1. Evaluation and Management
of Hemolytic Transfusion Reactions
Raul H. Morales-Borges, MD
Medical Director, Blood Services
American Red Cross, Puerto Rico Region
3. Acute Transfusion Reactions
in the Setting of Incompatible Transfusion
Differential Diagnosis
• Pertinent positives
• Pertinent negatives
Occam’s razor* does not always apply
* All things being equal, the simplest
explanation is usually correct.
Examples: Hyperhemolysis in Sickle Cell
DHTR with aplastic crises
7. Adverse Reactions Signs and Symptoms
• Nausea and/or vomiting
• Generalized bleeding; DIC
• Darkened urine; Hemoglobinuria
• Apprehension; Sensations of impending doom
• ANY adverse manifestation at time of transfusion
should be considered
7
8. Acute immune-mediated hemolysis
– Usually due to transfusion of ABO-
incompatible red cells
– May begin after infusion of as little as 10-
15 mL of blood
– Symptoms may be misleadingly mild
– Early recognition and vigorous treatment
are critical
8
9. Acute immune-mediated hemolysis
• Presentation may include any sign or
symptom, but most typically:
– Fever (may be the only symptom); chills
– Hemoglobinuria, hemoglobinemia
– Hypotension
– Back or flank pain; pain at infusion site
– Generalized bleeding/DIC
– Renal failure
10. Adverse Reaction
• Transfusion should be stopped
• Labels, forms and patient identification should
be rechecked at the bedside
• Patient’s physician and blood bank should be
notified immediately
• Maintain I.V. line with normal saline until
medical evaluation completed
11. Adverse Reaction
• Collect post-transfusion samples and send to
blood bank
– Avoid traumatic venipuncture and mechanical
hemolysis
• Depending on facility policy, send blood
product container, administration set and any
attached fluids to the Blood Bank.
• Urine sample may be useful for evaluation
12. AHTR as Systemic Inflammatory RXN
Common Involvement
Inflammatory Response
AHTR TRALI
Febrile Sepsis
Allergic Hypotensive
Capon, Goldfinger. Transfusion 1995:35;513-20
13. Reaction
Fever &/or Cardiovascular
chills/rigors Respiratory
FNHTR* No
Other Hemolysis
TRALI
Yes Hypotensive
AHTR AHTR
Bacterial Bacterial
Other Anaphylactoid
Volume Overload
Other
*FNHTR = Febrile, non-hemolytic transfusion reaction
14. Reaction
Fever &/or Cardiovascular
chills/rigors Respiratory
FNHTR No
Other Hemolysis
TRALI
Yes Hypotensive
AHTR AHTR
Bacterial Bacterial
Other Anaphylactoid
Volume Overload
Other
Complete clinical assessment
Ancillary laboratory testing
16. First Tier
• Clerical Check
- Bedside and Laboratory
• Repeat ABO/Rh (pre/post)
• Visual Check for Hemolysis
• Direct Antiglobulin Test*
* may be pos or neg with
immune hemolysis due to
RBC destruction
17. Second Tier
• Repeat ABO/Rh units
• Repeat antibody screen
• Repeat special antigen typing
• Full crossmatch
• pre/post-reaction specimens
18. Third Tier
• “Blood Bank Voodoo”
• enhanced techniques
• Clinical findings/history
• Contributing factors
• Ancillary tests-hemolysis
• Other pertinent testing
• Monitoring and treatment
19. Common Causes of Acute Adverse
Reactions - Immunologic
• RBC incompatibility, i.e., RBC antibody
• Antibody to plasma proteins
• Antibody to donor leukocytes
• Donor antibodies to patient leukocytes
19
20. Common Causes of Acute Adverse
Reactions – Non-Immunologic
• Volume overload
• Bacterial Contamination
• Physical or chemical destruction of RBCs
– Incompatible solutions or medications
– Excessive heat
– Freezing
20
22. Laboratory Evaluation
Immediate Investigation:
• Check for Clerical Errors
• Check for Hemolysis
• Check DAT for evidence of blood
group incompatibility
23. Clerical Errors
• The risk of getting the wrong unit of blood
exceeds all transmissible disease risks
combined.
• 1990-1999 data: 1 in 19,000 units was
administered to other than the intended
recipient
– 51% errors at patient care area
– 29% errors in Blood Bank
– 15% multiple, sequential errors
Linden JV, Wagner K, et al. Transfusion 2000
25. Checking for Clerical Errors
• Was the blood transfused
to the intended recipient?
