transfusion risks

www.labmedicine.com Summer 2012 | Volume 43, Number 5 Lab Medicine 217
CE Update
During the past 3 decades, much advancement
has been made in the field of transfusion medicine,
particularly regarding reductions in adverse events
associated with blood-product infusion. Improved
donor screening and innovations such as nucleic acid
testing have greatly helped to enhance safety and to
reduce transfusion-associated morbidity and mortality.
Nevertheless, substantial risks associated with trans-
fusion remain.1
The aim of this article is to provide a
thorough, up-to-date reference regarding the incidence,
pathogenesis, management, prevention, and reporting
of transfusion reactions.
Severe Complications
of Transfusion
Adverse events were selected for inclusion in this sec-
tion because they have been reported to have caused
transfusion-associated fatalities within the last 5 years,
per U.S. Food and Drug Administration (FDA) data and/
or are reactions which, historically, have been associ-
ated with adverse patient outcomes.2
The signs, symp-
toms, laboratory findings, and management of these
reactions are summarized in Table 1.
Transfusion-Related Acute
Lung Injury
Overview and Incidence
Transfusion-related acute lung injury (TRALI) has
gained prominence in recent years. Data regarding the
incidence of TRALI is variable, with early reports sug-
gesting rates as high as 1 per 4500 units transfused
Diagnosis, Treatment, and Reporting of Adverse
Effects of Transfusion
Richard Torres, MD,1,2
Barton Kenney, MD,1,3
and Christopher A. Tormey, MD1,2*
ABSTRACT
The risks of transfusion remain significant. Familiarity with the
incidence, etiology, management, and prevention of commonly
encountered transfusion reactions is integral to the practice of
transfusion medicine. This review intends to serve as a practical
guide reflecting the current understanding of adverse transfusion
events, clinical features helpful for diagnosis, and recommended
management strategies for typical scenarios. Severe and mild
transfusion reactions are covered, with a focus on the distinguishing
features of challenging clinical dilemmas. Topics include pulmonary
complications of transfusion, hemolytic reactions, allergic and
anaphylactic reactions, septic reactions, and febrile responses to
transfusion. We also discuss a consultative approach to evaluation
and reporting of transfusion reactions.
Educational Objectives
Readers should be able to describe the incidence, pathogenesis,
management, prevention, and reporting of transfusion reactions.
Keywords: transfusion reactions, adverse events transfusion, TRALI,
TACO, hemolysis, sepsis
DOI: 10.1309/LM3NAABJJK1HNYFU
Abbreviations
FDA, Food and Drug Administration; TRALI, transfusion-related acute
lung injury; FFP, fresh frozen plasma; PLTs, platelets; RBCs, red blood
cells; HLA, human leukocyte antigen; ARDS, acute respiratory distress
syndrome; BNP, brain natriuretic peptide; HTRs, hemolytic transfusion
reactions; DHTRs, delayed hemolytic transfusion reactions; AHTRs,
acute hemolytic transfusion reactions; IL, interleukin; TNF, tumor
necrosis factor; DAT, direct antiglobulin test; CBC, complete blood
count; HCT, hematocrit; LDH, lactate dehydrogenase; DIC, disseminated
intravascular coagulation; DHTRs, delayed hemolytic transfusion
reactions; Hp, haptoglobin; TACO, transfusion-associated circulatory
overload; IgA, immunoglobulin A; IVIg, intravenous gamma globulin;
PTP, post-transfusion purpura; HIT, heparin-induced thrombocytopenia;
HPAs, human PLT antigens; TTP, thrombotic thrombocytopenic purpura;
ELISA, enzyme-linked immunosorbent assay; TA-GVHD, transfusion-
associated graft versus host disease; HIV, human immunodeficiency
virus; FNHTRs, febrile nonhemolytic transfusion reactions; BRMs,
biologic response modifiers; WBCs, white blood cells; AHR, acute
hypotensive reaction; ACE, angiotensin-converting enzyme
1
Pathology and Laboratory Medicine Service, Veterans Affairs
Connecticut Healthcare System, West Haven, and Departments
of 2
Laboratory Medicine and 3
Pathology, Yale University School
of Medicine, New Haven, Connecticut
*To whom correspondence should be addressed.
