Complications of Blood Transfusion: An Overview

1
Complications of Blood TransfusionAn Overview

• Clinical Pathology Conference
• Dean Fong, DO
• January 6, 2006

2
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

3
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

4
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

5
Case Presentation

• Labs
• HCT 11/20 32.8
• 12/10 27.6 (1600)
• 12/10 34.7 (2000)
• 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

6
Case Presentation

• DIFFERENTIAL DIAGNOSIS?

7
Differential Diagnosis

• Circulatory overload
• Pulmonary embolism
• Anaphylactic reaction
• TRALI
• Bacterial/Sepsis

8
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

9
Non-infectious Complications of Transfusions

• Technical Manual
• Acute (lt 24)
• Immunologic
• Non-immunologic
• Delayed (gt 24)
• Immunologic
• Non-immunologic

10
Acute (lt 24) Immunologic

• Hemolytic
• Fever/chills, non-hemolytic
• Urticarial/Allergic
• Anaphylactic

11
Acute (lt 24) Non-Immunologic

• Hypotension associated with ACE inhibition
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Nonimmune hemolysis
• Air embolus
• Hypocalcemia
• Hypothermia

12
Delayed (gt 24) Immunologic

• Allo-immunization
• RBC antigens
• HLA
• Hemolytic
• Graft-versus-host disease (GVHD)
• Post-transfusion purpura
• Immuno-modulation

13
Delayed (gt 24) Non-Immunologic

• Iron overload

14
Acute (lt 24) Immunologic

• Hemolytic
• Fever/chills, non-hemolytic
• Urticarial/Allergic
• Anaphylactic

15
Hemolytic

• Most severe hemolytic rxns. occur when transfused
  RBCs interact w/ preformed aby
• Transfused aby rxns. w/ recipients RBCs rarely
  cause sxs.
• May cause accelerated RBC destruction
• Can occur after infusion of as little as 10-15 mL
  ABO-incompatible blood
• Etiology
• 138,000 to 170,000
• 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 11,000,000 transfusion

16
Hemolytic

• Highly variable in acuity and severity
• Severe
• Fevers and/or chills
• Hypotension
• Dyspnea
• Tachycardia
• Pain
• DIC
• ARF
• Shock

17
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

18
Hemolytic

• Laboratory findings
• Hemoglobinemia
• Hemoglobinuria
• ? LDH
• Hyperbilirubinemia
• ? Haptoglobin
• ? BUN, creatinine in ARF
• DAT

19
Hemolytic

• Differential diagnosis
• AIHA
• Nonimmune hemolysis
• Microangiopathic hemolytic anemia
• Drug-induced
• Infections
• Any causes of hemolysis

20
Hemolytic

• Treatment/Prevention
• Stop transfusion
• Supportive care to maintain renal function
• Goal of urine O/P 100 mL/hr. in adults for at
  least 18-24 hours
• Low dose dopamine
• Treatment of DIC
• ? Heparin direct anticomplement effect
• Prevention of clerical/human errors

21
Acute (lt 24) Immunologic

• Hemolytic
• Fever/chills, non-hemolytic
• Urticarial/Allergic
• Anaphylactic

22
Fevers/chills, non-hemolytic (FNHTR)

• Defined as a rise in temperature of 1C or
  greater.
• Incidence
• 43-75 of all transfusion rxn.
• PRBCs 0.5-6
• Plts 1-38
• Signs/Symptoms
• Chills/rigor
• HA
• Vomitting

23
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

24
Acute (lt 24) Immunologic

• Hemolytic
• Fever/chills, non-hemolytic
• Urticarial/Allergic
• Anaphylactic

25
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

26
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,leukoreduc
  tion?

27
Acute (lt 24) Immunologic

• Hemolytic
• Fever/chills, non-hemolytic
• Urticarial/Allergic
• Anaphylactic

28
Anaphylactic

• Rare
• Incidence
• 118,000 to 170,000
• Plt 11598-9630
• FFP 128,831
• RBCs 123,148-57,869
• Signs/Symptoms
• In addition to uritcarial/allergic
• Cardiovascular instability
• Cardiac arrhythmia
• Shock
• Cardiac arrest
• More pronounced respiratory involvement

29
Anaphylactic

• Etiology
• IgA aby (IgE, IgG, IgM) in IgA deficiency
• Serum IgA lt 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

30
Anaphylactic

• Treatment/Prevention
• Discontinue transfusion
• Supportive care
• Epinephrine
• Antihistamine/steroids
• In IgA deficient pts. ? IgA-deficient product,
  wash blood product

31
Acute (lt 24) Non-Immunologic

• Hypotension associated with ACE inhibition
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Nonimmune hemolysis
• Air embolus
• Hypocalcemia
• Hypothermia

32
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

33
Acute (lt 24) Non-Immunologic

• Hypotension associated with ACE inhibition
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Nonimmune hemolysis
• Air embolus
• Hypocalcemia
• Hypothermia