• Was the correct unit
tagged?
• Was the correct unit
issued?
• Was the correct sample
used for testing?
26. Visual Examination for Hemolysis
• Plasma from post-transfusion sample is
inspected for hemolysis
– May appear pink to red if significant hemolysis
has occurred in previous few hours
– May appear deep red/brown or yellowish if
hemoglobin has metabolized to bilirubin
– Increase in bilirubin may begin as early as 1 hour
after reaction, peaks in 5-7 hours and returns to
normal within 24 hours (assuming normal liver
function)
28. Direct Antiglobulin Test
• Used as serologic check for incompatibility
• Perform on post-transfusion specimen; test
pre-transfusion DAT for comparison
• DAT is likely to be positive if incompatible
rbcs or incompatible plasma was transfused
29. Direct Antiglobulin Test
• Incompatible red cell transfusion:
– DAT may have a mixed-field appearance
– If transfused cells were rapidly destroyed, post-
reaction DAT may be negative
– Time sample drawn is important, should be
collected ASAP after reaction occurs
– Type of AHG employed may affect results
30. Additional Evaluation – When?
• If any of initial checks and tests give
positive or suspicious results
• Clinical presentation is consistent with a
Hemolytic Transfusion Reaction (HTR)
31. Repeat ABO grouping
• Standard 7.4.2.1 [26th edition]
“For suspected hemolytic transfusion reactions…, a
repeat ABO group determination shall be performed on
the post-transfusion sample.”
Also repeat ABO testing on pre-transfusion sample and
blood from transfused unit or attached segment.
32. ABO grouping discrepancies
• Error in patient/sample identification
– Pretransfusion sample mislabeled
– Sample mix-up in the laboratory
– Transfusion given to wrong patient
• Error in original ABO-group interpretation
– Recording error
– Problem solving incorrect
• Error in blood product labeling
33. Additional Investigation
Non-Immune Acute Hemolytic Reaction:
• Examine blood in container and lines for abnormal
appearance, hemolysis
• Check records for any incompatible fluids or
medications which may have been administered
with blood
• Interview transfusionist/check records for details
(use of infusion devices, blood product handling, etc.)
Cont’
d
34. Additional Investigation
Causes of Non-Immune Acute Hemolysis
• Defective blood warmers or infusion pumps
• Use of small bore catheters and/or pressure
cuffs for infusion
• Improper storage (too warm, too cold)
– Use of solid ice or dry ice
– Use of microwave ovens, heating pads, room
heaters, hot water, etc. to warm blood
Cont’d
35. Additional Investigation
Causes of Non-Immune Acute Hemolysis
• Incompatible fluids, solutions or medications given
with blood, especially Lactated Ringer’s, 5%
Dextrose, and hypotonic saline solutions.
• The only approved solution for infusion with blood
is 0.9% sodium chloride injection, USP (normal
saline). 5% albumin may be used with physician
approval.
36. Additional Investigations
• Antibody Elution
• Antibody Screen: on post, repeat pre
• Crossmatch
– On pre and post
– With AHG, esp. if not done previously
• Repeat Antigen typings on donor red cells (if
applicable)
• Examination of urine specimen
38. Antibody Elution
• Removal of red-cell-bound antibody
• Common techniques include alteration in pH,
heat, organic solvents, detergents, sonication
• Heat and sonication methods not suitable for
recovering IgG antibodies; not recommended
for investigation of HTR
39. Antibody Elution
• May be helpful even when DAT is negative
• Test eluate for presence of antibody with:
– Antibody screen
– A1 and B cells (when appropriate)
– Cells from transfused donor units
– DAT negative, pre-transfusion autologous
cells (if possible)
40. Antibodies other than ABO
• Repeat antibody screen and crossmatches
– Use segment from container
– Test through AHG-phase
– May want to use different test methods, phases
• Type post-transfusion sample for
corresponding antigen
– May help determine if incompatible cells were
eliminated or if some are still in circulation
41. Other Tests
• Markers of hemolysis:
– Lactate dehydrogenase (LDH)
– Bilirubin
– Haptoglobin
• Most useful if pre- and multiple post-reaction
values are available
• Rising indirect bilirubin is associated with
extravascular hemolysis and HTR caused by
non-ABO antibodies
Cont’d
42.
