Common Transfusion Reactions

Randal B. Covin, M.D.Transfusion Medicine Symposium

August 6, 2016

Disclosures

• I have no financial relationships related to this presentation.

• I will not be speaking about any specific commercial product, device, or medication.

• I will not be speaking of any off label use of medications or devices

Objectives

• State the transfusion complication that is prevented by transfusing irradiated blood components

• State the common root cause of ABO hemolytic transfusion reactions and list 2 ways to prevent this

What will be covered?

Covered• Acute

– AHTR– FNHTR– TRALI– TACO– Bacterial sepsis

• Delayed– DHTR

Not Covered• Acute

– Allergic– Anaphylactic reactions

• Delayed– Alloimmunization– TA-GVHD– Iron overload– PTP

Case #1

• John R. Smith is a 71 year-old male admitted to the cardiology unit for unstable angina

• PMH– Coronary artery disease

» 2 vessel disease (LAD, RCA)» s/p stents to both vessels

– Type II DM» oral hypoglycemics

– Hypertension– Hypercholesterolemia

Case #1

• Laboratory Results– Hgb = 8.5 g/dL (14.0-18.0 g/dL)– Hct = 26% (42-52%)– PT = 12.5 sec (11-14.5 sec)– aPTT = 31.0 sec (24-36 sec)

• 2 units of RBC ordered

• Pretransfusion Evaluation– patient’s blood type: A-positive– patient’s antibody screen: negative

Case #1

• Shortly after the 1st unit of RBC was started– left lower back and abdominal pain– temperature increased from 37.2°C to 39.8°C– BP decreased from 130/75 mm Hg to 75/50 mm Hg– urine – dark red

• Transfusion was stopped• A new sample was sent to the blood bank

Blood Bank Evaluation

Pre-transfusion Post-transfusion

Clerical check OK OK

Plasma yellow red

DAT negative positive (C3d)

Antibody screen negative negative

Crossmatch compatible incompatible

Unit blood type A-positive A-positive

Patient blood type A-positive O-positive

Transfusion Reaction

Acute Hemolytic Transfusion Reaction(AHTR)

Case #2

• 38 year-old female s/p hysterectomy for severe abdominal pain and irregular vaginal bleeding due to uterine fibroids unresponsive to other therapy.

• PMH– 2 prior pregnancies– hypertension – well controlled

• Post-op day #2 she develops vaginal bleeding

Case #2

• Laboratory Results– Hgb = 6.4 g/dL (12.0-16.0 g/dL)– Hct = 19% (37-47%)– PT = 12.6 sec (11-14.5 sec)– aPTT = 28.2 sec (24-36 sec)

• 2 units of RBC ordered

• Pretransfusion Evaluation– patient’s blood type: O-negative– patient’s antibody screen: positive (anti-E)

Case #2

• Transfusion was uneventful

• Five days following the transfusion:– temperature increased from 37.2°C to 38.2°C– hemoglobin decreased from 8.9 g/dL to 7.1 g/dL– urine – dark brown– no other signs or symptoms

• A new sample was sent to the blood bank

Blood Bank Evaluation

Previous Evaluation Current Evaluation

Clerical check n/a n/a

Plasma yellow brown

DAT negative positive (IgG)

Antibody screen anti-E anti-E, anti-Jka

Unit blood type O-negative O-negative

Patient blood type O-negative O-negative

Transfusion Reaction

Delayed Hemolytic Transfusion Reaction(DHTR)

faculty.ccbcmd.edu

Hemolytic Transfusion Reactions

• Categorization– Acute: occurs within 24 hours of transfusion– Delayed: occurs after 24 hours of transfusion

• Immunologic incompatibility between blood donor and recipient– red cells– FFP– platelets

www.interactive-biology.com

Acute Hemolytic Transfusion Reaction

• Incidence – 1 : 76,000 – top 3 cause of transfusion-related death– fatal 1 : 1.8 million

• Etiology - red cell incompatibility– ABO– other RBC antigens (e.g. Kell, Duffy, Kidd)