E-mail: christopher.tormey@yale.edu

218 Lab Medicine Summer 2012 | Volume 43, Number 5 www.labmedicine.com
CE Update
and more recent estimates approaching approxi-
mately 1 per 260,000 for all components.3
Of interest,
these rates vary significantly by country; this issue
derives at least partly from definitions of the condi-
tion.3
One confounding variable is that the incidence of
TRALI is highly linked to the type of blood component
being administered, with the highest rates observed
for components with a high content of plasma.3-6
According to best estimates, the highest incidence
occurs with transfusion of fresh frozen plasma (FFP),
at roughly 1:66,000; followed by platelets (PLTs), at
roughly 1:420,000; and finally, red blood cells (RBCs),
at roughly 1:2,860,000.3
Transfusion-related acute lung
injury has been the most frequent cause of transfu-
sion-associated mortality in the United States for the
past several years.2
Pathogenesis
Transfusion related acute lung injury occurs when an-
tibodies (often anti–human leukocyte antigen [HLA] I
or II) present in transfused donor plasma interact with
recipient leukocytes, resulting in leukocyte activation
and adhesion to the pulmonary endothelium. This pro-
cess results in the release of proteolytic enzymes and
reactive oxygen species, causing endothelial injury.3,4
Leukocyte agglutination also occurs, leading to ob-
struction of pulmonary capillaries. Some authors5
have
suggested an additional, nonimmune mechanism that
contributes to TRALI, in which certain leukocyte-prim-
ing substances, presumed to be lipids, are present in
stored blood components; these components facilitate
activation. Based on these data, there may be a dou-
ble-hit process, in which leukocytes are first primed
by nonimmune compounds and then secondarily
activated by an immune mechanism.5,6
The resulting
Table 1. Summary of Diagnostic Findings and Management Strategy for Severe Transfusion Reactions
Diagnosis Symptoms Timing Lab Findings Management
TRALI Dyspnea/tachypnea, During or post- CXR = Diffuse lung infiltrate Stop transfusion if ongoing
Fever, Hypotension transfusion (Non-cardiogenic) Supportive =
(within 4-6hrs) BNP/proBNP = Normal Oxygen (O2
) Intubation,
Donor Anti-leukocyte Ab+ if necessary
Abnormal leukocyte crossmatch
HTR Fever/chills, Chest pain, Immediate up to several DAT+, Ab screen on repeat + Stop transfusion, Recheck
Hypotension, hours post transfusion ↑LDH, ↑Bilirubin crossmatch, Recheck
Severe ↓Haptoglobin documentation, Supportive care,
*Back or Abdominal pain Delayed–3 to 10 days Severe Oxygen support, Urine output
*Dyspnea post transfusion *↑PT/PTT >100mL/hr, Monitor hematocrit
*Vomiting/diarrhea *↑BUN/Cr
TACO Dyspnea/tachypnea, Cough, 4-6 hours post Tx ↑BNP/proBNP, CXR = Stop transfusion if ongoing
↓O2
saturation, Hyper- pulmonary edema Get patient upright, Diuretics,
tension/Tachycardia, ↑central venous pressure Slow infusion or split
Jugular vein distension units for future
Septic Fever/chills (>1-2°C rise), During transfusion or Gram stain + Bag culture + Stop transfusion, Empirical antibiotics
Hypotension/shock, shortly after Blood cultures + Hemodynamic stability
Oliguria, Dyspnea ↑D-dimer/↑ PT (if DIC) Respiratory support (O2
)
Anaphylactic Rash/erythema, Pruritus/ Seconds or minutes Normal CXR, Gram stain/ Stop transfusion, Supportive care
angioedema, Dyspnea/ into transfusion Blood cultures NEG (epinephrine, saline,
chest pain, Hypotension, Anti-IgA + IgA < 0.05 diphenhydramine,
Vomiting/diarrhea mg/dL on pre-transfusion airway patency)
sample
PTP Purpura, PLT-type bleeding 3-12 days post transfusion PLT count <15k/µL IVIg (+ random PLTs if needed)
(mucosal) (5-10 days usual) PLT Ab + HLA-matched PLTs
TA-GVHD Erythematous rash, Fever, 3-30 days post Tx Skin biopsy with mononuclear Supportive but poor prognosis
Diarrhea (8-10 days usual) cell infiltrate ↑LDH, ↑ALT/AST, Irradiation for prevention
Delayed in newborns ↑Bili (Hepatitis)
Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bili, total bilirubin; BNP, brain natriuretic peptide; BUN, blood urea nitrogen; Cr, creatinine;
CXR, chest x-ray; DAT, direct antiglobulin test; DIC, disseminated intravascular coagulation; HTR, hemolytic transfusion reaction; IVIg, intravenous immunoglobulin; LDH,
lactate dehydrogenase; PT, prothrombin time; PTP, post-transfusion purpura; PTT, partial thromboplastin time; TACO, transfusion-associated circulatory overload; TA-GVHD,
transfusion-associated graft-versus-host disease; TRALI, transfusion-related acute lung injury; TX, transfusion.

CE Update
lung injury is similar to that seen in acute respiratory
distress syndrome (ARDS).
Diagnosis
Diagnosis of TRALI relies on a clinical presenta-
tion characterized by low-grade fever, hypotension,
tachypnea, and dyspnea with diffuse lung infiltrates
observed via chest X-ray, all occurring within 4 to 6
hours of transfusion.3
Of importance, these signs and
symptoms are not secondary to volume overload; they
are often described as noncardiogenic pulmonary
edema. Measurement of brain natriuretic peptide (BNP)
and clinical evaluation of volume status, the results of
both of which should be normal, may be useful to con-
firm TRALI and/or to exclude other conditions (Table
1). As reported by Goldman et al7
, several groups have
developed consensus criteria for the clinical diagnosis
of TRALI incorporating the findings described herein
(Figure 1). Although clinical diagnosis is the mainstay,
laboratory testing can serve an adjunct role. Donor
plasma can be tested for antileukocyte antibodies,
which are found in a high percentage of TRALI cases.6
If antibodies are found, leukocyte incompatibility can
be tested by donor-recipient crossmatch or by recipi-
ent antigen typing. However, this is not required for
diagnosis of TRALI; also, results are generally not avail-
able in time to guide management.
Treatment and Prevention
Treatment of TRALI is mainly supportive in nature. For
mild cases, oxygen therapy is sufficient. However, for
more severe cases, intubation and artificial ventilation
may be required. Of importance, administration of
diuretics is not recommended because the condition
is not caused by volume overload and because this
measure may exacerbate hypotension. No convinc-
ing data have been published, to our knowledge,
regarding the efficacy of steroids in treating TRALI.
Most cases of mild TRALI resolve within 48 to 72
hours; typically, no sustained lung injury is incurred.
However, severe cases are not uncommon; overall
mortality for TRALI is estimated at between 5% and
25%.3
Prevention of TRALI is of high priority, given its
association with mortality.2
The most widespread ap-
proach thus far has been the use of male-only donor
plasma. The basic premise is that male plasma is less
likely to contain the antileukocyte antibodies that may
cause TRALI; some evidence supports this approach.
In a study8
conducted in the Netherlands, use of
male-only plasma reduced the rate of TRALI by 33%.