43. Other types of reactions
Delayed (>24 hours)
– Decreasing Hgb/Hct level, or absence of anticipated
post-transfusion elevation
– Mild to moderate jaundice
– Laboratory evidence of increased cell destruction
(increased bilirubin, LDH, etc)
– Fever
– Hemoglobinuria
– Demonstration of previously undetected rbc
alloantibody in plasma or eluate
44. Non-Hemolytic reactions
Anaphylactic Reactions
Confirmed by demonstration of anti-IgA in the
patient’s plasma or serum. Test is available in
specialized reference laboratories.
Screening for IgA deficiency should be the initial
study. Most patients with IgA-related anaphylaxis
have been IgA deficient.
Subclass or allotype-specific antibodies may develop
in patients with normal IgA levels
45. Non-Hemolytic reactions
Bacterial Contamination
– Onset typically rapid, occurring within 30 minutes
of completion of transfusion
– More common in components stored at RT
– Examine returned unit for abnormal appearance
(brownish or purple discoloration, clots, muddy
appearance)
– Gram’s stain and Culture of blood bag contents
should be performed if clinical presentation
suggests bacterial sepsis
46. Non-Hemolytic reactions
TRALI
– 3rd leading cause of transfusion-associated death
(CBER, FY2001 and FY2002)
– Suspect TRALI with any respiratory distress occurring
during or following blood or blood component
transfusion
– Notify facility that supplied blood component; test
remaining product or donor sample for antibodies to
HLA and/or granulocyte antigens
– Crossmatching donor sera with recipient lymphocytes
or granulocytes can provide supportive evidence
47. Non-Hemolytic reactions
Febrile, Non-Hemolytic (FNHTR)
– Typically present with fever/chills towards ends of
transfusion
– May be due to recipient antibody to donor WBC
antigen
– May also be caused by infusion of cytokines
released from WBCs during storage of component
– Since fever may be initial symptom of acute HTR
or septic reaction, prompt attention is warranted to
r/o life-threatening reaction
48. Non-Hemolytic reactions
Urticarial / Allergic (1% of transfusions)
• Usual presentation: Hives, itching, flushing
• Hypersensitivity immune response
• If symptoms limited to urticaria, may restart unit
after administration of antihistamines per
physician order.
• Report to blood bank; repeated urticarial reactions
will be evaluated to determine if washed blood
products are required.
49. Non-Hemolytic reactions
Circulatory overload
– Usually seen in patients with compromised cardiac
or pulmonary status
– Difficulty breathing, cough, cyanosis, tachycardia,
hypertension, headache, congestive heart failure
– Symptoms usually improve when infusion is
stopped and patient is placed in sitting position
50. Transfusion Associated
Circulatory Overload (TACO)
• The primary symptoms of TACO are: dyspnea, orthopnea, peripheral edema, and
rapid increase of blood pressure.
• It is difficult to determine the incidence of TACO, but its incidence is estimated at
about one in every 100 to 10,000 transfusions. The risk increases with patients over
the age of 60 and patients with cardiac or pulmonary failure, or anemia.
• Transfusion Associated Circulatory Overload is easily prevented by closely
monitoring patients receiving transfusions and transfusing smaller volumes of
blood at a slower rate.
• Differentiation from TRALI: While both are related to transfusion medicine and
both are important, TACO differs from TRALI in part by having longer hospital
stays and increased morbidity.
• The hypotension seen with TRALI and the hypertension seen with TACO provides
a clinical differentiation of the two.
53. INTRAVASCULAR (ACUTE) HEMOLYSIS
Free Hgb
Duvall et al. Hemoglobin catabolism
following an HTR in SS anemia.
Transfusion 1974;14:382-387.
Hemoglobinuria
Haptoglobin
1-6 hr 24 hr
56. EXTRAVASCULAR HEMOLYSIS
Hemoglobin Direct
bilirubin
Direct > Indirect
Indirect
bilirubin
Cummins et al. Ann Clin Biochem 1997:24:109-110.
Day 0 Day 7 Day 14
57. Free Hgb Heme
Spleen
Biliverdin
Indirect
Hgb-Haptoglobin bilirubin
Kidney
Urobilin
GUT Liver
Urobilinogen
Bilirubinuria
Hemoglobinuria Direct bilirubin
60. Peripheral Blood Smear
Anisopoikilocytosis
Spherocytes
Basophilia
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61. Reticulocyte Count
• DHTR, unexplained anemia
• Marrow responsive to anemia?
• Response appropriate?
