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Diagnosis & Management of Diagnosis & Management of Transfusion ReactionsTransfusion Reactions
Christopher J. Gresens, M.D.
VP & Medical Director, Clinical Services
BloodSource
Outline• Brief Contextual Discussions
– How We Manufacture Blood Components– Donor Blood Testing and the Transfusion
Transmitted Diseases
• Acute Transfusion Reactions• Delayed Transfusion Reactions• Evaluation/Management of Suspected
Transfusion Reactions• Miscellaneous Transfusion Reactions• Q & A
How We Make Blood ComponentsCollection Process((1) 1) Via Whole Blood DonationVia Whole Blood Donation: : Whole blood is collected from healthy Whole blood is collected from healthy blood donors into sterile blood bags blood donors into sterile blood bags that contain anticoagulant-preservative.that contain anticoagulant-preservative.
(2) (2) Via ApheresisVia Apheresis: Machines with : Machines with internal centrifuges separate a donor’s internal centrifuges separate a donor’s blood into individual components blood into individual components (e.g., platelets, plasma, RBCs, etc.). (e.g., platelets, plasma, RBCs, etc.). The desired components are retained, The desired components are retained, while the remainder is returned to the while the remainder is returned to the donor.donor.
Donor interview process
Finger-stick capillary blood sampling
CuSO4 Hemoglobin determination
Note: Other methods can also be used for this purpose.
BP, Pulse, and Temperature Check
The Collection Process
Arm Disinfection Prior to Donation
Phlebotomy (16 Gauge Needle)
The Collection Process
Multi-bag whole blood collection kits
Flow of whole blood into primary bag
Whole Blood Collection
Blood Component Manufacture fromBlood Component Manufacture fromWhole Blood (As Done in the USA)Whole Blood (As Done in the USA)
RBCsRBCs
Platelet-Rich Platelet-Rich PlasmaPlasma
WHOLE
BLOOD +Centrifuge
(low g forces)
Centrifuge Used for Component Manufacture
Multi-pack Collection Bag
Centrifuge - Interior
Blood Component Manufacture from Whole Blood
RBCsRBCs
Platelet-Rich Platelet-Rich PlasmaPlasma
+
or
Centrifuge
(higher g forces)
Freeze
Fresh Frozen Plasma (FFP)or
“Plasma Frozen with 24 hours”
Plasma
Platelets
+
• Leukoreduce• Possibly irradiate• Other
Blood ComponentManufacture from Whole Blood
FreshFrozenPlasma(FFP)
Cryo-Reduced Plasma
Cryoprecipitate
+•Thaw (4° C)
•Centrifuge
Using the “Leftovers” Wisely
Plasma DerivativesPlasma Derivatives AlbuminAlbumin Factor VIIIFactor VIII Immune globulinImmune globulin etc. etc.
Sent for
further processing
Plasma
Plasma
(of any kind)
(of any kind)
Blood can be optimally utilized by the
use of specifically required components instead of whole blood…
RBC
FFP
PLT
“Shotgun” Approach vs. . . .
Component Therapy
The Principles of Apheresis
Anticoagulant added
Remainingblood constituents
returned
Bloodconstituents separated by centrifuge and selectively
collected
(vein) (vein)
Plasma
Platelets
Mononuclear Cells
Granulocytes
Red Blood Cells
Whole Blood Whole Blood
Caridian BCT Trima Accel
Haemonetics PCS-2
Typically200 mL
to800 mL
Plasma Collected Via Apheresis
FFP Made from Apheresis
Donor sample tubes being readied for testing
Infectious Disease testing (Abbott PRISM)
Chagas Disease Testing (Ortho Platform)
NAT – We recently converted to Chiron Ultrio (HIV, HBV, and HCV); we also do WNV by NAT
Olympus PK-7200 (ABO, Rh, syphilis)
CBC analysis by Pentra XL-80
Platelet Bacterial Detection QC Testing by
BacT/ALERT
Donor Blood Testing
• ABO
• Rh
• Antibody Screen
• Infectious Diseases– Syphilis– HBsAg– Anti-HIV-1/2– Anti-HBc
Donor Blood Testing
• Infectious Diseases– Anti-HTLV-I/II– Anti-HCV– HIV Nucleic acid testing (NAT)– HCV NAT– WNV NAT– Anti-T. cruzi (Chagas disease)– (On some units) Anti-CMV
Transfusion Risks
• HIV: 1 in 2,135,000 units• HBV: 1 in 205,000-to-488,000 units • HCV: 1 in 1,935,000 units• HTLV-I/II: 1 in 514,000-2,993,000 units• CMV: << 1: 100 (when leukoreduced or CMV-
negative blood used)• WNV: ? (region-specific; very low)• vCJD: ? (risk very, very low—even in U.K.)Infectious Risks of Blood Transfusion. Blood Bulletin (America’s Blood Centers). December 2001.
