Transcript Complications of Blood Transfusion : An Overview

Complications of
Blood Transfusion:
An Overview
Clinical Pathology Conference
Dean Fong, DO
January 6, 2006
Case Presentation
63 y/o male status post AVR 2° to AS on
11/18.
 Developed fevers, weakness, sternal
erythema, SOB  readmitted on 12/3.

+
BC
 Echo  vegetations c/w endocarditis

12/10 AM
 Received
2U FFP 2°  PT and PTT
Case Presentation

Approximately 20 minutes after transfusion,
pt. developed…
 Shaking/rigors
 Tachycardia
 Hypoxia
 No
change in tempterature during transfusion
Pt. was given benadryl, lasix, intubation and
ventilatory support
 Pt. improved and was extubated later that
afternoon

Case Presentation
PMH: AVR S/P AS, endocarditis, left arm
septic thrombophlebitis
 CXR:

 “fluid overload, unchanged, LLL
consolidation, pneumonia R base”
 12/10 (AM after transfusion)  “bibasilar
atelectasis/consolidation”
 12/10 (later AM)  “↑ pulmonaty edema,
unchanged LLL consolidation)
 12/11  “no change”
 12/9
Case Presentation

Labs:
 HCT
11/20
32.8%
12/10
27.6% (16:00)
12/10
34.7% (20:00)
12/12
34.7%
 Haptoglobin
100 mg/dl (30-200 mg/dl)

Blood bank:
is O+, DAT –
 Backtype on both units FFP –
 Gram stain -, cultures (after 7 days) –
 Donor information:
 Pt.


33 y/o female, O+, G2, CMV+
64 y/o male, O+, CMV+
Case Presentation
DIFFERENTIAL
DIAGNOSIS?
Differential Diagnosis
Circulatory overload
 Pulmonary embolism
 Anaphylactic reaction
 TRALI
 Bacterial/Sepsis

Complications of Transfusion
Transfusion reactions occur in 2% of units or
within 24 hours of use.
 Most common adverse side effects are
usually mild and non-life-threatening
 Two categories:

 Infectious

complications
i.e HIV and HCV  1 transmission/2 million
transfusion
 Non-infectious
complications
Non-infectious Complications of
Transfusions
Technical Manual
 Acute (< 24°)
 Immunologic
 Non-immunologic

Delayed (> 24°)
 Immunologic
 Non-immunologic
Acute (< 24°) Immunologic
Hemolytic
 Fever/chills, non-hemolytic
 Urticarial/Allergic
 Anaphylactic

Acute (< 24°) Non-Immunologic







Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysis
Air embolus
Hypocalcemia
Hypothermia
Delayed (> 24°) Immunologic

Allo-immunization
 RBC
antigens
 HLA
Hemolytic
 Graft-versus-host disease (GVHD)
 Post-transfusion purpura
 Immuno-modulation

Delayed (> 24°) Non-Immunologic

Iron overload
Acute (< 24°)
Immunologic
Hemolytic
Fever/chills, non-hemolytic
Urticarial/Allergic
Anaphylactic
Hemolytic


Most severe hemolytic rxns. occur when transfused RBCs
interact w/ preformed aby
Transfused aby rxns. w/ recipient’s RBCs rarely cause sxs.



May cause accelerated RBC destruction
Can occur after infusion of as little as 10-15 mL ABOincompatible blood
Etiology



1:38,000 to 1:70,000
Clerical and other human error most common causes of ABOincompatible transfusion
CAP survey – 3601 institution


834 HTR over 5 year period w/ 50 (6%) fatality
Mortality estimated to be 1:1,000,000 transfusion
Hemolytic

Highly variable in acuity and severity
 Severe








Fevers and/or chills
Hypotension
Dyspnea
Tachycardia
Pain
DIC
ARF
Shock
Hemolytic

Pathophysiology


Intravascular hemolysis, opsonization, generation of anaphylotoxins
Complement activation  classical pathway







