Transfusion Complications Flashcards
Suspected Reaction Workup
Suspected reaction workup
- General philosophy: Assume all reactions are hemolytic, and work to disprove your assumption.
- Stop the transfusion!
a. This doesn’t necessarily mean to disconnect the unit (though in most cases that will eventually happen); at least stop the flow of blood.
b. Main indicator of survival of an acute HTR: amount of incompatible blood infused.
c. Leave a line open with saline. - Necessary parts of workup (things everyone should do).
a. Clerical check
1) Bedside paperwork and bag check to ensure right unit went to right patient
2) Blood bank paperwork check to answer the same question
b. Visible hemoglobinemia check
1) Spin a post-transfusion sample.
2) Compare to pretransfusion sample if abnormal.
3) Detects as little as 2.5 to 5 ml of hemolysis
4) Fastest and best way to detect acute intravascular hemolysis
c. Direct antiglobulin (Coombs) test (DAT)
1) Discussed in BB I
2) Compare to pretransfusion if positive.
d. Repeat ABO testing - Other things often done (but not required)
a. Repeat additional serologic testing.
1) Repeat antibody screen.
b. Indirect bilirubin
1) Really more useful to confirm, not make diagnosis
2) Rises quickly, peaks in less than 10 hours, may be normal within 24 hours (if liver is OK)
c. Haptoglobin
1) Scavenger of free hemoglobin, so levels decrease in acute intravascular hemolysis.
2) Turnaround time and acute phase reaction make for limited usefulness in acute setting.
a) If you must use, be sure to compare pre and posttransfusion levels
d. Urine hemoglobin
1) Not as good or as early as hemoglobinemia
2) Remember that hematuria does not equal hemoglobinuria!
Classification of reactions
With Fever:
Acute -
Acute Hemolytic
Febribe Nonhemolytic
Bacterial Contamination
TRALI
Delayed -
Delayed Hemolytic
TA-GVHD
Without Fever:
Acute -
Urticarial
Anaphylactic
Anaphylactoid
Curculatory Overload
Medicated Febrile
Delayed -
Post-transfusion Purpura
Iron Overload
Acute reactions presenting with fever
- Acute hemolytic transfusion reactions (AHTRs)
a. Disastrous, may be fatal
b. Clerical errors (both in BB and at bedside)
c. May be intravascular or extravascular
1) Fatal ones are usually ABO-related and are usually intravascular.
d. Signs/symptoms
1) Fever and chills
a) Most common presenting symptom (> 80%)
2) Back or infusion site pain
3) Hypotension/shock
4) DIC/increased bleeding (important in anesthetized patients)
5) Hemoglobinuria
6) Sense of “impending doom”
e. Lab findings
1) Hemoglobinemia (pink or red serum/plasma)
2) Positive DAT (unless all donor cells destroyed)
3) Elevated indirect bilirubin
4) Lab findings of DIC
5) Hemoglobinuria
6) RBC abnormalities
a) Schistocytes: intravascular hemolysis
b) Spherocytes: extravascular hemolysis
f. Pathophysiology
1) Most commonly ABO-related
a) Group O recipients getting blood from a group A donor is most common (and most commonly fatal).
b) ABO antibodies are mostly IgM and are great complement-fixers.
2) Rapid destruction of transfused red cells by IgM antibodies
3) Antigen-antibody complexes activate factor XII (Hageman factor) and numerous cytokines (IL-1, TNF, etc), and activates bradykinin.
a) Coagulation consequences:
- Direct intrinsic pathway activation by factor XII and indirect activation of intrinsic pathway by tissue factor
- This combination leads to DIC in 10% of patients.
b) Circulatory consequences:
- Increased bradykinin leads to systemic hypotension, which leads to sympathetic activation.
- Alpha-adrenergic receptors in kidney lead to renal vasoconstriction and eventual acute tubular necrosis.
- Renal failure in about 1/3 of confirmed acute HTRs
g. Treatment
1) Support volume and blood pressure
2) Maintain urine output
3) Watch for DIC
Febrile nonhemolytic transfusion reactions
a. Most frequently reported reaction (about 1%)
b. Increase in temperature of 1 C or 2 F with no other explanation.