Acute Transfusion Reactions
Case Study
• 42-year-old male; S/P CABG surgery; group O
• Transfused with 2 units RBCs postoperatively
• Develops nausea, 1.5° C temperature elevation, hypotension, and red urine
• Pre-transfusion DAT 0; post-transfusion DAT 4+
• Diagnosis and Management???
Acute Immune-Mediated Hemolytic Transfusion Reactions
• Cause: Antigen-antibody reactions• Consequences: Shock, DIC, acute renal failure, and/or
(sometimes) death• Presentation: Fever/chills, hypotension, nausea,
chest/back/infusion site pain, flushing, dyspnea, hemoglobinuria, oliguria, anuria, shock, generalized bleeding
• Pathophysiology: Complement, coagulation, and neuroendocrine system involvement
• Therapy: Treat hypotension, renal, and other problems• Prevention: Vigilance
A Pictorial Representation of What Happens
Acute Non-Immune Hemolytic Transfusion Reactions
• Examples:• Osmotic lysis• Accidental freezing• Accidental overheating• Inadequate deglycerolization• Mechanical hemolysis• Intrinsic defects in either donor’s or
recipient’s RBCs (e.g., G-6PD deficiency, sickle cell disease)
Case Study
• 7-year-old female with AML; post-chemotherapy; group A
• Transfused ½ plateletpheresis unit (CMV-negative, irradiated, & leukoreduced)
• 20 minutes into transfusion, developsnausea, 2.4° C temperature elevation, hypotension, and red urine
• Diagnosis and Management???
Septic Transfusion Reactions• Presentation: High fever, shock, DIC,
hemoglobinuria, renal failure, GI complications, generalized muscle pain
• RBC Contaminants: Yersinia enterocolitica, Pseudomonas species, E. coli, etc.
• Platelet Contaminants: Coagulase-negative Staphylococci, Salmonella, Staphylococcus aureus, etc.
• Prevention: QC testing of all platelets, visual inspection of all blood products
Bacteria from donor arm’s skinbefore and after cleansing
AfterBefore
Case Study
• 60-year-old male; GI bleeding; group AB
• Transfused one unit RBCs
• 2 minutes into transfusion, develops nausea, hypotension, and respiratory failure with wheezing (at first), followed by shallow, rapid breathing without wheezing
• Diagnosis and Management???
Anaphylactic Transfusion Reactions
• Cause: Reaction against IgA or otherplasma-soluble antigens in blood component
• Presentation: (Absence of fever), respiratory andGI symptoms, shock, and/or syncope
• Treatment: Give epinephrine, corticosteroids, etc.; maintain airway
• Prevention: Transfuse with IgA-deficient (and/or carefully washed) products when necessary
Case Study
• 22-year-old female; spontaneous bleedingand coagulopathy (cause unknown); group O
• Transfused with 2 units of FFP
• 2 minutes into transfusion, develops 1.4° C temperature elevation, hypotension, rapid respiratory compromise requiring intubation, foamy sputum, bilateral pulmonary edema on chest X-radiograph
• Diagnosis and Management???
Transfusion-Related Acute Lung Injury (TRALI)
• Causes
Major—Interaction between pre-existing (most often donor) HLA or granulocyte antibodies and WBCs of (usually) patient origin
Minor (?)—Neutrophil priming agent within donor blood that primes PMN oxidase in patient
• Presentation: Acute respiratory insufficiency, fever, hypotension, CXR c/w pulmonary edema
• Treatment: Respiratory support; ? corticosteroids
Pre-TRALI Chest X-Radiograph
Chest field consistent with TRALI
Currently Accepted Risks of Transfusion
• Acute immune-mediated hemolytic transfusion reactions: 1 in 12,000 risk for ABO mismatched transfusion; 1 in 33,000 for major ABO mismatch; 1 in 600,000 for death (Linden et al. Transfusion 1992; 32: 601-606)
• Anaphylactic transfusion reactions: 1 in 20,000 to 1:47,000 (Salama A, et al. Transfusion 2004; 44: 509-511)
• TRALI: 1in 300 to 1:5,000 (Kao S, et al. Transfusion 2003; 43: 185-191)
Febrile Non-Hemolytic Reactions
• Presentation: temperature > 1° C with no other explanations (sometimes with chills and rigors)
• Causes
• Reaction between recipient antibodies anddonor WBCs or …
• Production of cytokines during product storage
• Treatment: Give antipyretics & symptomatic relief
• Prevention: Pre-storage leukoreduction of blood
Allergic Transfusion Reactions
• Cause: Unidentified (usually) plasma-soluble substances in donor blood reacting with recipient IgE
• Presentation: Local erythema, hives, urticaria, (generally without other effects)
• Treatment: Antihistamine (sometimes you may even restart transfusion)
• Prevention: Pre-treatment with antihistamine or(very rarely) washing of cellular blood products
Allergic Mechanism
Circulatory Overload• Cause: Poor patient tolerance for rapid increases
in blood volume
• Presentation: Dyspnea, severe headache, peripheral edema, rapid increase in systolic BP
• Treatment: Sit patient up (if possible); diurese; give O2; very rarely dialyze or even phlebotomize
• Prevention: Transfuse in smallest volume increments possible, as slowly as possible
Other Acute Transfusion Reactions
• Hypothermia and arrhythmias
• Citrate toxicity and hypocalcemia
• Air embolism
• Decreased 2,3-DPG levels
• Hyperkalemia
Delayed Transfusion Reactions
Case Study
• 30-year-old male; MVA; O-negative
• Transfused with 43 RBCs approximately5 weeks ago
• Now has 3+ DAT, gradual decline in hemoglobin, no new serum antibody
• Diagnosis and Management???