Cytokines activation


IgM and IgG
C1q binds to Ig
C3 activation  cleavage of C3 leads to C3a being released into plasma and C3b
deposition onto RBC membrane
 C3a  proinflammatory effects
 C3b  erythrophagocytosis
C5 cleaved  C5a into plasma
 C5a  proinflammatory (100-fold more potent than C3a)
Assembly of remaining components of the MAC then occurs on RBC surface
Lysis of RBC
TNF, IL-1, IL-6, IL-8
Coagulation activation

Bradykinin
Hemolytic

Laboratory findings
 Hemoglobinemia
 Hemoglobinuria

LDH
 Hyperbilirubinemia
  Haptoglobin
  BUN, creatinine in ARF
 DAT +
Hemolytic

Differential diagnosis
 AIHA
 Nonimmune
hemolysis
 Microangiopathic hemolytic anemia
 Drug-induced
 Infections
 Any causes of hemolysis
Hemolytic

Treatment/Prevention
 Stop
transfusion
 Supportive care to maintain renal function

Goal of urine O/P 100 mL/hr. in adults for at least 1824 hours
 Low
dose dopamine
 Treatment of DIC

? Heparin – direct anticomplement effect
 Prevention
of clerical/human errors
Acute (< 24°)
Immunologic
Hemolytic
Fever/chills, non-hemolytic
Urticarial/Allergic
Anaphylactic
Fevers/chills, non-hemolytic
(FNHTR)


Defined as a rise in temperature of 1°C or greater.
Incidence
 43-75%
of all transfusion rxn.
 PRBCs 0.5-6%
 Plts
1-38%

Signs/Symptoms
 Chills/rigor
 HA
 Vomitting
Fevers/chills, non-hemolytic
(FNHTR)

Etiology

Reaction…



Differential Diagnosis:

Other causes of fever ruled out



Between recipient WBC antibodies (HLA, WBC antigens) against
transfused WBC in product
Cytokines that accumulates in blood bag during storage
Hemolytic
Bacterial/Septic
Treatment/Prevention



Discontinue transfusion?
Acetaminophen/meperidine
Leukoreduced blood component
Acute (< 24°)
Immunologic
Hemolytic
Fever/chills, non-hemolytic
Urticarial/Allergic
Anaphylactic
Uritcarial/Allergic

Continuum




Incidence


Mild – urticarial
“Anaphylactoid”
Severe – anaphylactic
1-3% of all transfusion rxn.
Signs/Symptoms



Uriticarial/hives – upper trunk and neck
Fever
Pulmonary signs (10%) – hoarseness, stridor, “lump in throat”,
bronchoconstriction



No cutaneous involvement
GI – N/V, abd. pain, diarrhea
Circulatory – tachycardia, hypotension
Uritcarial/Allergic

Etiology

Circulating aby against soluable material in the blood


Binds to preformed IgE aby on mast cells


C3a, C5a, leukotrienes
Differential Diagnosis:




Release of histamine
Vasoactive substances


Proteins in donor plasma
Hemolytic
Bacterial
TRALI
Treatment/Prevention



Discontinue transfusion
Antihistamine/steroids
Washing of blood products, pretreatment,leukoreduction?
Acute (< 24°)
Immunologic
Hemolytic
Fever/chills, non-hemolytic
Urticarial/Allergic
Anaphylactic
Anaphylactic


Rare
Incidence





1:18,000 to 170,000
Plt
1:1598-9630
FFP
1:28,831
RBCs
1:23,148-57,869
Signs/Symptoms
 In addition to uritcarial/allergic…

Cardiovascular instability




Cardiac arrhythmia
Shock
Cardiac arrest
More pronounced respiratory involvement
Anaphylactic

Etiology
 IgA aby (IgE, IgG, IgM) in IgA deficiency
 Serum IgA < 5 mg/dL
 Estimated
1 in 342 blood donors
 C4

aby
 Aby against nonbiologic origin
 Haptoglobin deficiency (IgG or IgE anti-haptoglobin)
?
Differential Diagnosis:




