function
• electrolytes
• urine output
• daily weights

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175 mg/dl
Plasma Hgb
11.5
87
4.6
Urine
1.5 ml/min
67
673
Renal Blood Flow
220 ml/min
2.5 hrs
15 gm Hgb
Hemoglobinuria
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Sobatta Hammerstein Histology
A
Proximal tubules
glomerulus
RBC Pigment Cast
Loops of Henle
Loops of Henle stained with hemoglobin.
Also shown is an isolated pigment cast of
hemoglobin.
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Normal kidney nondilated tubules
Kidney with AHTR Dilated, distended tubules
DeGowin Warner. Arch Int Med 1938
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Coagulation Studies

• Monitor Disseminated Intravascular Coagulation
  (DIC)
• Platelet count (CBC)
• Fibrinogen
• PT/PTT
• D-dimer
• Peripheral smear

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Free Hgb
Platelet
Fibrinogen
12 hr
24 hr
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Case 1

• Laboratory Findings
• Serum Hemoglobin87 (?)
• Haptoglobinlt6 (?)
• UAHemoglobinuria
• LDH821(?)
• Total Bilirubin1.9
• Indirect Bilirubin1.4 (?)
• 1 Spherocytes
• Normal renal function
• No evidence of DIC

• Acute Symptoms
• Fever
• Tachycardia
• Hypertension
• cranberry urine
• Hx transfusion
• Hx pregnancy

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Case 1 Blood Bank
Acute HTR Secondary to Anti-C and Anti-S

• First Tier
• Clerical check OK
• Repeat ABO/Rh
• Pre O
• Post O
• DAT Negative
• Hemolysis Positive

• Second Tier
• Units O
• Repeat Ab screen
• Routine negative
• Enhanced methods
• Anti-Le(a)
• Anti-C
• Anti-S
• Antigen Typing
• Unit 2 C S

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Treatment Acute HTR

• Fluid and O2 support
• Closely monitor patient
• Maintain urine output gt 100cc/hr
• Normal saline (if anuric, restrict after 1 liter)
• diuretic (furosemide, mannitol)
• necessary, dopamine (1-5 ug/kg/min)
• Nephrology consult

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Treatment Acute HTR

• Fluid and O2 support
• Maintain urine output gt 100cc/hr
• /- IV Steriods
• If DIC develops
• Hematology consult
• Component therapy (FFP, PLT, Cryo)
• Consider Heparin
• 5000 U loading dose
• 1500 U/hr infusion (up to 24 hrs)

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• Case 3.
• 60 year old man with relapsed MM after an
  auto-HPC transplant in 1997. The patient has a
  history of 3 transfusion reactions to platelets.
  His first was in 12/05, characterized by fever
  rigors. He was seen in the ED and noted to have
  no increase in platelet count. Two years later,
  he had severe reactions, with no increment,
  following 2 platelet transfusions
• Pre-PLT Post-PLT Symptom
• 3/08 29 21 rigors, RR24,
  hypotension, nausea, fever (T99.9),
• 3/08 23 26 fever, rigors

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Non-Hemolytic Transfusion RXN

• Febrile Nonhemolytic
• Allergic
• TRALI
• TACO
• Hypotensive
• Bacterial Contamination

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Febrile Nonhemolytic (FNHTR)

• 1?C or 1.5?F rise temperature with transfusion
• 0.5-1.0 RBC transfusions
• 20-30 platelet transfusions
• Etiology
• Antibody mediated (HLA, platelet alloantibody)
• Inflammatory Mediators
• Risk factors
• multi-transfused or multiparous (HLA antibodies)
• ?storage time (inflammatory mediators)

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• Evaluation
• Severe febrile reaction
• Evidence of platelet refractoriness
• Suspect HLA antibodies
• HLA workup HLA Alloimmunization (PRAgt99)
• Anti-A2, A3, A11, A23, A24, A25, A26, A29, A30,
  A31, A32, A33, A34, A43, A66, A68, A69, A74
• Anti-B57, B58.