Critical in hemoglobinopathies
– Differential Diagnosis (DDx): DHTR
with marrow suppression
62. Coagulation Studies
Monitor for Disseminated Intravascular
Coagulation (DIC)
• Platelet count
• Fibrinogen
• PT and aPTT
• D-dimer
64. Intrinsic Pathway
XII
Tissue Damage XIIa
Intrinsic System (aPTT)
XI
XIa
Extrinsic System (PT)
IX
Tissue Factor IXa
VIIa X VIIIa VIII
Xa
Va
II IIa
Fibrinogen Fibrin
65. Extrinsic Pathway
Hgb
Cytokines
ex.TNF Monocyte
XII
XIIa
Intrinsic System (aPTT)
Tissue Factor XI
XIa
Extrinsic System (PT)
IX
IXa
VIIa
X VIIIa VIII
Xa
Va
II IIa
Fibrinogen Fibrin
66. WBC Procoagulant Activity Induced by
ABO Incompatibility
Davenport R, Polar TJ, Kunkel SL.
Transfusion 1994;34:943-9
WBC Procoagulant Activity
ABO Incompatible
ABO Compatible
Time (hours)
67. The role of Disseminated Intravascular
Coagulation in Shock Induced by Transfusion
of Human Blood in Dogs
Takaki A et al. Transfusion 1979;19:404-409.
5 min
Unsensitized Dogs
Sensitized Dogs
Note abrupt immediate drop in platelet count in
both sensitized and unsensitized dogs
69. (-) CHARGED SURFACE
Coagulation Assays
ex. COLLAGEN
PT, aPTT, fibrinogen
XII
Tissue Damage XIIa
Intrinsic System (aPTT)
XI
XIa
Extrinsic System (PT)
IX
Tissue Factor IXa
VIIa X VIIIa VIII
Xa
Va II IIa
Fibrinogen Fibrin
70. Generation and Breakdown of Fibrin
Fibrinogen D E D
a,b
peptides
thrombin
D D E D D E D D
E D D E D D E
Protofibril
Fibrin
Bundles of
protofibrils
(14-22n)
71. Evaluation of DIC
DD EE D D 1. Fall in Fibrinogen
thrombin fibrinopeptide
2. Generation of
D D E D fibrinopeptides a & b
D E D D E D
D D E D
Plasmin plasminogen
D E D D 3. Generation of
fibrin split products
D-dimer
(FDP) and d-dimers
74. Etiology Acute Renal Failure in HTR
• Ischemic
- Shock
- Vasoconstriction afferent renal arteries
o Cytokine mediated (ex IL-1)
o Nitric oxide absorption
• Hgb-induced nephrotoxicity
• Tubular obstruction
• All of the above
75. 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.
DeGowin and Warner, Arch Int Med 1938; 609-630.
76. Normal kidney Kidney with AHTR
nondilated tubules dilated, distended tubules
DeGowin and Warner, Arch Int Med 1938; 609-630.
77. Infusion of Hemoglobin Leads to Vasoconstriction
148
8.5%
126
SBP
93
78 8.3%
DBP
67
HR
56
8.3%
Control Increases in systolic (SBP) and
Period
diastolic (DBP), with
15 gm decreases in heart rate (HR)
Hgb Miller and McDonald, J Clin Invest 1951;1033-1040.
78. Plasma Hgb
175 mg/dl
Urine
11.5 87% 1.5 ml/min 4.6
Renal Blood Flow
673 67%
220 ml/min
2.5 hrs
15 gm Hgb Hemoglobinuria
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Please see the full disclaimer appearing on the Disclaimer slide of this presentation.
85. Treatment: Kidney
Hydration
• Normal saline
• Goal >100 mL urine/hr
• If oliguric, consider addition of diuretics
• If anuric, restrict after 1 liter
86. Treatment: Kidney
Diuretics
• Loop diuretics (Furosemide/Lasix)
• Osmotic agents (Mannitol)
• Additive, synergistic effects
• Precautions
– Not appropriate in all patients
87. Synergism with mannitol
and furosemide
Linear Dose-response
between urine production
and dose/kg BW.