Hemolytic
Bacterial
TRALI
Circulatory overload
Anaphylactic

Treatment/Prevention
 Discontinue
transfusion
 Supportive care
 Epinephrine
 Antihistamine/steroids
 In IgA deficient pts.  IgA-deficient product, wash blood
product
Acute (< 24°) NonImmunologic
Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysis
Air embolus
Hypocalcemia
Hypothermia
Hypotension associated with ACE
inhibition


Pt. on ACEI  receiving albumin during plasma exchange
Etiology

Inhibition of bradykinin catabolism by ACEI



Bradykinin activation by prekallikrein in plasma protein
Differential diagnosis


Bradykinin activation by activator (low level prekallikrein) in albumin
Rule out hemolysis
Treatment/Prevention



Withdraw ACEI/supportative care
Avoid albumin
Avoid bedside leukofiltration
Acute (< 24°) NonImmunologic
Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysis
Air embolus
Hypocalcemia
Hypothermia
Transfusion-related acute lung injury
(TRALI)

What Is TRALI?
 Transfusion
related noncardiogenic pulmonary edema
 Differential Diagnosis




Circulatory overload (TACO)
Allergic/Anaphylactic
Bacterial
Acute hemolytic reaction
 Clinical presentation (“classic”, severe form)
 Acute respiratory distress
 Pulmonary edema
 Hypoxemia
 Hypotension
 Transfusion usually within 6 hours (majority of cases during
transfusion or within 2 hours of transfusion)
TRALI

Clinical criteria
 Insidious,
acute onset of pulmonary insufficiency
 Profound hypoxemia  PaO2/FiO2 < 300 mmHg
 CXR  b/l fluffy infiltrates c/w pulmonary edema
 Cardiac  PA wedge pressure  18 mmHg
 No clinical evidence of LA HTN
TRALI

Definition
 TRALI w/out clinical risk factors for ALI:
New ALI temporally related to transfusion
 Worsening of pre-existing pulmonary insufficiency
temporally related to transfusion

 TRALI
in pts. w/ clinical risk factor for ALI:
New ALI temporally related to transfusion
 New ALI thought to be mechasnistically related to the
transfusion
 Worsening of pre-existing pulmonary insufficiency
temporally related to transfusion

TRALI

Syndrome of TRALI (Weber KE et. al., Transfusion
Med Rev, 2003)
 Very

common
Dyspnea, hypoxemia, pulmonary edema, hypotension, fever (12°C increase)
 Common

Tachycardia, cyanosis
 Uncommon

Hypertension

Leukopenia, hypocomplements, monocytopenia
?
TRALI

Implicated Blood Products
 RBCs,
FFP, apheresis platelets, platelet
concentrates
 Rare cases of IVIG, cryo No cases of albumin reported
TRALI

Clinical Course
 100%
TRALI patients require O2 and 72% require
ventilation support
 81% resolves within 4 days and 17% resolve within 7
days

Most pts. recover with 72 hours
 Mortality
rate 6% (subsequent series up to 14-25%)
 No long term sequela

Treatment
 Respiratory
support
 No role for treatment w/ steroids or diuretics
TRALI

Why Is TRALI Important?
2001 – 2003, FDA report on causes of
transfusion related deaths
 Between



TRALI
ABO/Hemolytic transfusion reaction
Bacterial contamination
 UK

16.3%
14.3%
14.1%
SHOT Data 7 years experience (from 1996)
Total 155 cases

32 Deaths
TRALI

Why Is TRALI Important? (cont.)
 UK
SHOT Data 7 years experience (from 1996)
Reaction Type 1996/1997 1997/1998 1998/1999 1999/2000 2000/2001
2001/2002
2003
IBCT
81
110
144
201
213
258 (343)
358
ATR
27
28
34
34
37
38 (49)
44
DTR
27
24
31
28
40
33 (46)
32
PTP
11
11
10
5
3
3 (3)
1
TA-GVHD
4
4
4
0
1
0 (0)
0
TRALI
11 (6.5%) 16 (8.2%) 16 (6.3%) 19 (6.5%) 15 (4.8%) 26 (7.2%) (32) (6.7%) 37 (7.7%)
TTI
8
3
9
6
6
5 (5)
8
Unclassified
0
0
7
0
0
0
0
TOTAL
169
196
255
293
315
363 (478)
480
2001/2002
Red cells 2.7 million
Platelets 250K
Fresh frozen plasma 385K
Cryoprecipitate 88K
TOTAL 3.4 million
TRALI