1) Don’t get too hung up on this definition, though; an increase of less than this has the same physiology.
c. Cause: increased pyrogenic cytokines (eg, tumor necrosis factor, IL-1β)
1) Where do the cytokines come from?
a) Cytokines secreted before transfusion
- Donor WBCs may secrete cytokines while in the storage bag.
- More common in platelets
b) Cytokines secreted after transfusion
- Recipient anti-WBC antibodies stimulate donor (transfused) WBCs to secrete cytokines.
- Recipient’s WBCs secrete cytokines secondary to interaction with donor WBCs.
- More common with RBC transfusions
d. Signs/symptoms
1) Fever and chills (generally no rigors)
e. Lab findings
1) None
f. Treatment
1) Antipyretics (acetaminophen)
g. Prevention
1) Acetaminophen premedication will often prevent febrile manifestations.
2) Preventing FNH during RBC transfusions
a) Most occur due to post-transfusion secretion of pyrogenic cytokines, as above.
b) Leukocyte reduction usually prevents these reactions.
• Timing of leukoreduction is not critical; bedside works fine, prestorage works fine.
3) Preventing FNH during platelet transfusions
a) Most due to pre-transfusion cytokine secretion
b) Bedside (or other “pretransfusion”) leukoreduction often ineffective because the cytokines are already in the bag!
c) “Prestorage” leukoreduction works best.
Bacterial contamination (septic reaction)
a. Bacteria may proliferate in storage.
1) Bacterial contamination is the #1 infectious risk from transfusion.
2) Some sources: as many as 1 in 3000 platelet units are contaminated.
b. Organisms depend on product.
1) Red cells
a) Yersinia enterocolitica
b) Citrobacter freundii
c) E. coli
d) Pseudomonas species
2) Platelets
a) Gram positive cocci
b) Y. enterocolitica has been reported.
c. Signs/symptoms
1) Rapid onset high fever
2) Rigors
3) Abdominal cramping
4) Nausea/vomiting
5) Shock
d. Lab findings
1) Discolored product (+/-)
2) May have hemoglobinemia/uria
3) DAT negative
4) Gram stain + in only half of proven cases!
5) Culture positive (both from the unit and the recipient)
e. Know your source
1) In my opinion, the source of the gram stain and culture is very important.
2) Culturing or staining a segment to me is useless (unless nothing else is available); the product in the bag is what actually went into the patient!
f. Treatment
1) Immediate IV antibiotics
2) Pressure support
g. Prevention
1) Careful donor history (many just report extremely mild symptoms).
2) Proper phlebotomy technique
3) Some evidence that leukocyte reduction filters may decrease risk.
4) AABB Standard (March 2004) discussed earlier; platelet products must have methods to limit and detect bacterial contamination
Transfusion-related acute lung injury (TRALI)
a. Though underdiagnosed, currently the #1 cause of transfusion-related fatality in the US!
b. Two almost identical standard definitions:
1) National Heart, Lung, and Blood Institute (NHLBI) Working Group and Canadian Consensus Conference Panel
a) New acute lung injury within 6 hours of a completed transfusion
b) Hypoxemia
c) Bilateral infiltrates on chest radiograph
d) Lack of other risk factors for pulmonary edema
2) Usually also with fever, chills, possibly hypotension
3) Most common with platelets and plasma transfusions
c. Clinical differential diagnosis:
1) ARDS: TRALI may look exactly like ARDS, but usually resolves in 24-48 hours.
2) Circulatory overload (TACO): Again, may be very similar clinically, complete with a “wet” chest x-ray, but TRALI does not respond to diuretics.
3) Acute pulmonary and myocardial disorders
d. Pathophysiology: two current mechanisms
1) Immune (“Donor antibody”) hypothesis (probably more common)
a) Anti-HLA or anti-neutrophil antibodies from the donor attack the recipient white cells (neutrophils in particular).
b) Antibody-WBC complexes deposit in and damage pulmonary vasculature.
c) Sequence leads to damage to capillaries with leakage and resultant edema.
d) This mechanism may also occur with recipient antibodies against donor WBCs, but this is less common.
