Complications of Blood Transfusion:An Overview
Clinical Pathology ConferenceDean Fong, DOJanuary 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.+ BCEcho vegetations c/w endocarditis
12/10 AMReceived 2U FFP 2° PT and PTT
Case Presentation Approximately 20 minutes after transfusion,
pt. developed…Shaking/rigorsTachycardiaHypoxiaNo 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:
12/9 “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”
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:
Pt. is O+, DAT – Backtype on both units FFP – Gram stain -, cultures (after 7 days) – Donor information:
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°)
ImmunologicNon-immunologic
Delayed (> 24°) ImmunologicNon-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-immunizationRBC antigensHLA
Hemolytic Graft-versus-host disease (GVHD) Post-transfusion purpura Immuno-modulation
Delayed (> 24°) Non-Immunologic
Iron overload
Acute (< 24°) Immunologic
HemolyticFever/chills, non-hemolytic
Urticarial/AllergicAnaphylactic
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 ABO-incompatible blood
Etiology 1:38,000 to 1:70,000 Clerical and other human error most common causes of ABO-
incompatible 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
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
Cytokines activation TNF, IL-1, IL-6, IL-8
Coagulation activation Bradykinin
Hemolytic
Laboratory findingsHemoglobinemiaHemoglobinuria LDHHyperbilirubinemia Haptoglobin BUN, creatinine in ARFDAT +
Hemolytic
Differential diagnosisAIHANonimmune hemolysisMicroangiopathic hemolytic anemiaDrug-induced InfectionsAny causes of hemolysis
Hemolytic Treatment/Prevention
Stop transfusionSupportive care to maintain renal function
Goal of urine O/P 100 mL/hr. in adults for at least 18-24 hours
Low dose dopamineTreatment of DIC
? Heparin – direct anticomplement effect
Prevention of clerical/human errors
Acute (< 24°) Immunologic
Hemolytic
Fever/chills, non-hemolyticUrticarial/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…
Between recipient WBC antibodies (HLA, WBC antigens) against transfused WBC in product
Cytokines that accumulates in blood bag during storage
Differential Diagnosis: Other causes of fever ruled out
Hemolytic Bacterial/Septic
Treatment/Prevention Discontinue transfusion? Acetaminophen/meperidine Leukoreduced blood component
Acute (< 24°) Immunologic
HemolyticFever/chills, non-hemolytic
Urticarial/AllergicAnaphylactic
Uritcarial/Allergic Continuum
Mild – urticarial “Anaphylactoid” Severe – anaphylactic
Incidence 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 Proteins in donor plasma
Binds to preformed IgE aby on mast cells Release of histamine
Vasoactive substances C3a, C5a, leukotrienes
Differential Diagnosis: Hemolytic Bacterial TRALI
Treatment/Prevention Discontinue transfusion Antihistamine/steroids Washing of blood products, pretreatment,leukoreduction?
Acute (< 24°) Immunologic
HemolyticFever/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°) Non-Immunologic
Hypotension associated with ACE inhibitionTransfusion-related acute lung injury (TRALI)
Circulatory overloadNonimmune hemolysis
Air embolusHypocalcemia
Hypothermia
Hypotension associated with ACE inhibition
Pt. on ACEI receiving albumin during plasma exchange Etiology
Inhibition of bradykinin catabolism by ACEI Bradykinin activation by activator (low level prekallikrein) in albumin
Bradykinin activation by prekallikrein in plasma protein
Differential diagnosis Rule out hemolysis
Treatment/Prevention Withdraw ACEI/supportative care Avoid albumin Avoid bedside leukofiltration
Acute (< 24°) Non-Immunologic
Hypotension associated with ACE inhibition
Transfusion-related acute lung injury (TRALI)Circulatory overload
Nonimmune hemolysisAir embolus
HypocalcemiaHypothermia
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 (1-2°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?
Between 2001 – 2003, FDA report on causes of transfusion related deaths
TRALI 16.3% ABO/Hemolytic transfusion reaction 14.3% Bacterial contamination 14.1%
UK 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) 358ATR 27 28 34 34 37 38 (49) 44DTR 27 24 31 28 40 33 (46) 32PTP 11 11 10 5 3 3 (3) 1
TA-GVHD 4 4 4 0 1 0 (0) 0TRALI 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) 8Unclassified 0 0 7 0 0 0 0
TOTAL 169 196 255 293 315 363 (478) 480
2001/2002Red cells 2.7 millionPlatelets 250KFresh frozen plasma 385KCryoprecipitate 88KTOTAL 3.4 million
TRALI Pathogenesis
Two current working model hypothesis Both models are directed against increase in pulmonary
microvascular permeability
Pulmonary Microvascular Permeability
Leukocyte AntibodyBioactive Lipids
“Two-Hit” Model
Pulmonary Edema
TRALI UK and SHOT (7 Year Experience)
Data between 1996 to 2003 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
32 Deaths 11 Other Demise
4 Partial Recovery
94 Fully Recovered
TRALI UK and SHOT (cont.)
Serological testing Leukocyte antibody investigation 71 cases of leukocyte antibodies
Incomplete samples or not done
2%
Donor and patient
negative 19%
Patient positive
8%
1 or more donors positive
71%
50 HLA Class I or II
5 HLA and HNA
16 HNA
18 Crossmatched
14 Antibody only in donor
18 Multiple antibodies
TRALI UK and SHOT (cont.)
Products implicated 45/139 FFP/Cryo- 34/139 RBCs 27/139 Platelets
Estimation FFP/Platelet 1 in 50-60K RBC/Cryo- 1 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 Male donor ONLY for FFP 2004 Import FFP for children April 2004 Previously transfused donors
excludedFuture 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°) Non-Immunologic
Hypotension associated with ACE inhibitionTransfusion-related acute lung injury (TRALI)
Circulatory overloadNonimmune hemolysis
Air embolusHypocalcemia
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°) Non-Immunologic
Hypotension associated with ACE inhibitionTransfusion-related acute lung injury (TRALI)
Circulatory overload
Nonimmune hemolysisAir embolus
HypocalcemiaHypothermia
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°) Non-Immunologic
Hypotension associated with ACE inhibitionTransfusion-related acute lung injury (TRALI)
Circulatory overloadNonimmune hemolysis
Air embolusHypocalcemia
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 Citrate rapidly metabolized manifestations transient Prolonged apheresis
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-immunizationHemolytic
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 PRBCs hemolysis Plts. refractoriness
Treatment/Prevention Plts.
Leukoreduction Cross-matched and/or HLA-matched plts.
Delayed (> 24°) Immunologic
Allo-immunization
HemolyticGraft-versus-host disease (GVHD)
Post-transfusion purpuraImmuno-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-immunizationHemolytic
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-immunizationHemolytic
Graft-versus-host disease (GVHD)
Post-transfusion purpuraImmuno-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-immunizationHemolytic
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…
Pt. had received 11 units PRBCs and 2 units Plts. Over plast 1 month
Conclusion… ? TRALI
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 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.