Delayed Hemolytic Reactions• Primary
• Mild; significant hemolysis is rare
• Usually manifest a number of weeks after transfusion
• Caused by primary alloimmunization
• Ave. risk of alloimmunization to a significant RBC antigen (other than D) is approximately 1%
• As antibody increases in titer and avidity, it may react with still-circulating RBCs
• Diagnosis is suggested by: (1) unexplained fall in hemoglobin coupled with (2) positivity in DAT and/or (3) production of new RBC alloantibody
Case Study
• 60-year-old female; MVA; O-positive
• Transfused 45 units RBCs approximately 6 days ago
• Now has 3+ DAT, rapid decline in hemoglobin (with ↑ LDH and creatinine), and red urine
• Diagnosis and Management???
Delayed Hemolytic Reactions
• Anamnestic High levels of antibody typically appear within 3-7 days Occurs in previously alloimmunized individuals Combination of high antibody concentrations plus
large numbers of incompatible RBCs results in readily apparent manifestations, e.g., …
• Fever, unexplained fall in Hgb, mild jaundice, hemoglobinuria, positivity of DAT, and appearance of new alloantibody
Treatment rarely needed (still, monitor renal function, just in case)
Case Study
• 65-year-old male; S/P prostatectomy20 days ago
• Transfused one RBC unit from grandson18 days ago
• Now has episodic fevers; desquamative skin rashes, elevated transaminases, and profuse diarrhea
• Diagnosis and Management???
Transfusion-Associated Graft-Versus-Host Disease
• Rare; usually fatal• Generally affects severely immunocompromised
patients (exception to be discussed)• Mechanism: Donor T cells engraft in recipient and
react against his/her “foreign” tissues• Clinical syndrome includes: Fever, skin rash,
hepatitis, diarrhea, bone marrow suppression, infection, bleeding
• Prevention: Irradiation of blood componentswith 25 Gy
Fate of Transfused LymphocytesTransfusion of Lymphocytes with blood unit
Lungs, Liver, ? Spleen
Persistent Bloodstream Microchimera
Engraftment TA-GVHD
Apoptosis,Elimination
Subset Proliferation, recirculation via Thoracic Duct
TA-GVHD Diagnosis
• Skin– Degeneration of epidermal
basal layer with vacuolization– Dermal-epidermal layer
separation and bullae formation
– Mononuclear cell infiltration of upper dermis
– Hyperkeratosis
TA-GVHD Diagnosis
• Liver– Degeneration and eosinophilic
necrosis of small bile ducts withintense periportal inflammationand MNC infiltration
• Bone marrow– Pancytopenia– Fibrosis– Lymphocytic infiltration
Indications for Irradiated Blood
• Pre-/post-hematopoietic stem cell transplant• Hodgkin’s disease• Low birth weight neonate (< 1,200 g)• Neonatal exchange transfusion• Intrauterine fetal transfusion• Related donor• HLA-matched donor or crossmatch-
compatible platelet donor• Treatment with either fludarabine or 2-CDA
Case Study
• 40-year-old female; S/P mastectomy
• Transfused 1 unit RBCs 8 days ago
• Yesterday, platelet count ↓’d from258 K/uL to 4 K/uL
• Diagnosis and Management???
Post-Transfusion Purpura• Rare• Usually occurs in multiparous women• Precipitous drop in platelet count approximately
one week post-transfusion• Thrombocytopenia, though severe, usually is
self-limiting• Affected patients usually have anti-HPA-1a• 98.3% of Caucasian population has HPA-1a on
surface of their platelets• Treatment: IVIG (2nd choice—plasma exchange)
Other Delayed Transfusion Reactions
• Iron Overload
• Immunomodulation
• Other?