2) Non-immune (“Two-event”) hypothesis
a) First event: pre-existing condition that activates (“primes”) neutrophils (makes them susceptible to stimuli).
• Examples include sepsis, major surgery, massive transfusion
b) Second event: transfusion of stored blood product
- Stored blood products accumulate lipids that can further activate the primed neutrophils.
- These lipids are called “biologic response modifiers” (BRMs).
c) The combination of these events leads to capillary damage and subsequent pulmonary edema.
e. Diagnosis
1) May be difficult, as it is often confused for something else
2) Typical early findings: bilateral CXR infiltrates, oxygen saturation less than 90%, no evidence of volume overload (no jugular venous distention, normal wedge pressure, normal BNP levels)
3) Lab findings may include demonstration of anti-HLA and/or anti-neutrophil antibodies, and possibly increased biologic response modifiers in the blood bag.
a) Remember, this is a clinical and radiographic diagnosis; confirming the presence of donor antibodies may take days or weeks!
f. Treat with respiratory support (oxygen, maybe intubation).
1) Mortality reported between 5 and 25%.
g. Prevention
1) None generally necessary, since the donor is usually the problem.
2) Implicated donors should usually be deferred (if antibodies outlined above are found)
3) Use of all (or mostly) male plasma has been shown to decrease the risk of TRALI (females have higher incidence of anti-HLA and anti-neutrophil antibodies because of pregnancy).
Hypersensitivity-type reactions
a. Urticarial transfusion reactions
1) Second most frequently reported reaction
2) Usually just localized hives
3) Mechanism
a) Type I hypersensitivity to donor plasma proteins
4) Prevention and treatment
a) Diphenhydramine (Benadryl)
b) Transfusion may be restarted after localized urticarial reactions clear.
b. Anaphylactic transfusion reactions
1) The opposite end of the hypersensitivity reaction spectrum
2) Uncommon (thankfully)
3) Classic history: IgA deficient recipient (discussed previously)
4) Anaphylactic shock within the first few drops of the transfusion
a) Classic presentation: acute hypotension, abdominal distress, systemic crash!
b) Don’t rely on wheezing, gradual dyspnea, etc. to make the diagnosis (though they may occur).
5) Prevention
a) Washed products (or IgA deficient products)
b) Benadryl is insufficient for prevention and for treatment!
6) Treatment
a) Epinephrine immediately
b) SQ or IM preferred, but may give IV if already crashed.
Anaphylactoid reactions
a. Term used for two main types:
1) Reactions associated with ACE inhibitors
a) Rapid onset of flushing and hypotension in transfused patients who are on ACE inhibitors (drugs such as Vasotec, Lotensin, Zestril, Capoten).
b) Famous in association with bedside leukoreduction filters (negatively charged)
c) Possibly caused by accumulation of increased bradykinin from contact with filter
- ACE inhibitors prevent metabolism of bradykinin.
- Bradykinin causes hypotension.
2) Milder forms of IgA deficiency
a) These patients may not completely lack IgA, and may have milder symptoms and consequences from IgA exposure.
b. Reactions managed with same principles as with anaphylactic reactions
Transfusion-associated circulatory overload (TACO)
a. Main differential diagnosis: TRALI
b. Acute onset of congestive heart failure as a direct result of blood transfusion
1) Dyspnea, orthopnea
2) Systolic hypertension (widened pulse pressure), tachycardia, bilateral rales, jugular venous distension
3) Often have headache
4) Usually afebrile
c. Radiographs similar to TRALI
d. Patients most at risk
1) Patients with pre-existing CHF
2) Very young and very old patients
3) Renal failure patients
4) Patients with chronic anemias, eg, sickle cell, thallasemias (due to compensation for anemia with increased plasma volume)
e. Distinguishing from TRALI
1) Clinical (response to diuretics in TACO, fever in TRALI but not in TACO)
2) Lab: elevated brain natriuretic peptide (BNP) suggests TACO, antibodies as above
f. Treatment
1) Discontinue transfusion, evaluate
2) Diuretics +/- oxygen
g. Prevention in at-risk patients
1) Control infusion rates (1 mL/Kg/hour).