The United Kingdom has also demonstrated a signifi-
cant reduction in TRALI incidence after implementing
a male-only plasma program.9
Hemolytic Transfusion
Reactions
Hemolytic transfusion reactions (HTRs) involve
antibody-mediated lysis of donor RBCs. The most
dangerous type of hemolytic reaction involves acute,
intravascular destruction of transfused RBCs. Acute
hemolysis, often attributable to ABO antibodies, is esti-
mated to occur in approximately 1 of every 30 to 70,000
RBC transfusions and has historically accounted for
Figure 1
Transfusion-related Acute Lung Injury Criteria (TRALI) Guidelines.3,8
PaO2
indicates partial pressure of oxygen in arterial blood; FlO2
,
flow of oxygen; pulse ox, pulse oximetric reading.

CE Update
many transfusion-related fatalities.10
More recently, how-
ever, delayed hemolytic transfusion reactions (DHTRs),
in which an evanescent antibody is redeveloped as a
memory response to antigen stimulation,11
have be-
come increasingly recognized as a significant cause of
mortality.2
A report12
indicates the overall incidence of
delayed reactions is higher than that of acute reactions,
with estimates ranging from approximately 1 in 300 to 1
in 1:11,000 RBC transfusions.
Acute Hemolytic Transfusion
Reactions
Pathogenesis
Acute hemolytic transfusion reactions (AHTRs) occur
when donor RBCs are lysed intravascularly in the pres-
ence of preformed antibodies in the recipient. Most
commonly, this involves naturally occurring ABO blood-
group antibodies. In this setting, anti-A or anti-B anti-
bodies bind to the transfused, incompatible RBCs, with
ensuing activation of the complement cascade.13
Various
compounds are released during hemolysis (eg, interleu-
kin [IL]–1, IL-6, and tumor necrosis factor [TNF]–α) that
mediate fever, hypotension, and endothelial activation.14
Non-ABO antibodies that repair complement, such as
anti-Jka, can also drive acute, intravascular hemolysis.
Diagnosis
Acute hemolytic transfusion reactions tend to present
immediately or within several hours after transfusion
as fever, chills, chest pain, or hypotension.13
Less com-
mon signs and symptoms include flushing, lower back
pain, dyspnea, abdominal pain, vomiting, and diarrhea.
In severe cases, coagulopathy can develop and renal
failure can occur.13
If such signs or symptoms are pres-
ent, a direct antiglobulin test (DAT) should be performed
immediately on a freshly drawn blood specimen. If the
DAT results are positive, elution should be performed
and the antibody identified. Repeat antibody screen-
ing and identification performed with a fresh blood
specimen from the patient may also be warranted. A
complete blood count (CBC) should be determined to
establish a baseline hematocrit (HCT) value that can
be followed thereafter in a serial manner. Serum lactate
dehydrogenase (LDH), bilirubin, and haptoglobin levels
should be monitored for evidence of hemolysis. Con-
currently, repeat crossmatch and rechecking of ABO
type and other documentation is necessary to ensure
that a technical error has not occurred.
At the first sign of AHTR, the transfusion should be
ceased and the patient treated supportively. Oxygen
and fluids should be administered, as appropriate.
Monitoring and maintaining urine output, at greater
than 70 to 100mL/hour if possible, is important in
helping maintain renal function. Further transfusion
should be avoided if possible until repeated blood-
bank testing has been completed and cross-matched,
compatible RBCs can be obtained. If patients dem-
onstrate evidence of coagulopathy or disseminated
intravascular coagulation (DIC), use of plasma and
PLT products is also warranted. For patients who have
received large volumes of incompatible RBCs, con-
sideration may be given to RBC-exchange therapy to
reduce the circulating, incompatible RBC burden and
to limit hemolysis.
Data indicate that most ABO-related AHTRs result from
clerical errors involving patient or donor-unit identifica-
tion.12
Therefore, much focus has been placed on proper
specimen labeling. At VA Connecticut, as a safety-im-
provement measure, we have employed a witness-based
system to verify (and to document) the identity of patients
undergoing blood-bank specimen collection. Additional
improvements in safety rely on ensuring patient identifi-
ers during blood-bank testing and at the time of transfu-
sion. Blood-banking software and technology, such as
bedside barcode scanning of blood products, have been
developed to address potential errors. Non-ABO AHTRs,
which occur less frequently due to errors and are more
often associated with undetectable antibodies, are best
avoided by careful antibody screening in the blood bank.
Other approaches for the prevention of HTRs due to non-
ABO antibodies are discussed herein.
Delayed Hemolytic Transfusion
Reactions
Pathogenesis
Delayed hemolytic transfusion reactions (DHTRs) may
result from 2 situations. In most cases, re-emergence
of a non-ABO antibody occurs in the recipient. This
antibody has been developed at an earlier time through
transfusion or pregnancy but has become evanescent
(ie, titers have decreased to undetectable levels).11
Once
re-exposed to the antigen in question, an anamnestic
response (ie, an enhanced and quickened immune re-
sponse on re-exposure) results in re-formation of the

CE Update
antibody. Because re-emergence of an evanescent
antibody takes 3 to 10 days on average, the resulting
hemolysis is delayed. Less commonly, development of
a new antibody against a non-ABO blood group antigen
in donor RBCs is the underlying cause of DHTR.15
Diagnosis
Rather than presenting with acute clinical symptoms,
DHTRs manifest at a delayed interval after transfu-
sion. The reaction may be subclinical or mild; however,
severe DHTRs with significant hemolysis and even
death can also occur.16
Often, DHTRs are detected by
laboratory studies such as repeat antibody screening
rather than by clinical manifestations. Some delayed
reactions are hemolytic, with a consequent decrease
in HCT and haptoglobin (Hp) and an increase in LDH
and bilirubin. However, others are purely serologic (ie,
re-emergence of an alloantibody is detected on repeat
screening); however, no clinical or laboratory evidence
is observed for hemolysis.17
To confirm the presence of
DHTR, it is necessary to demonstrate the emergence
of an alloantibody. If a DHTR is suspected on clinical
grounds, a new blood-bank sample should be obtained
and subjected to repeat antibody screening, DAT, and
elution studies. By these methods, the specificity of the
alloantibody can be confirmed and documented, and
appropriate antigen-negative RBC units can be pro-
vided for future transfusions.