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Febrile Nonhemolytic Reactions

• STOP the transfusion
• R/O hemolytic transfusion reaction
• Administer antipyretic
• Tylenol (common)
• severe chills, rigors morphine
• /- Restart transfusion
• severity of symptoms
• clinical status of patient
• Clinical decision
• Monitor post-transfusion response

38
Febrile Nonhemolytic Reactions

• Future Transfusions
• Premedicate with Tylenol
• (prospective study--didnt make a difference)
• Monitor transfusion efficacy

39
Case 3

• The patient is a 41 y/o man with a gt10 year
  history of chronic relapsing TTP. The patient had
  a history of mild hives and was premedicated with
  Tylenol and IV Benadryl per routine. The patient
  was also on prednisone (40 mg/day).
• At the end of the procedure, the patient c/o
  itching and feeling flushed. On exam, hives were
  observed on arms, neck, chest and abdomen. Vital
  signs remained stable and chest was clear to
  auscultation. The patient was given IV benadryl
  and procedure was terminated early.

40

• After 15 minutes, the patient still felt unwell
  and was now c/o of abdominal pain, chest pain and
  SOB.
• Pre BP 115/61 P 71 RR 16 O2ND
• Post BP 101/54 P 104 RR 20 O270
• The patient was given O2, IV Solucortef The
  patient continued to have CP, hypoxia (O2
  sat40-50), tearing, slight slurring of speech
  and a brief moment of unconsciousness. The
  patient was given epinephrine 11000 SQ and the
  code team called.
• Within 2-3 minutes, the patient O2 sats95-99.
  Chest pain resolved with SL nitroglycerin.

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Allergic Reaction

• 1-3 transfusions
• FFP most common
• 4 per platelet
• 0.4 per RBC

42
Allergic Transfusion Reaction

• Immediate hypersensitivity reaction
• Immune-Mediated (IgE)
• donor origin
• patient origin
• soluble substances (ex drugs)
• plasma proteins
• Allotypic differences
• Congenital deficiencies (anaphylactic)
• Severe IgA
• Haptoglobin (Asian)

43
Allergic Transfusion Reaction

• Immediate hypersensitivity reaction
• Immune-Mediated (IgE)
• Chemokine-Mediated
• Platelet transfusions
• RANTES (a-granules)
• eosinophil chemoattractant
• Enhances mast cell degranulation

44
Allergic Rxn Signs Symptoms

• MILD
• (most common)
• Hives
• Erythema/rash
• Trunk/Face

• SEVERE
• Generalized rash/hives
• Angioedema
• Dyspnea, wheezing, coughing, tight chest
• Sneezing, rhinorrhea, itching/watery eyes
• /-?BP or ?BP

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ANAPHYLACTIC SHOCK

• Transient hypertension?Hypotension
• Bronchospasm
• Flushing
• Chills
• NO FEVER (cold shock)
• GI-cramps, nausea, vomiting
• Unconsciousness
• Consider congenital protein deficiencies

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Treatment Allergic Reactions

• Mild Rxns Antihistamine, may restart unit
• Severe/Anaphylactic
• Antihistamine (50 mg Benadryl IV up to 250 mg
  total)
• /- H2 blocker (eg. Ranitidine)
• Steriod
• Hydrocortisone 50-100 mg IV
• or SoluMedrol 40 mg IV
• Epinephrine
• 0.3-0.4 mL 11000 SubQ
• 1 mL 110,000 IV over 5 min
• (0.1 mL 11000/10 mL nl saline)
• Fluid support, O2 (mask)
• DO NOT RESTART TRANSFUSION

47
Case 4

• 18 yo black male was admitted for mononucleosis
  and ITP. On HOD2, the patient was transfused
  with 5-pack pooled platelets for mild
  hemoptysis. The patient was premedicated prior to
  transfusion. Because of ongoing bleeding, the
  patient received a 2nd platelet transfusion. 20
  minutes after starting the 2nd transfusion, the
  patient developed rigors, vomiting, tachycardia,
  tachypnea and hypoxia.
• The Blood Bank was immediately notified of a
  possible transfusion reaction.

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Vital Signs

PRE POST
Temp 99.6 99.5
BP 116/66 128/60
HR 97 120
RR 16 28
O2 sat NA 82 RA
Premedicated with Tylenol and Benadryl
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POST
72 hrs
Improvement in airspace opacities, particularly
left base.
Bilateral airspace opacities, Consistent with
hemorrhage or edema from blood products.
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Transfusion Related Acute Lung InjuryTRALI

• Incidence 1/2500-1/5000
• Leading cause of transfusion-related fatalities
• 5-10 mortality rate
• American Red Cross (2003-05)
• 550 suspected TRALI
• 38 fatalities
• 24/38 - plasma infusions (OR12.5)
• 5/38 - apheresis platelets (OR7.9)

75 all fatalities
AABB Bulletin 06-07.
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Blood Products Linked to TRALI