Pathogenesis
 Two
current working model hypothesis
 Both models are directed against increase in pulmonary
microvascular permeability
Bioactive Lipids
Leukocyte Antibody
“Two-Hit” Model
 Pulmonary Microvascular Permeability
Pulmonary Edema
TRALI

UK and SHOT (7 Year Experience)
 Data between 1996 to 2003




32 Deaths
Define TRALI as “Acute dyspnea, hypoxia, bilateral
pulmonary infiltrates within 24 hours after transfusion with
no other apparent causes”
1996
< 10 cases
2003
 40 cases
Total
155 cases
 138 cases examined, others were excluded
11 Other
Demise
4 Partial
Recovery
94 Fully
Recovered
1 or more
donors positive
71%
TRALI

UK and SHOT (cont.)
 Serological


50 HLA
Class I or II
testing
Leukocyte antibody investigation
71 cases of leukocyte antibodies
16 HNA
5 HLA and
HNA
18 Crossmatched
14 Antibody only in donor
18 Multiple antibodies
Patient
positive
8%
Donor and
patient
negative
19%
Incomplete
samples or
not done
2%
TRALI

UK and SHOT (cont.)
 Products implicated
45/139
 34/139
 27/139

FFP/CryoRBCs
Platelets
 Estimation
FFP/Platelet
1 in 50-60K
 RBC/Cryo1 in 500-600K
 Frequency
1 in 1,000-2,500 patients transfused
 Would expect to see 300-750 cases/year

TRALI

UK and SHOT
 What UK is doing



October 2003
2004
April 2004
Male donor ONLY for FFP
Import FFP for children
Previously transfused donors
excluded
 Future Considerations
 ? Male plasma only to suspend platelet pools
 ? Female apheresis platelet donor for leukocyte antibody
 ? Effects of decreased plasma (additive solution) in
platelet concentrates/apheresis platelets
 ? Mild TRALI. Does it exist?
Acute (< 24°) NonImmunologic
Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysis
Air embolus
Hypocalcemia
Hypothermia
Circulatory overload


Acute pulmonary edema due to volume overload
Incidence
 One
of the most common complications of transfusion
 Young children and elderly at risk
 Cardiac and pulmonary compromise
 Chronic anemia with expanded plasma volume
 Infusion of 25% albumin


Shifts large volume of extravascular fluid into the vascular space
Signs/Symptoms
 Dyspnea,
cyanosis, orthopnea, severe HA, HTN, CHF
during or soon after transfusion
Circulatory overload

Differential diagnosis:
 TRALI
 Allergic
rxn.
 Other causes of CHF

Treatment/Prevention
 Stop
transfusion
 Supportive care
 Phlebotomy
 Diuretic
 Slow transfusion


Usually 4 hours, can be extended to 6 hours
Other strategies
Acute (< 24°) NonImmunologic
Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysis
Air embolus
Hypocalcemia
Hypothermia
Nonimmune hemolysis


Lysis of RBCs as a result of storage, handling, or
transfusion condition
Incidence
 Rare

Signs/Symptoms
 Transient
hemodynamic
 Pulmonary impairment
 Renal impairment
 Hemoglobinemia and hemoglobinuria
 Hyperkalemia (renal failure)
 Fever
Nonimmune hemolysis

Differential diagnosis






Hemolytic
Autoimmune
Bacterial/sepsis
PNH, drug-induced, oxidative stress, etc.
Diagnosis of exclusion
Treatment/Prevention