Because most DHTRs are mild, only supportive treat-
ment is usually necessary. However, close monitoring
of the patient is recommended, including serial assess-
ment of renal function and HCT. In the event of signifi-
cant hemolysis, hydration and maintenance of sufficient
urine output is needed, similar to the approach dis-
cussed herein for AHTRs. Prevention of DHTR is the
main goal; this can be addressed in several ways.
Most importantly, improved alloantibody data sharing
between institutions would be beneficial. Use of an ob-
jects that to alert health care providers to a history of
alloimmunization, such as a medical bracelet or wallet
card, would serve this purpose. Web-based platforms
documenting alloantibody history are another option.
Unfortunately, the latter mechanisms are typically un-
available or underutilized at this point. Therefore, in the
absence of other modes of information sharing, data re-
garding previous antibody status may be obtained by a
telephone call to an institution at which the patient had
previously undergone blood-bank testing or transfusion
(if such history is readily available for the patient).
Transfusion-associated
Circulatory Overload
Although TRALI is likely the best known (and most feared)
pulmonary complication of transfusion, transfusion-
associated circulatory overload (TACO) is no less clini-
cally significant. In fact, according to recent FDA data, 2
TACO was the second most common cause of transfu-
sion-associated fatality in the United States from 2009
through 2010. Because of its tendency to affect critically
ill patients, it is difficult to adequately ascertain the true
incidence or prevalence of TACO. Nevertheless, a recent
report18
estimates that approximately 6% of transfusions
in critically ill patients may be associated with TACO. Pa-
tients at highest risk for TACO include those in intensive
care settings, elderly individuals, and patients with estab-
lished cardiac disease or dysfunction.18,19
Pathogenesis
Unlike other causes of transfusion reactions, which
typically have complex etiologies, the onset of TACO
is most often related to a patient’s underlying cardiac
function and/or volume status. Those patients with a
disease or condition that predisposes them to volume
overload can develop TACO if too many blood prod-
ucts are infused in a too- brief period or if a single
unit is infused at a rate more rapid than can be toler-
ated. When the circulatory system is overwhelmed in
TACO, fluid accumulates in the air space, leading to
pulmonary edema, decreased air exchange, and re-
spiratory distress.
Diagnosis
The symptoms of TACO typically manifest as dyspnea,
tachypnea, and/or cough occurring during or within a
few hours of the completion of transfusion(s). Vital-sign
changes may include hypertension, tachycardia, and
decreased oxygen saturation. On physical examination,
patients may demonstrate jugular venous distension
and, if in an intensive monitored setting, evidence of
increased central venous pressure. However, these
signs, symptoms, and vital-sign changes are not spe-
cific for TACO; in many cases, it may be difficult to
exclude TRALI based on the clinical presentation only.19
Hence, other clues for differentiating between these 2
diagnoses may be useful (Table 2). From a laboratory
testing perspective, at least 2 studies20,21
have shown
that BNP and/or N-terminal pro-BNP may be valuable

CE Update
in distinguishing between the diagnoses. It is uncertain
whether chest X-ray imaging may be helpful in estab-
lishing a diagnosis because, in TACO, chest imaging
typically shows a picture of pulmonary edema that may
not be distinguishable from TRALI. Finally, extracting a
history of previous episodes of volume overload may
help to support a diagnosis of TACO.
At the onset of any signs of respiratory distress dur-
ing transfusion, cessation of the infusion is the correct
first step. In some mild cases, merely ceasing the infu-
sion and placing the patient in an upright position may
be sufficient to overcome TACO. For more advanced
cases, the use of diuretics can relieve patients of ex-
cess fluids and reduce respiratory symptoms. If these
measures fail, more drastic steps, such as transfer to an
intensive care setting or intubation, may be warranted
to maintain adequate air exchange. Failure to respond
to diuretics or other therapies aimed at correcting vol-
ume overload may be signs that the patient is experi-
encing TRALI.
By itself, the transfusion community can do little from
a preventative standpoint because TACO is not a reac-
tion caused by the blood product itself; rather, it results
from excessive fluid infusion. As such, prevention of
these reactions relies on a coordinated effort between
the clinical services department and the blood bank.
Patients recognized as being at risk for TACO should
receive transfusions as slowly as possible for as long
as 4 hours. If transfusion requires larger volumes or if
infusions cannot be accomplished within 4 hours, blood
banks may choose to split units in a sterile manner for
administration. Patients with evidence of volume over-
load or a predisposition to TACO may also benefit from
pretransfusion diuretic administration.
Septic Transfusion Reactions
Septic transfusion reactions result from bacterial con-
tamination of donor blood components. Due to the
need for room-temperature storage, PLTs are, by far,
the leading culprit in septic reactions. Before 2004, the
overall incidence of septic reactions was approximately
1 per 25,000 PLT transfusions.22
In 2004, standards
were introduced to attempt to limit sepsis associated
with PLTs by formal testing for bacterial contamina-
tion using microbial detection systems. The incidence
of septic reactions has been reported to be reduced
since the implementation of preventive measures, with
estimated ranges of 1:100,000 transfusions.23
Despite
the implementation of these measures, septic reactions
have not been completely eliminated.