Top 10 Causes of AHTR

1) Clerical Error

2) Clerical Error

3) Clerical Error

4) Clerical Error

5) Clerical Error

6) Clerical Error

7) Clerical Error

8) Clerical Error

9) Clerical Error

10) Clerical Error

Errors

Linden, et al Transfusion 2000; 40:1207-1213

Intravascular vs Extravascular Hemolysis

Intravascular Hemolysis

• Clinical– hemoglobinemia/-uria– fever / chills– hypotension– tachycardia– dyspnea– nausea/vomiting– pain– jaundice – complications if severe

• Laboratory– hemoglobinemia/-uria– ↑ ↑ Bilirubin– ↑ ↑ LDH– +DAT – C3d

Extravascular Hemolysis

• Clinical– fever/chills– jaundice – clinically stable– complications very rare

• Laboratory– hemoglobinemia/-uria – rare– ↑ Bilirubin– ↑ LDH– +DAT - IgG

Differential Diagnosis

• Non-immune hemolysis– thermal injury– hypotonic solutions– mechanical injury– outdated blood

• Autoimmune hemolysis• Bacterial contamination• FNHTR• TRALI• Anaphylactic reactions

Laboratory Evaluation

• clerical check• visual inspection of serum / plasma• DAT• repeat ABO (pre- and post-)• as indicated:

– repeat antibody screen (pre- and post-)– repeat antibody identification (pre- and post-)– repeat crossmatch (pre- and post-)– bilirubin, LDH, haptoglobin, urinalysis, etc.

researchdx.com

Treatment

• Stop the transfusion• Supportive treatment for the patient

– Blood pressure support– maintain urine output (> 1 mL/kg/hr)– pain relief

• Report the reaction to the Blood Bank• Blood for future transfusion

Prevention

• Event reporting system

• Proper patient identification– when samples are drawn– when blood transfused

• Proper labeling of samples at the bedside

• Special wristbands / electronic identification systems

• Two determinations of a patient’s blood type

• Proper laboratory technique and documentation– meticulous attention to detail– good judgment and critical thinking

Aftermath

• Wrong patient was drawn– roommate was drawn instead of the patient– patient was not properly identified prior to phlebotomy

• Patient died from complications following the transfusion reaction.

Questions for Discussion

• What if the DAT had been negative on the post-transfusion sample:– Would that rule-out an AHTR?– Why could the DAT be negative after an AHTR?

• Is it OK to allow the patient’s doctor to correct a mislabeled blood bank specimen if they can positively identify the tube and the patient?

AABB Technical Manual

“When a sample is received in the laboratory, a trained member of the staff must confirm that the information on the label and on the transfusion request is identical. If there is any doubt about the identity of the patient, a new sample must be obtained. It is unacceptable for anyone to correct identifying information on an incorrectly labeled sample.”

Technical Manual, 15th edition. AABB Press, 2005

Delayed Hemolytic Transfusion Reaction

• Incidence 1:5000 – 1:11,000

• Etiology– anamnestic immune response to RBC antigen– rapid production of new antibody (very rare)– usually extravascular hemolysis

• Hemolytic vs serologic

• Most commonly involved antibody:– anti-Jka

Timing of DHTR

020406080

100120140

1-7 8-14 15-21 22-28 29-35 36-42 43-49 >49

Days after Transfusion

Num

ber o

f Cas

es

• Most occur within the first 2 weeks after transfusion

Davenport RD in Popovsky MA, ed. Transfusion Reactions, 4th ed; 2012

Clinical Presentation and Diagnosis

• Clinical Presentation– fever– decreasing hemoglobin– jaundice – new positive antibody screening test

• Laboratory Evaluation– DAT– antibody screen and identification– tests for hemolysis

researchdx.com

Treatment and Prevention

• Treatment– supportive care– identify antibody– transfuse compatible cells as needed

• Prevention– prevention as for AHTR– previous records– honor all previously identified antibodies– not always preventable

Case #3

• 62 year-old male with GI bleeding

• PMH– Cirrhosis

» alcohol abuse» esophageal varices» coagulopathy

– COPD» mild» tobacco use

Case #3

• Laboratory Results– Hgb = 6.5 g/dL (14.0-18.0 g/dL)– Hct = 20% (42-52%)– PT = 20.6 sec (11-14.5 sec)– aPTT = 39.2 sec (24-36 sec)

• 2 units of RBC and 2 units of FFP are ordered for transfusion

• Pretransfusion Evaluation– patient’s blood type = A-positive– patient’s antibody screen = negative