Stop transfusion
Investigation of blood bag and tubing
Investigate for hemolytic transfusion rxn.
Check serum K
Supportive care
Maintain urine O/P (except for contraindication…i.e. renal failure)
Acute (< 24°) NonImmunologic
Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysis
Air embolus
Hypocalcemia
Hypothermia
Air embolus
Air infusion via line
 Rare
 Cough, dyspnea, chest pain, shock
 If suspected…

 Pt.

placed on left side with head down
Displace air bubble from pulmonary valve
Hypocalcemia

Large volumes of FFP, whole blood, plts.
transfused rapidly  plasma citrate levels may
rise  binds iCa+2
rapidly metabolized  manifestations transient
 Prolonged apheresis
 Citrate


Periorbal/peripheral tingling paresthesias,
shivering, lightheadedness, tetanic sxs.,
hyperventilation, depressed cardiac function
Ca+2 replacement
Hypothermia

Rapid infusion of large volumes of cold blood
 Ventricular
arrhythmias
 More likely via central catheters
 Increased toxicity of hypocalcemia and hyperkalemia
 Impaired hemostasis
 Increase caloric requirement

Blood warmer
Delayed (> 24°)
Immunologic
Allo-immunization
Hemolytic
Graft-versus-host disease (GVHD)
Post-transfusion purpura
Immuno-modulation
Allo-immunization


Occurs weeks to months after transfusion
Incidence
 1-1.6%
to RBC antigens
 10% to HLA

Signs/Symptoms
 hemolysis
 Plts.  refractoriness
 PRBCs

Treatment/Prevention
 Plts.


Leukoreduction
Cross-matched and/or HLA-matched plts.
Delayed (> 24°)
Immunologic
Allo-immunization
Hemolytic
Graft-versus-host disease (GVHD)
Post-transfusion purpura
Immuno-modulation
Hemolytic

Once allo-immunization has occurred, abys may diminish to
undetectable levels



Especially Kidd system (anti-Jka and anti-Jkb)
Hemolysis typically extravascular
Anamnestic response


W/in hours or days (up to 6 weeks), IgG aby reacts with transfused
red cells
Prospective study


58 of 2082 (2.8%) RBC recipients were found to have alloabys (previous
undetected) w/in 7 days of transfusion
Incidence


Based on above study, only 1 recipient w/ new aby w/in 7 days of
transfusion was shown to have hemolysis
Estimated rate



1 in 2082 recipients
1 in 11,328 units
Other reports at 0.02 to 0.009%
Hemolytic

Signs/Symptoms
 Fever
 Declining
Hb
 Mild jaundice
 Hemoglobinuria
 ARF – uncommon


Check for alloaby in both serum and RBC
Treatment/Prevention
 Rarely
necessary
 May need to monitor urine O/P, renal function,
coagulation functions
 IVIG
 Appropriate units for transfusion
Delayed (> 24°)
Immunologic
Allo-immunization
Hemolytic
Graft-versus-host disease (GVHD)
Post-transfusion purpura
Immuno-modulation
Graft-versus-host disease
(GVHD)

Fatal complication cause by engraftment and clonal
expansion of donor lymphocytes in susceptible host

Attack recipient tissues
 Immunocompromised pts.







Hematologic malignancies or certain solid tumors receiving
chemotherapy radiation
Stem cell transplant
Recipients of HLA matched products or familial blood donation
Lupus or CLL requiring fludarabine
Not reported in AIDS pts.
2-30 days after transfusion
Incidence

Rare (0.002-0.005%)
GVHD

Signs/Symptoms
 Appears
w/in 10-12 days of transfusion
 Skin – whole body erythroderma, desquamation
 GI  N/A, diarrhea
 Liver
 BM  failure leading to pancytopenia

Treatment/Prevention
 No
effective treatment
 Gamma irradiation


Render T-cells incapable of replication
FDA requirement


Minimum of 2500 cGy target to the midline of the container
Minimum of 1500 cGy target to all other part of component
Delayed (> 24°)
Immunologic
Allo-immunization
Hemolytic
Graft-versus-host disease (GVHD)
Post-transfusion purpura
Immuno-modulation
Post-transfusion Purpura (PTP)