Pathogenesis
Contamination of the donor unit may occur by several
means. The most common mechanism involves in-
troduction of a low concentration of skin bacteria into
the component at the time of donor phlebotomy. Less
commonly, asymptomatic donor bacteremia may be at
fault. Finally, and least frequently, bacteria may be intro-
duced during processing of donor components.24
Once
inoculated, the donor unit serves as a culture medium
for bacterial proliferation.25
Platelet units are at high-
est risk due to their requirement for room-temperature
storage,23,25
with RBCs demonstrating lower risk due
to cold-storage temperatures. The most frequently im-
plicated bacteria in PLTs are Gram-positive organisms,
most commonly skin flora such as Streptococcus spp.
and Staphylococcus spp. Gram-negative contamination
may also occur, the most common example being con-
tamination of RBC components by Yersinia enteroco-
litica, a bacterium that thrives at cold temperatures.22-25
Diagnosis
The diagnosis of a septic reaction is vital because the
condition must be treated quickly to avoid an adverse
outcome. The most common signs and symptoms in-
clude fever and/or chills beginning during or shortly after
transfusion. Because fever may be a component of sev-
eral other types of reactions, a temperature elevation of
greater than or equal to 2°C has been recommended as
a more specific indicator of septic reaction (Table 2).22
Nevertheless, any temperature increase during transfu-
sion warrants concern for a septic reaction. Other signs
and symptoms of sepsis may also occur, including nau-
sea, vomiting, hypotension, shock, oliguria, respiratory
distress, or DIC.22
Once suspicion has been raised for
a septic reaction, the diagnosis is investigated by Gram
stain and culture of the patient’s blood and the compo-
nent storage bag. Correlative growth of the same organ-
ism in both cultures represents strong evidence for a
septic reaction. Exclusion of other bacterial sources (eg,
an infected central line) is also imperative to confirm that
bacteremia has resulted from transfusion.
Management of a septic reaction requires immediate
attention to hemodynamic stability, with fluid man-
agement and respiratory support.22
Empiric antibiotic

CE Update
therapy should be initiated immediately;
the positive results of any culture should be
used to guide appropriate therapy thereafter.
Many efforts have been made to prevent
septic reactions. A study26
has shown that
improved donor skin sterilization is a strong
first step for reducing the risk for bacterial
contamination. Platelet products are now
also subjected to formal bacterial detection
methodologies to detect possible contami-
nation.27
Various methods of pathogen inac-
tivation have also been proposed 28
but none
have been implemented for clinical use in
the United States thus far, to our knowledge.
Anaphylactic Transfusion
Reactions
Although estimates vary widely, severe
anaphylactic transfusion reactions are rare.
They most commonly occur with PLT trans-
fusions; FFP is the second most common
culprit. Red blood cells are rarely implicated.
The overall incidence is estimated in the
range of 1 in every 20,000-30,000 transfu-
sions,29
making them approximately 10-fold
less common than penicillin anaphylactic
reactions.
Pathogenesis
Classically, severe anaphylactic transfusion reactions
have been associated with anti-IgA antibodies develop-
ing in an immunoglobulin A (IgA)–deficient patient.30
However, it has since been recognized that other an-
tigens are responsible for many such reactions. For
example, antihaptoglobin antibodies in haptoglobin-
deficient patients may form in response to transfusion
and may result in anaphylaxis.31
Numerous potential
allergens exist. In an illustrative case, 32
a child with a
peanut allergy developed an anaphylactic reaction to
a blood product from a donor that had eaten peanuts
before donation. Conversely, recipients who have con-
sumed food products to which their blood-product do-
nors have sensitivity have also developed anaphylactic
reactions.33
A common end pathway is postulated to
involve systemic activation of complement, mast cells,
and basophils accounting for the symptomatologic
manifestations described herein.
Diagnosis
Severity and rapidity of symptom onset define a reac-
tion as anaphylactic. The typical manifestation is a
combination of skin, respiratory, cardiovascular, and
gastrointestinal problems beginning within seconds
or minutes of the start of a transfusion.30,33
In severe
cases, the most common findings are generalized
erythema, pruritus, urticarial eruption, and/or angio-
edema. Signs of upper or lower airway obstruction
may accompany skin changes; they include substernal
pain, wheezing, dyspnea, and cyanosis. Circulatory
collapse has the potential to result in cardiac arrest.
Vomiting and diarrhea are also common. A general rule
of thumb is that the time to symptom onset also often
corresponds to the severity of the reactions; the quick-
est reactions tend to be most severe. Beyond that,
symptoms such as hypotension, dyspnea, and nausea
are the most specific for anaphylactic reactions (Table
2). Compared with TACO, allergic cardiovascular
symptoms typically occur much more quickly.
Table 2. Signs/Symptoms and Associated Differential
Diagnoses
Sign/ Transfusion-related
Symptom Differential Diagnosis Non–transfusion-related
Fever AHTR (moderate) Infection/sepsis
Sepsis (marked, often >2°C increase) Post-operative fever
TRALI (mild) Medication effect
FNHTR (mild to moderate)

Hypotension AHTR Volume depletion
Sepsis Vasodilation (medication/shock)
Severe allergic/anaphylactic reaction Vasovagal response
Acute hypotensive reaction
Dyspnea TRALI CHF
TACO Volume overload due to other
tAllergic/anaphylactic reaction non-transfused products
AHTR (eg normal saline)
Rash/flushing Allergic reaction Medication reaction
AHTR Allergic reaction
PTP
Pain AHTR (ie, chest or flank pain) Postoperative pain
Idiosyncratic pain reaction Muscle cramping
Nausea AHTR Medication effect
Sepsis Infection
Allergic/anaphylactic reaction
AHTR, acute hemolytic transfusion reactions; TRALI, transfusion-related acute lung injury;
TACO, transfusion-associated circulatory overload; CHF, congestive heart failure; PTP,
post-transfusion purpura.