Case #3

• During 2nd unit of RBC– temperature increased from 36.8°C to 38.5°C– mild chills– urine – clear yellow– no other signs or symptoms

• Transfusion was stopped

• A new sample sent to the blood bank

Blood Bank Evaluation

Pre-transfusion Post-transfusion

Clerical check OK OK

Plasma yellow yellow

DAT negative negative

Antibody screen negative negative

Crossmatch compatible compatible

Unit blood type A-positive A-positive

Patient blood type A-positive A-positive

Transfusion Reaction

Febrile, Nonhemolytic Transfusion Reaction (FNHTR)

Incidence

• 0.1-1% of blood transfusions

• Multiple transfusions or pregnancies - risk

• Varies by component– platelets 4.6%– red cells 0.33%– FFP – rare

Clinical Presentation

• Fever– rise in temperature of ≥ 1ºC (2ºF)– not explained by the patient’s clinical condition– may be absent

• Chills / rigors / cold / discomfort• Headache• Nausea / vomiting• Timing

– typically occur towards the end of the transfusion– 5-10% occur 1-2 hours after the transfusion

Etiology

• Alloimmunization – WBC or platelets– Antibodies in patient react with donor WBC or platelets– Donor antibodies react with patient WBC or platelets

• Storage-related cytokines– WBC-derived: IL-1β, IL6, IL8, TNFα, etc.– Platelet-derived: CD154, CCL5, PF4, MIP1α, TGF-β1, etc.

www.sinobiological.com

Differential Diagnosis

• Acute hemolytic transfusion reactions

• Bacterial sepsis

• TRALI

• Patient’s underlying condition

• Medications

Laboratory Evaluation

• Rule-out hemolysis– clerical checks– DAT– visual check for hemolysis– repeat typing / crossmatch– etc.

• Rule-out bacterial sepsis– gram stain– culture

researchdx.com

Treatment and Prevention

• Treatment– stop transfusion– keep IV line open– medication

» fever» shaking chills

• Prevention– leukoreduction of blood components– premedication– slower rate of infusion – washing cellular components

Questions for Discussion

• What if the temperature increases by only:– 1°F?– 0°F?

• Should you send all these units out for culture?

• If the blood bank evaluation is negative can the transfusion be restarted (does the unit have to be discarded)?

Case #4

• 67 year-old male with GI bleed

• PMH– h/o gastric ulcers– h/o GI bleed x 2– hypercholesterolemia– coronary artery disease

» s/p angioplasty» s/p stent placement (LAD, RCA)

Case #4• Laboratory Results

– Hgb = 9.04 g/dL (14.0-18.0 g/dL)– Hct = 27% (42-52%)– Plt = 225,000/μL (130,000-400,000/ μL)

• 1 unit of RBC was ordered for transfusion

• Pretransfusion Evaluation– patient’s blood type = O-negative– patient’s antibody screen = negative

Case #4

• 45 minutes after the completion of the transfusion the patient developed:– severe shortness of breath (dyspnea)– severe decrease in blood oxygen level (hypoxemia)– low blood pressure (hypotension)– temperature increased from 37.1°C to 38.5°C

• Chest x-ray – severe bilateral pulmonary edema

• A new sample was sent to the blood bank

Case #4

Amber Henry, MD, Darrell Triulzi, MD, and Mark Yazer, MD. http://path.upmc.edu/cases/case509.html. May, 2007

Pre-transfusion Post-transfusion

Blood Bank Evaluation

Pre-transfusion Post-transfusionClerical check OK OK

Plasma yellow yellow

DAT negative negative

Antibody screen negative negative

Crossmatch compatible compatible

Unit blood type O-negative O-negative

Patient blood type O-negative O-negative

Clinical Evidence of Volume Overload (per patient’s MD): none

Transfusion Reaction

Transfusion-Related Acute Lung Injury (TRALI)

www.immucor.com

TRALI

•

• Incidence– 1 : 1200–1 : 190,000 components transfused

Graph: Fatalities Reported to FDA Following Blood Collection and Transfusion: Annual Summary for Fiscal Year 2014. www.fda.gov