Characterized by abrupt onset of severe
throbocytopenia (< 10K)

Average of 9 days (range 1-24 days)
 PRBCs or whole blood
 Reported in plts., plasma, frozen deglycerolized PRBCs

Incidence

Rare
 Over 200 cases published
 Male:Female
1:5
 Median age
51 years (range 16-83)

Clinical course

Usually self-limited, recovery w/in 21 days
 10-15% mortality

Intracranial hemorrhage
PTP

Signs/Symptoms

Profound thrombocytopenia
 Purpura
 Bleeding
 Fever (reported)

Etiology

Plt. specific IgG aby that are auto-aby


All HPA implicated but HPA-1a most common
3 mechanisms



Immune complex – pt. aby and donor antigen
Concersion of antigen- autologous plts. to aby targets to antigen in
transfused components
Cross-reactivity of pts. autoaby w/ autologous plts.
PTP

Differential diagnosis








ITP
TTP
Alloimmunization
Sepsis
DIC
BM failure
Drug-induced
Treatment/Prevention
Steroids – controversial
 Plasma exchange – achieves plts. counts to 20K in 1-2 days (up to 12 days)
 IGIV – recovery of plts. Counts of 100K w/in 3-5 days
 Block aby-mediated clearance



Splenectomy – refractory pts., high risk of life-threatening
hemorrhage
Plts. transfusion not effective
 Antigen-negative blood product
Delayed (> 24°)
Immunologic
Allo-immunization
Hemolytic
Graft-versus-host disease (GVHD)
Post-transfusion purpura
Immuno-modulation
Immuno-modulation
? Increases risk of recurrent cancer and
bacterial infection
 WBCs  cytokines during storage 
interfere w/ immune function
 Uncertain clinical significance
 Leukoreduction of blood products

Delayed (> 24°)
Non-Immunologic
Iron overload
Iron overload




Each unit of PRBC  200-225 mg of Fe
Chronic transfusion
> 50-100 units of PRBC
Storage in RE sites  saturation  other sites
 Heart,

liver, endocrine glands (pancreas)
Removal of Fe
 Desferoxamine

– Fe-chelating agent
Chronic transfusion in hemoglobinopathy
 Prolong
intertransfusion interval or PRBC exchange
Case Presentation
Follow-up
Case Presentation

Donor FFP from 33 y/o female (G2)


Anti-HLA aby resulted positive for several anti-HLA aby
Recipient


Positive anti-HLA aby, HLA Class II antigen, HLA DQ1
But…


Conclusion…

? TRALI



Pt. had received 11 units PRBCs and 2 units Plts. Over plast 1 month
Pt. was transfused with 2 U FFP over a 6 hour period w/out incident
? Other
Recommendation…


? What to do with donor
? What to do with patient
References
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Brecher ME et. al., Technical Manual, 14th Ed., AABB Press, 2002.
Davenport RD, “Pathophysiology of Hemolytic Transfusion Reactions”
Seminars in Hematology 2005; 42: 165-168.
Gilstad CW, “Anaphylactic transfusion reactions”, Current Opinion in
Hematology 2003; 10: 419-423.
Kuriyan M, Carson JL, “Blood transfusion risks in the intensive care unit”,
Crit Care Clin 2004; 20: 237-253.
MacLennan S, Barbara JAJ, “Risks and side effects of therapy with
plasma and plasma fractions”, Best Practice and Research Clinical
Haematology 2006; 19(1): 169-189.
Mintz PD, Transfusion Therapy Clinical Principles and Practice, AABB
Press, 2005.
Shander A, Popovsky MA, “Understanding the Consequences of
Transfusion-Related Acute Lung Injury”, Chest 2005; 128: 598-604.
Silliman CC, McLaughlin NJD, “Transfusion-related acute lung injury”,
Blood Reviews 2005; article in press.