CE Update
If a patient is experiencing symptoms suggestive of an
anaphylactic reaction, the most important step is ces-
sation of the transfusion, followed by supportive care
addressing the specific symptoms. This may include
subcutaneous or intravenous epinephrine, volume
expansion with saline for circulatory collapse, diphen-
hydramine for skin symptoms, and intubation to restore
airway patency.30,33
Corticosteroids are not effective in
the acute-care setting. Finally, despite past theories of
passive transfer of donor leukocyte–derived cytokines,
prestorage leukoreduction does not reduce the inci-
dence of anaphylactic reactions.34
Risk for IgA-related acute transfusion reaction occurs
only when recipient IgA levels are less than 0.05 mg/
dL; most assays typically have lower limits of sensitivity
100-fold higher (ie, 5 mg/dL). Hence, higher sensitiv-
ity testing must be used to identify patients truly at
risk for anaphylaxis. Oddly, the presence of anti-IgA
in an IgA-deficient patient does not imply that a reac-
tion will definitely take place on exposure, for reasons
that remain unclear. If anti-IgA is identified in a patient
at any time, conventional wisdom dictates that special
IgA-deficient blood products and derivatives, including
intravenous gamma globulin (IVIg), should be provided
to the patient. If such products are not readily available
and immediate transfusion outweighs the risk of an
anaphylactic reaction, a slow and carefully monitored
infusion may be the only option.30,33
Corticosteroid or
diphenhydramine administration may help reduce the
severity of symptoms. For PLT and RBC transfusions,
procedures for extensive washing and/or saline replace-
ment are recommended to help minimize risk. However,
while efficacious, these procedures are not a viable op-
tion for urgent needs.
Post-transfusion Purpura
Post-transfusion purpura (PTP) is a rare disorder with
a historical incidence estimated to be between 1 in
25,000 to 100,000 transfusions.35-37
It is possible that
PTP is underdiagnosed or misdiagnosed, primarily
due to its similarity at presentation to heparin-induced
thrombocytopenia (HIT) and its association with disor-
ders such as DIC, which may cloud proper identifica-
tion. The vast majority of PTP cases occur in women
who have previously been pregnant. Post-transfusion
purpura has also been reported in adults who have
been previously exposed to foreign PLTs through trans-
fusion or transplantation.35
Pathogenesis
Alloimmunization to PLT antigens is the hallmark of
PTP; however, the mechanism by which this process
leads to widespread destruction of host PLTs is in-
completely understood.38
Human PLT antigens (HPAs)
are the result of polymorphisms, mainly in the surface
glycoproteins (eg, GPIa, GPlb, GPIIa, GPllb, GPIIIa,
and GPIIIb), that serve as receptors for collagen, von
Willebrand factor, and fibrinogen.38
Oddly, in PTP, the
alloimmune response against foreign HPAs somehow
gains autoimmunity, with host PLTs ultimately becom-
ing the target of destruction. Some evidence exists
that autoantibodies develop, although this theory is not
universally accepted.35
Human PLT antigen-1a PLT ex-
posure in a homozygous HPA-1b (ie, PLA2) host is the
most common scenario for alloimmunization; however,
the prevalence of HPA-1b in the general US population
is less than 2%, meaning that the probability of such a
mismatch is low.35
Moreover, evolution into full-blown
PTP is rare in cases of clear exposure. Regardless of
the mechanism, in selected cases of PTP, unbridled PLT
activation can result in severe thrombocytopenia and
bleeding complications.35
Diagnosis
Identification of PLT alloantibodies in the context of
severe thrombocytopenia (<15,000/µL) and occasional
bleeding, which occurs 3 to 12 (usually 5-10) days after
blood transfusion, is the basis for diagnosis.35-37
By con-
trast, HIT typically results in only moderate reductions
in PLT count (> 30,000/µL) and is temporally related to
heparin exposure. The differential diagnosis should also
include conditions such as thrombotic thrombocytope-
nic purpura (TTP), which can be observed with a similar
precipitous decrease in PLT counts. However, TTP can
be ruled out by its association with microangiopathic
hemolytic anemia.
Several tests are available for detection of PLT anti-
bodies. These include detection of antibodies on intact
PLTs or on immobilized PLT antigens by immunofluo-
rescence, flow cytometric testing, and enzyme-linked
immunosorbent assay (ELISA)–based methods.35
These tests vary in their performance characteris-
tics, particularly pertaining to sensitivity to different
HPAs, which may be modified depending on reagent
preparation. A combined testing approach is generally
needed; several reference laboratories (including Mayo

CE Update
Medical Laboratories and BloodCenter of Wisconsin)
offer PTP workup panels aimed at maximizing sensitiv-
ity. Some of these include genotyping of PLTs, which
may provide additional circumstantial evidence in
certain cases.
Therapeutic options for addressing antibody-mediated
PLT destruction are similar to those offered for autoim-
mune disorders. Plasmapheresis and IVIg have been
successful, with IVIg generally considered to be the
first-line therapy.39,40
In patients with PTP and exten-
sive or life-threatening hemorrhage, transfusion with
antigen-negative PLTs may be warranted.41
However, in
many cases, antigen-negative PLTs may not be readily
available. Thus, the provision of random-donor PLTs,
although not ideal, may be effective in temporarily limit-
ing the extent of an episode of bleeding. Some authors
recommend, along with transfusions of blood products
from random donors, provision of IVIg or other immuno-
suppressants because this practice may enhance PLT
survival.42
Few specific preventative strategies are avail-
able for PTP. If a patient is known to lack HPA-1a and
has a history of PTP, the patient should receive HPA-1a
negative PLTs in future transfusions. Other blood prod-
ucts may contain HPA-1a positive PLTs or, theoretically,
soluble HPA-1a, which could be absorbed into host
PLTs (in this scenario, the risk would remain). Human
PLT antigen matching of these other blood products is
usually not practical.
Transfusion-Associated Graft
Versus Host Disease
The true incidence of transfusion-associated graft ver-
sus host disease (TA-GVHD) is unknown; however, it is
rare and its incidence has decreased since the advent
of irradiation of blood products (as discussed herein).