2) Split units when possible.
3) Consider lower volume units (using CPD-RBCs rather than AS-RBCs, for example) or volume reduction of certain products.
Premedicated FNH
a. A fabulous oxymoron!
b. Premedicated patients may only have chills without fever.
Delayed reactions presenting with fever
- Delayed hemolytic transfusion reactions
a. Hemolysis occurring several days to weeks after transfusion.
b. Pathophysiologic possibilities
1) Anamnestic response
a) A previously formed antibody comes roaring back after re-exposure.
b) Typical for Kidd, Duffy
2) Primary response
a) New antibody is formed while foreign RBC is still circulating.
b) Less common
c. Classically extravascular
1) Delayed HTRs due to Kidd antibodies may be intravascular and severe.
d. Signs/symptoms
1) Often none
a) If asymptomatic and without lab findings other than newly positive antibody screen, may be called “delayed serologic reaction.”
2) Fever of unknown origin
3) Mild jaundice
e. Lab findings
1) Icteric serum
2) DAT positive (classically “mixed field”)
3) Anemia
4) Positive antibody screen (may change from previously negative).
5) Spherocytes on peripheral smear
f. Treatment
1) As for AHTR if severe and intravascular
2) Often no treatment necessary - Transfusion-associated graft-vs-host disease
a. Discussed in BB III.
Delayed reactions presenting without fever
- Post-transfusion purpura
a. Marked thrombocytopenia about one week following transfusion (may be below 10,000/μL)
1) The triggering transfusion does not have to be platelets: platelets or RBCs can start the reaction.
b. Multiparous females especially at risk
c. Anti-PLA1 (HPA-1A) most common (~70%)
1) Almost everyone is PLA1 positive.
2) PLA1 negative patients are exposed through pregnancy or transfusion.
3) Transfusion after antibody is formed leads to devastating destruction of platelets.
4) PLA1 positive and negative platelets destroyed (isn’t that weird?)
d. IVIG is successful in reversing the process and dramatically increasing the platelet count.
1) Due to this success, plasma exchange is used less often today.
2) Mortality is about 10% or so without treatment.
e. Platelets should not be given. - Iron overload
a. Each unit of RBCs: 200 mg iron
b. Lifetime load of ~150 transfusions in 70 Kg person =
risk for overload.
c. Deferoxamine treatment is painful and awful!
Consequences of significant reactions
- FDA requirements
a. If there is suspicion that a death is transfusion-related, FDA requires notification within 24 hours by phone.
1) This may seem too restrictive, and the official rule says “confirmed”, but I have seen numerous FDA citings for not reporting “suspicions.”
b. This phone report must be followed up by a full investigation and written report within 7 days.
c. FDA is aggressively enforcing this rule during recent site visits. - JCAHO
a. Acute hemolytic transfusion reactions are “sentinel events” and require intensive investigation (Root Cause Analysis) and reporting to JCAHO.
Current risk of viral disease transmission
- For perspective, risk of acute hemolytic reaction stated as 1 in 25,000 transfusions
- Risk of dying in the hospital from something other than transfusion problem: 6 per 1000!
- Our current best guesses (from AABB Tech Manual, 16th ed, 2008):
Virus Current Risk Estimate
HIV-1 1 in 2,300,000
Hepatitis B 1 in 220,000
Hepatitis C 1 in 1,800,000
HTLV-I 1 in 2,993,000
HIV-2 Remote
WNV Remote
Syphilis Remote
T. cruzi Unknown, likely remote
Bacteria 1 in 75,000 platelet transfusions
1 in 500,000 RBC transfusions
Hepatitis A virus
a. Fecal-oral transmission (30 day incubation)
b. Generally not a big blood banking problem (not tested)
c. Some concern in pooled products
1) Solvent-detergent treatment doesn’t deactivate HAV (nonenveloped).
2) Transmission documented in pooled factor concentrates
d. Not prone to chronicity like HBV and especially HCV