Sirevella et al. Ann Thorac Surg. 2000
88. Furosemide (lasix)
Loop diuretic
• Acts at medullary portion of
ascending limb of Henle
Ascending loop • Inhibits Na+, K+ readsorption
of Henle
• Increase osmosis, H20 loss
(medulla)
89. Furosemide Administration
Adults
• 20-40 mg IV over 1-2 min
• Can be repeated 2 hrs,
Monitor
dose to effect
K+, Na+, glucose
Uric acid, hx gout • Do not exceed 1 gm/day
Renal Insufficiency
Drug Interactions
ACE Inhibitors • 2.5 < 4 mg/min IV infusion
Cardiac glycosides
Aminoglycosides
Pediatric (Edema doses)
Lithium
Indomethacin • 1 mg/kg/dose IV q 4-12 hrs
Ref. DrugPoints
91. Mannitol/Osmitrol Administration
Adults
• 200 mg/kg test dose over 3-5 min.
or 50-100 gm as single dose
• 30-50 ml urine (1-2 hrs)
If no/little response
• Second test dose
• If no response, stop & re-evaluate
Pediatrics
• 0.75 gm/kg over 3-5 min
• If no response, stop
92. Contraindications Mannitol
• Intracranial bleeding*
• Pulmonary edema
• Capillary leak syndromes
• Heart failure*
• Anuria
• Increasing renal failure after
Monitor
Blood pressure
initiation
Renal function • Dehydration
Fluid/electrolytes
*Commonly used in cardiac
surgery and neurosurgery
93. Vascular smooth muscle
Titrate dose to desired effect
• 0.5-2.0 mcg/kg/min IV
– Increase renal perfusion
– No BP
Dopamine • 2-5 mcg/kg/min IV
Sympathomimetic
Vasopressor – Increase renal perfusion
Vasodilator – Increase cardiac output, BP
Contraindications:
• > 5-20 mcg/kg/min
Ventricular fibrillation
Tachyarrhymias – vasoconstriction, urine output
Pheochromocytoma
94. Intermittent Continuous
Diuretics Infusion Solution: 1 gm furosemide
per 500 ml 20% mannitol
Rate: 0.3-0.4 ml/kg/hr
Dopamine Rate:
0.2-0.3 mcg/kg/min
Siverella et al. Ann Thorac Surg 2000; 69:501
Prophylactic infusion of mannitol, furosemide and dopamine
(Group B) significantly decreased the need for post-
operative dialysis due to TCV surgery and pigment
nephropathy (Hgb, myoglobin).
95. Treatment: DIC
• Consider Heparin*
• Blood product support for bleeding
• Hematology consult
*If bleeding despite factor replacement
96. Heparin binds Antithrombin III (ATIII) & IIa (thrombin)
Induces change enzyme conformation ATIII
Increases ATIII inhibitory activity 15-19 fold
Heparin
ATIII ATIII IIa Inhibition IIa
binding
XII
ATIII is broad serine Tissue Damage XIIa
Intrinsic System (aPTT)
XI
Protease inhibitor Extrinsic System (PT)
XIa
IX
Inhibitor of multiple Tissue Factor IXa
coagulation factors VIIa X VIIIa VIII
in the extrinsic and Xa
extrinsic pathways Va
II IIa
Fibrinogen Fibrin
97. Heparin Contraindications:
• Cerebral hemorrhage
Loading dose • Recent neurosurgery
• 5000 units IV • Recent eye surgery
• Recent organ biopsy
Continuous drip • Major arterial injury
• 500-1000 units/hr • Hx heparin-associated
– Thrombosis (HITT)
– Thrombocytopenia
Monitor
• Allergic hypersensitivity
• PTT > 1.5x nl range to heparin
98. Heparin Treatment of Intravascular Coagulation
Accompanying Hemolytic Transfusion Reactions.
Rock RC, Bove JR, Nemerson Y. Transfusion 1969
DIC following transfusion of 260 mls Group A blood to
a Group O patient, treated with heparin
Rise in fibrinogen after
giving heparin
99. Heparin Treatment of Intravascular Coagulation
Accompanying Hemolytic Transfusion Reactions.
Rock RC, Bove JR, Nemerson Y. Transfusion 1969
DIC following transfusion of 2 units Fya incompatible
blood, treated with heparin.
100. Summary
• The importance of prompt recognition and
reporting of suspected Transfusion Reactions
cannot be over-emphasized.
• Assess reactions quickly and efficiently to rule
out the most serious causes first
• Communicate results with responsible
physicians so appropriate actions can be taken
without unnecessary delay
105. Dr. Raúl H. Morales Borges
Hematology/Oncology
• American Red Cross • Ashford Medical Center
– Biomedical Services – Suite # 107
– PR Medical Center – Condado, San Juan
– Tel. 787-759-8100 – Tel. 787-722-0412
– Ext. 3873 – Fax 787-723-0554
– Dir. 787-993-3873 – Cel. 787-354-0758
– Cel. 787-505-5814 – rmoralesborges@yahoo.com
– Raul.Morales@redcross.org
– ww.ihoapr.com