The overall probability of developing TA-GVHD has
been estimated to be less than 1 per 1,000,000 units
transfused in Canada and is likely even lower at present
in the United States.43
Pathogenesis
Transfusion-associated graft versus host disease is
caused by donor lymphocyte-mediated injury to recipi-
ent tissues. For TA-GVHD to occur, several initial events
must take place. Viable donor lymphocytes must be
delivered in sufficient quantities to foster circulation,
donor lymphocytes must evade recognition by host
cellular immune defenses that would otherwise destroy
donor lymphocytes within a few days, engraftment must
take place within host organs, lymphocytes must be
activated by recipient HLA class II antigen presentation,
and cytotoxic donor lymphocytes must then proliferate
in sufficient numbers to cause destruction of end or-
gans.44
The evasion of host defenses by donor lympho-
cytes is far more likely if the donor lymphocytes have an
HLA class I type recognized as “self” by the host or if
the host’s cellular immune defense system is immature
or heavily impaired.44
However, a case report45
was pub-
lished of immunocompetent host individuals who have
experienced TA-GVHD.
Diagnosis
Symptoms related to TA-GVHD include fever, skin
rash, diarrhea, and hepatitis, all of which are directly
related to the pathogenesis of the disorder. Fever,
a universal finding, is usually the first symptom to
appear, resulting from the cytokine release related
to indiscriminate, systemic donor T-cell activation.
An erythematous skin rash, arising from activated,
cytokine-releasing engrafted donor lymphocytes
within the epidermis, often follows shortly thereafter.
Characteristic skin biopsy findings include basal cell
vacuolation, mononuclear cell infiltrate throughout the
epidermis, degeneration of the basal cell layer, forma-
tion of bullae, and skin ulceration.44
Enteric or colonic
invasion by donor lymphocytes will often result in
diarrhea. Hepatic disease is often also noted at later
stages with increases in levels of LDH, transaminases,
and bilirubin. Over time, pancytopenia ensues as a
prelude to death. Cytotoxic donor lymphocytes take
time to engraft and to become stimulated; hence, the
onset of symptoms occurs between 3 and 30 days
after transfusion (8-10 days is typical).44
Thus, TA-
GVHD is typically a delayed-onset reaction.
Mortality rates from TA-GVHD have been observed
to be between 90% and 100%, with death usually
expected 3 to 4 weeks after transfusion for adults
(and after 1-2 months for newborns).44
Therefore, pre-
vention is the most effective mode of management.
Appropriate use of irradiation can help eliminate the
likelihood of TA-GVHD.46
Subgroups identified as being
at particular risk (Table 3) should receive irradiated
cellular blood products, namely, RBCs, PLTs, and
granulocytes. Of note, TA-GVHD is not associated
with human immunodeficiency virus (HIV) infection

CE Update
or AIDS. Irradiation is also not necessary for patients
with solid tumors or for those with other hematologic
deficiencies.46
Finally, two reports28,44
have indicated
that leukocyte reduction and pathogen inactivation
technologies may help lower the risk for TA-GVHD;
however, it remains unclear whether these treatments
completely incapacitate donor lymphocytes. Thus, at
present, irradiation should be considered the only reli-
able means to prevent TA-GVHD.
Mild-to-Moderate
Complications of Transfusion
Mild-to-moderate transfusion reactions are those with
short-lived symptoms not typically associated with
mortality. These clinically benign reactions are com-
monly encountered. Hence, detailed knowledge of the
pathogenesis, diagnosis, and treatment of these reac-
Table 3. Indications for Irradiation of Cellular Blood Products
Patient Group When to Irradiate Rationale
Directed donor transfusions from blood relatives Always Can evade host cellular immune defense
HLA-matched transfusiona
Always Can evade host cellular immune defense
Granulocyte transfusions Always Immunocompromise and high lymphocyte doseb
Intrauterine transfusions Always Host defenses low
Exchange transfusions in newborns Always Host defenses low and large lymphocyte load
Congenital cellular immunodeficiencyc
Always Immunocompromise
Bone marrow and stem cell transplant patients Per clinical decision made from 14 d before Immune defect
to 3-6 mo or an indefinite period after
Hodgkin disease Always Persistent immune defect
Non-Hodgkin lymphoma Per clinical decision, usually yes Some immune defect but lower risk than in
Hodgkin disease
Purine analog medication recipient During therapy Host defenses low
HLA, human leukocyte antigen.
a
Eg, for idiopathic thrombocytopenic purpura.
b
No irradiation is necessary for HIV, solid tumors, or other heme deficiencies.
c
Eg, severe combined immune deficiency, Wiskott-Aldrich syndrome, DiGeorge syndrome, and ataxia-telangiectasia.
Table 4. Summary of Diagnostic Findings and Management Strategy for Mild Transfusion Reactions
Diagnosis Symptoms Timing Laboratory Findings Management
FNHTR Fever (ie, >1°C rise)a
DTx DAT results: NEG Cease Tx if ongoing
Rigor/chills As long as 1-2 h ATx If necessary (results): Antipyretics
Mild dyspnea *Gram stain: NEG If necessary:
*Culture: NEG *Meperidineb
*CBC: unchanged *Wash unitsc
Mild allergic reaction Urticaria DTx DAT results: NEG Cease Tx if ongoing
(or DMSO toxicity Pruritus As long as 2 h ATx Antihistamines
for HPC infusion) Flushing Restart: clinical decision
Mild wheezing If necessary:
Usually none needed *Corticosteroids
*Wash unitsc
Acute hypotension Isolated decrease in DTx Usually none needed Cease Tx if ongoing
blood pressure D/C ACE inhibitors
for future transfusions
FNHTR, febrile nonhemolytic transfusion reaction; DTx, during transfusion; ATx, after transfusion; DAT, direct antiglobulin test; NEG, negative; CBC, complete blood count;
DMSO, dimethylsulfoxide; HPC, hematopoietic progenitor cells; D/C, discontinue; ACE, angiotensin-converting enzyme.
a
Fever may be absent.
b
For severe rigor.
c
As a last resort.