Clinical Presentation

• Symptoms– dyspnea

• CXR– diffuse, bilateral

alveolar and interstitial infiltrates

– no evidence of cardiac failure

– no other cause for pulmonary failure

• Signs– tachypnea– hypoxemia– cyanosis– fever ≥ 1°C– hypotension– rales

Occurring within 6 hours of transfusion

Two-Hit Model

• First Hit– Clinical status of the patient

» hematologic malignancy» recent surgery (especially CPB)» active infection or sepsis» massive transfusion» kidney and/or liver disease

Two-Hit Model

• Second Hit– Transfusion of an activator

» antibody» non-antibody

bioactive lipids cytokines / cytokine receptors other

Activators

• Antibody-related (75-95%)– donor antibodies (94%)

» HLA (90%)» neutrophil (10%)

– recipient antibodies (6%)

• Non-antibody-related (5-25%)– bioactive lipids– cytokines/cytokine receptors– immunoglobulins

Differential Diagnosis

• Acute lung injury / ARDS

• Transfusion-associated circulatory overload

• Severe allergic / anaphylactic reaction

• Dyspnea of unknown etiology

• Acute hemolytic transfusion reaction

Diagnosis• Rule-out hemolysis, if necessary

• Evaluation– volume status– oxygenation status– CXR– BNP – HLA-typing*– HLA antibody screen and specificity*– Neutrophil antibody screen and specificity*– WBC crossmatch*

* patient and donor

Treatment• Discontinue transfusion• Supportive therapy

– supplemental O2– intubation and mechanical ventilation– intravenous fluids– inotropes and vasopressors

• Additional therapy– corticosteroids– diuretics

Prognosis

• Complete resolution– ≤ 4 days in 80%– > 4 days in 20%

• Mortality = 6-14%

Implicated Components

• All blood components have been implicated

• All types of anticoagulant / preservative solutions have been implicated

• Leukoreduced units have been implicated

• IVIg

Prevention

• High plasma volume products from:– Males– Females with no history of pregnancy– Females with a history of pregnancy who have been

tested and found negative for HLA antibodies

• Pooled solvent/detergent-treated (SD) plasma

• Platelets in platelet additive solutions

Plasma-Containing Components

• High plasma-volume components– FFP– plasma frozen within 24 hours after phlebotomy– cryoprecipitate-reduced plasma– apheresis platelets– buffy-coat-derived platelets– whole blood

• Lower plasma-volume components– red blood cells– platelets prepared from whole blood– cryoprecipitate

Case #5

• 71 year-old male admitted with left lower lobe pneumonia

• PMH– Coronary artery disease

» s/p CABG x 3 – 5 years ago» h/o CHF

– COPD» moderate» quit smoking – 15 years ago

– Type II Diabetes Mellitus – oral hypoglycemic

Case #5

• Laboratory Results– Hgb = 7.2 g/dL (14.0-18.0 g/dL)– Hct = 22% (42-52%)

• 3 units of RBC are ordered for transfusion

• Pretransfusion Evaluation– patient’s blood type = A-positive– patient’s antibody screen = negative

Case #5

• 15 minutes after transfusion of the 3rd unit of RBC the patient developed shortness of breath– decreased blood oxygen level– blood pressure increased slightly– developed a cough productive of white sputum

Case #5

• Further patient evaluation:– I/O = 2250 / 575 cc

• Treatment:– furosemide 60 mg IV

• Response to treatment:– patient responded with 1250 cc of urine output– shortness of breath improved significantly

Case #5

http://www.meddean.luc.edu/lumen/MedEd/medicine/pulmonar/cxr/atlas/cxratlas_f.htm

Post-transfusion Post-treatment

Transfusion Reaction

Transfusion Associated Circulatory Overload (TACO)

Presentation

• Incidence < 1%

• Etiology volume overload

• Clinical Presentation– shortness of breath (dyspnea)– shortness of breath when lying flat (orthopnea)– cough– increased heart rate (tachycardia)– hypertension– headache

Risk Factors

• Small size

• Elderly

• Preexisting heart disease

• Renal failure

• Obstetrical patients

• Chronic anemia100fstreet.com

Diagnosis/Treatment/Prevention

• Diagnosis– chest x-ray– intravascular volume assessment

• Treatment / Prevention– oxygen– upright posture– diuretics– fluid restriction– prevention

» Identifying patients at risk» avoidance of unnecessary transfusions» diuretics» slow rate of infusion / split unit

Case #6

• John D. Smyth is a 67 year-old male admitted for acute myelogenous leukemia.