Management of Suspected Transfusion Reaction
• Floor:• Stop transfusion and inform physician• Keep venous access open with normal
saline and treat patient as needed• Do clerical check to confirm appropriate
patient is receiving appropriate transfusion• Report suspected reaction to hospital
transfusion service• Send any required samples plus
discontinued bag, administration set, IV solutions, etc. to transfusion service
Management of Suspected Transfusion Reaction
• Transfusion Service must honor first 4 items:• Check for clerical errors
• Repeat ABO/Rh typing of recipient and donor to ensure compatibility
• Visually inspect pre- and post-transfusion sera (and urine, if available) for hemolysis
• Perform DAT on post-transfusion sample (and possibly also on pre-transfusion sample)
• Extras:o Repeat antibody screening on pre- and post-transf. samples
o Perform repeat crossmatch on pre- and post-transf. samples
o Etc.
Blood Banking Review/Updates
• Miscellaneous Transfusion Complications
• Is There a Problem with Older RBCs?
• Septic Transfusion Reactions Revisited
• FDA-Reported Transfusion-Related Fatalities for 2005-06
Is There a Problem with Older RBCs?
• Study Methods Retrospective review of 6002 coronary artery
bypass graft/heart valve patients (1998-2006).
o 2872 received 8802 RBC units < 14 days old (median RBC age = 11 days).
o 3130 received 10782 RBC units > 14 days old (median RBC age = 20 days).
Outcomes and survival rates were assessedC.J. Koch, et al. “Duration of Red-Cell Storage and Complications After Cardiac Surgery. NEJM. 2008; 358: 1229-39.
Is There a Problem with Older RBCs?
S t u d y R e s u l t s
Outcome RBCs < 14 Days RBCs > 14 Days
In-Hospital Mortality 1.7% 2.8%
Intubation > 72 Hours 5.6% 9.7%
Renal Failure 1.6% 2.7%
Sepsis/Septicemia 2.8% 4.0%
1-Year Mortality 7.4% 11.0%p = 0.03 to < 0.001
C.J. Koch, et al. “Duration of Red-Cell Storage and Complications After Cardiac Surgery. NEJM. 2008; 358: 1229-39.
Is There a Problem with Older RBCs?
• Caveats to Study– It was a retrospective study.– The authors assessed a very specific population
of older heart surgery patients (i.e., results may not generalize to other populations).
– A prospective randomized clinical trial is needed to confirm or refute these findings.
C.J. Koch, et al. “Duration of Red-Cell Storage and Complications After Cardiac Surgery. NEJM. 2008; 358: 1229-39.
Septic Transfusion Reactions• Methods
Screened 43,230 platelets for bacterial contamination using large-volume, automated culture method on samples obtained 24 hours post-donation.
Also, 4-day-old and outdated units were re-cultured.
• Results 35 (0.08%) of initial screenings were positive Results of Repeat Cultures …
o 18 of 8,282 (0.22%) expired units were positiveo 4 of 3,310 (0.12%) 4-day-old units were positive
Overall sensitivity of initial screening test was 29.2%W.G. Murphy, et al. “Screening Platelet Concentrates for Bacterial Contamination.” Vox Sang. 2008 [E-pub ahead of print].
Transfusion FatalitiesReported to FDA 1990-98
From Lee JH. FDA Workshop on Bacterial Contamination of Platelets, 1999
Cases Number % of DeathsHemolysis 161 50
Bacterial Contamination 46 10
Transfusion Related Acute Lung Injury 29 9
Non-Bacterial Infection 23 7
Transfusion Graft-Vs-Host Disease 18 6
FDA-Reported Transfusion-Related Fatalities For 2005-06
ComplicationFY05 No.
FY05 Pctg.
FY06 No.
FY06 Pctg.
FY05-06 No.
FY05-06 Pctg.
TRALI 29 47% 35 56% 64 51%
HTR (non-ABO) 16 26% 9 14% 25 20%
Microbial Infection
8 13% 7 11% 15 12%
HTR (ABO) 6 10% 3 5% 9 7%
TACO 1 2% 8 13% 9 7%
Other 2 3% 1 2% 3 2%
Totals 62 100% 63 100% 125 100%
From www.fda.gov/cber/blood/fatal0506/htm
Transfusion Reactions
Summary – A Case Study-Based Focus on…
• Acute Transfusion Reactions• Delayed Transfusion Reactions
• Evaluation/Management of Suspected Transfusion Reactions
• Miscellaneous Transfusion Complications
Q & A?
Thank you!
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