• High-volume plasma products (200-300 mL)
• Plasma
• apheresis platelets
• Occur with any component
• RBC
• Pooled platelets
• Cryoprecipitate
• Granulocytes
• Mononuclear cells (PBPC)
• IVIgG
• Rh Immune globulin

52
Etiology TRALI

• Product Factors
• Anti-leukocyte antibodies (90 cases)
• Muliparous females
• Anti-HLA
• Anti-granulocyte-specific
• Biologic mediators
• Bioactive lipids
• Oxidation membrane over storage

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Immune Model
1. Anti-leukocyte Ab - HLA class 1 -
Neutrophil-specific
Neutrophil activation Endothelial damage
Endothelial Cell
3. HLA class 2 Ab - Monocytes - Cytokine release
2. HLA class 1 Ab
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Lyso-Phosphotidylcholine (lyso-PC) Oxidation of
PC PAF-like biological activity
CH2-O-PO3-CH2CH2N(CH3)3
CHO CHOH COOH
PAF-Like Epitope
CH-O-C-
O
CH2-O-C-CH2-(CH2)n-CH3
O
Biologic Mediators
55
Patch of PAF Cell membrane
Neutrophil priming -granular enzyme release
-respiratory burst Neutrophil activation -
CD11/CD18 activation - Redistribution PSGL-1
- ?Cell Motility - ?Cell Polarization
PAF Receptor neutrophils
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Etiology TRALI

• Product Factors
• Anti-leukocyte antibodies
• Biologic mediators
• Bioactive lipids
• Host Factors
• Cytokine administration (G-CSF)
• Active infection
• sepsis
• pneumonia
• Recent surgery
• Massive transfusion
• Silliman et al Transfusion 199737719-726.

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Richard Benjamin. Transfusion 2008 calender

• Pulmonary sequestration of neutrophils
• Leukocyte activation /- WBC agglutination
• Endothelial damage
• Capillary leak edema

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TRALI Diagnosis

• Acute onset
• lt 6 hrs transfusion
• Usually lt1-2 hrs
• Hypoxia
• O2 lt 90
• PaO2/FiO2lt300 mm Hg
• Dyspnea
• Tachypnea
• PA pressure lt 18 mm Hg
• Common
• Fever, chills
• Hypotension

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Acute, transient drop in WBC Count Recovery of
counts within 6-12 hrs
WBC Count
Nakagawa Toy Transfusion 2004441689
Hours
FFP from G3P4 donor with class 1 (99) and 2
(90) Abs. Recipient-donor pair for class 2
(DR15).
60
Treatment

• Supportive (ABCs)
• Oxygenation
• /- ventilation
• BP pressure support
• Avoid diuretics (if possible)
• Risk-benefit of transfusion
• ? High dose steriods
• No evidence of efficacy

61
Evaluation TRALI

• Laboratory
• Blood Bank First Tier
• Clerical check
• ABO/Rh
• DAT
• Visual hemolysis
• Gram stain culture
• Patient
• CBC differential
• /- HLA type recipient

• Clinical
• Vital signs, O2 sats
• Time to onset
• Exam findings CXR
• Exclude volume O/L
• Fluid balance
• Infusion rates
• BNP
• Cardiac
• Cardiac history
• EKG
• cardiac enzymes
• Medications
• Response to treatments

62
TRALI Evaluation

• Laboratory Testing
• Patient Evaluation
• Contact Blood Supplier
• Quarantine other products from donor(s)
• Donor Investigation Testing
• Donor deferral
• Product recall, Lookback investigations

63
Red Cross Evaluation (5 months later)

• Platelet Pool 4 males/1 female
• 1 female 2 children, no transfusions
• Female donor serology
• HLA class 1 Positive (PRA91)
• HLA class 2 Positive (PRA89)
• Granulocyte immunofluorescence Positive
• Neutrophil-specific Ab Negative
• Granulocyte crossmatch Positive?

64
ARC Product Recall
Case 4 (Pooled PLTs) Recall-FFP
PLT1-male
PLT2-male
PLT3-male
PLT4-male
PLT5-female FFP1 Acute hypotension Death 1 hr Report to FDA
65
Case 5

• 38 yo women with AML s/p an allogenic
  ABO-mismatched MUD transplant 4 months earlier.
  Her transplant complicated by GVHD and BK
  cystitis. She was recently admitted for suspected
  sepsis and meningitis with fever, headache
  nuchal rigidity. She also was treated for
  possible fungal infection of liver. On HOD2,
  she was transfused with 1 unit PLTs and 2 units
  of RBC. Over the course of infusions, the
  patient became increasingly hypoxic and was
  intubated midway thru the 2nd RBC transfusion.
  The patient has a history of mitral valve
  prolapse.