• PMH– Acute myelogenous leukemia

» s/p induction induction chemotherapy» pancytopenic

– Hypertension– Hypercholesterolemia

Case #6

• Laboratory Results– Hgb = 7.1 g/dL (14.0-18.0 g/dL)– Hct = 22% (42-52%)– Plt = 9/μL (130,000-400,000/μL)

• 1 unit of platelets ordered

• Pretransfusion Evaluation– patient’s blood type: A-positive– patient’s antibody screen: negative

Case #6

• Shortly after the transfusion was started– temperature increased from 37.2°C to 40.1°C– rigors developed– patient became hypotensive (BP = 70/42 mmHg)

• Transfusion was stopped• A new sample was sent to the blood bank

Blood Bank Evaluation

Pre-transfusion Post-transfusion

Clerical check OK OK

Plasma yellow yellow

DAT negative negative

Antibody screen negative negative

Crossmatch N/A N/A

Unit blood type A-positive A-positive

Patient blood type A-positive A-positive

Gram stain platelet unit = gram-negative rods

Transfusion Reaction

Bacterial Sepsis

Bacterial Contamination

• 1:3000 cellular blood components

• Risk varies among blood components– platelets– red blood cells– frozen components (FFP, cryo)

• Where do the bacteria come from?– skin overlying the venipuncture site– unsuspected bacteremia

Increasing Risk

Bacterial Infection

• Most common transfusion-transmitted infection

• Platelet transfusion– Sepsis – 1:107,000– Fatality – 1:1 million

• Red cell transfusion– Sepsis – 1:500,000– Fatality – 1:10 million

Microbiology

• Platelets– skin flora– gram-positive organisms

» Coagulase-negative staphylococci, Propionibacterium acnes» Staphylococcus aureus, Corynebacterium, Streptococci

– gram-negative organisms

• Red Cells– gram-negative organisms

» Yersinia enterocolitica» Serratia liquifaciens» Pseudomonas fluorescens

– gram-positive organisms– autologous units affected as well (? increased risk)

Clinical Presentation• Variable

• Fever

• Chills/rigors

• Hypotension

• Diaphoresis

• Complications – renal failure– ARDS– multiorgan failure– disseminated intravascular coagulation (DIC)

lifespa.com

Diagnosis

• Differential Diagnosis– hemolytic transfusion reaction– FNHTR– TRALI– underlying disease

• Blood Bank Evaluation– rule-out hemolysis– gram stain and culture of unit in question– blood cultures from the patient

Prevention• Appropriate transfusion of blood components

• All components– blood donor screening– skin disinfection prior to venipuncture– diversion of the first 30-50 cc of blood from collection

• Platelet-specific– single-donor (apheresis) platelets– reducing storage duration– bacterial detection

» culture-based» rapid immunoasay

– pathogen inactivation

Component ModificationsModification Decreases risk of or prevention of….Leukoreduction CMV infection

FNHTRalloimmunizationreperfusion injury in CABG

Irradiation TA-GVHD

Washing anaphylcatic reactionsrecurrent allergic reactionsrecurrent FNHTR

Who should get irradiated blood?

• Clearly at risk:– BMT (allo and auto)– Congenital immune deficiency

syndromes– Intrauterine transfusions– Neonatal exchange

transfusions– Hodgkin’s disease– Directed donations from blood

relatives– HLA-matched transfusions– Granulocyte transfusions– Patients treated with purine

analogue drugs (e.g. fludarabine)

• Possibly at risk:– Acute leukemia– Non-Hodgkin’s lymphoma– Low birthweight infants– Extensive chemotherapy/XRT

for solid tumors– Solid organ transplants– ECMO

• Not at risk:– HIV / AIDS

Objectives• State the transfusion

complication that is prevented by transfusing irradiated blood components

• State the common root cause of ABO hemolytic transfusion reactions and list 2 ways to prevent this

TA-GVHD

Clerical error - proper patient identification - proper labeling of samples at the bedside - special wristbands / electronic identification systems - requiring second sample for determining blood type

Any questions?Any answers?Any rags, any bones, any bottles today?

- Professor Quincy Adams Wagstaff, President, Huxley College, 1932.

Perelman SJ, Kalmar B, Ruby H, Johnstone WB. The Four Marx Brothers - Horse Feathers. Paramount Pictures (1932)