34
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)

35
TRALI

• Clinical criteria
• Insidious, acute onset of pulmonary insufficiency
• Profound hypoxemia ? PaO2/FiO2 lt 300 mmHg
• CXR ? b/l fluffy infiltrates c/w pulmonary edema
• Cardiac ? PA wedge pressure ? 18 mmHg
• No clinical evidence of LA HTN

36
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

37
TRALI

• Syndrome of TRALI (Weber KE et. al., Transfusion
  Med Rev, 2003)
• Very common
• Dyspnea, hypoxemia, pulmonary edema, hypotension,
  fever (1-2C increase)
• Common
• Tachycardia, cyanosis
• Uncommon
• Hypertension
• ?
• Leukopenia, hypocomplements, monocytopenia

38
TRALI

• Implicated Blood Products
• RBCs, FFP, apheresis platelets, platelet
  concentrates
• Rare cases of IVIG, cryo-
• No cases of albumin reported

39
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

40
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

41
TRALI

• Why Is TRALI Important? (cont.)
• UK SHOT Data 7 years experience (from 1996)

2001/2002 Red cells 2.7 million Platelets
250K Fresh frozen plasma 385K Cryoprecipitate
88K TOTAL 3.4 million
42
TRALI

• Pathogenesis
• Two current working model hypothesis
• Both models are directed against increase in
  pulmonary microvascular permeability

Bioactive Lipids Two-Hit Model
Leukocyte Antibody
? Pulmonary Microvascular Permeability
Pulmonary Edema
43
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 lt 10 cases
• 2003 ? 40 cases
• Total 155 cases
• 138 cases examined, others were excluded

94 Fully Recovered
4 Partial Recovery
32 Deaths
11 Other Demise
44
TRALI
1 or more donors positive 71

• UK and SHOT (cont.)
• Serological testing
• Leukocyte antibody investigation
• 71 cases of leukocyte antibodies

Patient positive 8
Donor and patient negative 19
16 HNA
50 HLA Class I or II
5 HLA and HNA
Incomplete samples or not done 2
18 Crossmatched 14 Antibody only in donor 18
Multiple antibodies
45
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

46
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
  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?

47
Acute (lt 24) Non-Immunologic

• Hypotension associated with ACE inhibition
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Nonimmune hemolysis
• Air embolus
• Hypocalcemia
• Hypothermia

48
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

49
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

50
Acute (lt 24) Non-Immunologic

• Hypotension associated with ACE inhibition
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Nonimmune hemolysis
• Air embolus
• Hypocalcemia
• Hypothermia

51
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

52
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 contraindicationi.
  e. renal failure)

53
Acute (lt 24) Non-Immunologic

• Hypotension associated with ACE inhibition
• Transfusion-related acute lung injury (TRALI)
• Circulatory overload
• Nonimmune hemolysis
• Air embolus
• Hypocalcemia
• Hypothermia

54
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

55
Hypocalcemia

• Large volumes of FFP, whole blood, plts.
  transfused rapidly ? plasma citrate levels may
  rise ? binds iCa2
• Citrate rapidly metabolized ? manifestations
  transient
• Prolonged apheresis
• Periorbal/peripheral tingling paresthesias,
  shivering, lightheadedness, tetanic sxs.,
  hyperventilation, depressed cardiac function
• Ca2 replacement

56
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

57
Delayed (gt 24) Immunologic

• Allo-immunization
• Hemolytic
• Graft-versus-host disease (GVHD)
• Post-transfusion purpura
• Immuno-modulation

58
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.

59
Delayed (gt 24) Immunologic

• Allo-immunization
• Hemolytic
• Graft-versus-host disease (GVHD)
• Post-transfusion purpura
• Immuno-modulation

60
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

61
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

62
Delayed (gt 24) Immunologic

• Allo-immunization
• Hemolytic
• Graft-versus-host disease (GVHD)
• Post-transfusion purpura
• Immuno-modulation

63
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)

64
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

65
Delayed (gt 24) Immunologic

• Allo-immunization
• Hemolytic
• Graft-versus-host disease (GVHD)
• Post-transfusion purpura
• Immuno-modulation

66
Post-transfusion Purpura (PTP)

• Characterized by abrupt onset of severe
  throbocytopenia (lt 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
• MaleFemale 15
• Median age 51 years (range 16-83)
• Clinical course
• Usually self-limited, recovery w/in 21 days
• 10-15 mortality
• Intracranial hemorrhage

67
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.

68
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

69
Delayed (gt 24) Immunologic

• Allo-immunization
• Hemolytic
• Graft-versus-host disease (GVHD)
• Post-transfusion purpura
• Immuno-modulation

70
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

71
Delayed (gt 24) Non-Immunologic

• Iron overload

72
Iron overload

• Each unit of PRBC ? 200-225 mg of Fe
• Chronic transfusion
• gt 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

73
Case Presentation

• Follow-up

74
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

75
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.