66
Vital Signs Case 3
PLT RBC1 RBC2 Post
Temp 99.3 98.3 98.5 97.5
BP 110/86 110/80 112/84 146/96
HR 93 108 120 114
RR 20 28 36 60
O2 sat 100 (2L NC) 95 81 (6L NC) 60 NRB
Inf rate 25 min 1.5 hrs 2 hr -
67
Case 3 Evaluation

• CXR bilateral patchy confluent opacities
  consistent with multifocal pneumonia, although
  hemorrhage/edema also possible
• Blood Bank Evaluation
• No hemolysis or bacterial contamination
• Fluid balance (2359 in/2000 out)
• Pre/post WBC 8.1 (unchanged)
• Pre/post BNP 1700 pre / gt5000 post!

68
Transfusion-Associated Volume Overload (TACO)

• Excess intravascular volume
• Patients at risk Cardiopulmonary disease
• Chronic anemia
• Infusion gt 2L fluids/hr

69
TACO Features

• Systolic hypertension
• Headache
• Plethora
• Neck vein distension
• Dypsnea

• Hypoxia
• Rales
• Elevated BNP
• CXR-
• cardiomegaly
• fluffy infiltrates

70
Brain Natriuretic Peptide (BNP)

• Heart- response to volume expansion
• Diuretic, natriuretic, and hypotensive effects
• Diagnostic chronic heart failure
• Acute rises helpful in TACO diagnosis

500CHF
gt1.5X rise
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Circulatory Overload (TACO)

• Treatment
• Oxygen
• Diuresis
• If severe, phlebotomy
• 250 mL increments up to 500-1000 mL
• Prevention
• Smaller volumes ? infusion rates
• ex 1 ml/kg/hr
• /- Pre-medicate diuretic

72
Hypotensive Reactions

• Severe hypotension (gt30 mm Hg) within minutes of
  a transfusion.
• Often associated platelet transfusions, apheresis
• Risk factors ACE inhibitors
• critically ill
• bedside leukofiltration
• Voluntary report to FDA (MedWatch) per May 1999
  letter

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Hypotensive Reactions

• Hypotension
• (gt 30 mm Hg ?systolic/diastolic)
• reports of unconsciousness, seizures
• Dyspnea /- O2 saturation
• Flushing
• abdominal pain/cramping, nausea
• /- Fever, chills, rigors
• Rapid resolution of symptoms after stopping
• transfusion

74
charged surface
Factor XII Hageman Factor
XIIa Activated Factor XII
PreKallikrien
Kallikrien
High MW Kininogen
Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Bradykinin
Vasodilation Increased Vascular
Permeability Decreased GI Motility/pain t1/2 lt 30
sec
75
ACE Inhibitors block Bradykinin
Breakdown Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Bra
dykinin (BK)
Angiotensin Converting Enzyme (ACE) 66
Aminopeptidase P 21
Kininase I 3.5
ACE Inhibitors 80 Inhibition
des-Arg9-BK
ACE
76
Hypotensive Reactions

• Treatment
• STOP the transfusion
• Fluid support
• Oxygen
• Symptoms should resolve after stopping infusion
• Prevention
• Change/Hold ACE inhibitors if repeated problems
• Mandatory 24 hour hold for patients undergoing
• HPC collection
• Therapeutic apheresis

77
Bacterial Contamination

• Platelets
• 1100,000 units
• 15000 culture
• seldom fatal
• ? febrile rxns
• Organisms
• Gram positive cocci
• Skin organisms

• Red Cells
• 1 6 million units
• RBC gt 25 days old
• Fatal
• Organisms
• Gram negative rods
• Psychrophilic (4 C)

Transfusion-associated sepsis
78
Diagnostic Features Endotoxin

• Laboratory
• Gram stain, Cx unit
• culture patient
• /- discoloration of unit
• Hematology
• ? WBC with left shift
• Abnormal coags

• Clinical
• High fever
• Chills
• Hypotension
• Shock
• GI-nausea, vomiting, cramps
• Bleeding
• DIC

79
Treatment

• STOP the transfusion
• Fluid, O2 support
• IV Antibiotics
• Monitor/Treat DIC
• Mortality (esp. RBC) 15-50!!

80
Summary
First Tier
CBC diff BNP CXR other
Hemolysis labs Cultures