CE Update
tions is an important aspect of the routine practice of
transfusion medicine. The signs, symptoms, laboratory
findings, and management of these reactions are sum-
marized in Table 4.
Febrile Nonhemolytic
Transfusion Reactions
According to several reports,34,47,48
febrile nonhemolytic
transfusion reactions (FNHTRs) are among the most
common adverse events reported to blood banks. An
estimated 0.2% to 1.0% of all RBC transfusions may
be associated with an FNHTR, with even higher rates
observed for PLT transfusions.49
It should be noted that
many earlier studies on rates of FNHTR were performed
at times when universal leukoreduction was uncommon.
As discussed herein, leukoreduction decreases the fre-
quency of FNHTRs. With growing usage of leukoreduced
blood products, it is likely that rates for FNHTRs should
decrease in turn. The main importance of establishing a
firm diagnosis of FNHTR is to rule out more significant
reactions associated with fever (Table 2).50
Pathogenesis
Despite years of observational studies and in vitro ex-
periments, the definitive mechanisms underlying FNHTRs
remain elusive. Current evidence51
suggests that FNHTRs
are likely mediated by antileukocyte antibodies pres-
ent in recipient plasma and/or biologic response modi-
fiers (BRMs) that accumulate in blood products during
storage. In the first model, antileukocyte antibodies in
recipients interact with residual donor white blood cells
(WBCs) to induce activation and release of mediators of
fever and inflammation, such as TNF-α, IL-1β, and IL-6.51
Some authors51
have argued that anti-WBC antibodies
are the mechanism most likely underlying FNHTRs as-
sociated with RBC transfusion. However, FNHTRs due to
PLTs have been more definitively linked with the second
mechanistic model, namely, the accumulation of BRMs
over time during storage. In this model, PLTs and WBCs
in the component release cytokines, chemokines, and
byproducts of the complement cascade during storage.51
On infusion, these BRMs induce a self-limited febrile re-
sponse.
Diagnosis
Febrile nonhemolytic transfusion reactions are fre-
quently defined as a 1°C (or approximately 2°F) increase
in temperature above baseline during or within 1 to 2
hours of completion of a transfusion.50
Most FNHTRs
are typically accompanied by rigor and chills; in some
cases, they may be associated with mild dyspnea or
tachypnea.50
Of interest, Heddle51
reports cases of
atypical febrile reactions (or nonfebrile reactions) in
which patients experience rigor or chills without an in-
crease in temperature. In these cases, patients may be
unable to generate an adequate temperature response
due to underlying conditions or pretransfusion adminis-
tration of antipyretics. For pure FNHTRs, patients gen-
erally display no additional signs or symptoms.
Laboratory testing (eg, DAT, CBC) should reveal no
changes compared with pretransfusion levels. Because
other, more serious transfusion reactions are associ-
ated with fever (Table 2), FNHTR should be a diagnosis
of exclusion. Also, because many patients undergoing
transfusion are immunosuppressed or have comorbid
conditions, health care professionals should also con-
sider the possibility that the temperature increase is
unrelated to transfusion and may rather be the result of
an underlying or emerging infectious process.
As with nearly every reaction, the first step in dealing
with an FNHTR is to discontinue the infusion. Although
there has been some controversy regarding whether
this is necessary for FNHTRs,52
in our opinion, complete
cessation of infusion is the safest approach when con-
fronted with a fever during transfusion. Fever is a com-
mon and nonspecific finding; because mild fevers can
be observed with severe reactions such as TRALI (Table
2), continuing transfusion may be considerably risky.53
For many FNHTRs, increases in temperature and associ-
ated symptoms will resolve without specific treatment.
However, although FNHTRs are mostly benign reactions,
patients may experience uncomfortable adverse effects,
including high temperatures or severe rigor. Patients
experiencing such symptoms often benefit from a one-
time dose of an antipyretic such as acetaminophen. Also,
meperidine can be useful to counteract severe rigor and
chills associated with an FNHTR.
Because the mechanistic models of FNHTRs are based
on the activation of infused WBCs or the accumulation
of WBC-derived BRMs, many investigators have exam-
ined the role of leukoreduction in preventing FNHTRs.
Certain studies34,48
have found that prestorage leuko-
reduction yields a significant reduction in FNHTRs.
There is some debate regarding the usefulness of pre-
transfusion medication with antipyretics. This practice,

CE Update
although showing no proven benefit for the prevention
of FNHTRs,54
may be of limited use for patients with
repeated reactions. Removal of the supernatant plasma
of RBC and PLT products by washing or saline replace-
ment is another option. However, due to the labor-inten-
sive and potentially deleterious nature of these actions,
washing or saline replacement should be reserved only
for patients with repeated, severe reactions.
Mild Allergic Reactions
Along with FNHTRs, mild allergic reactions are arguably
the most common adverse event associated with trans-
fusion.47,48,55
Although it can be difficult to define mild
versus severe allergic reactions, for the purposes of this
review, we use the term “mild” to refer to those adverse
events associated only with pruritis, flushing, and/or
urticaria.55
Severe allergic reactions, best characterized
as those with evidence of anaphylaxis,55
are discussed
in detail in an earlier section herein.
According to a recent large-scale study,55
mild allergic
symptoms were reported in approximately 0.05% of total
transfusion events at the investigators’ facility. Similar to
FNHTRs, mild allergic reactions typically result only in
fleeting discomfort to the transfusion recipient and are
not usually associated with long-term morbidity.
Pathogenesis
Similar to other adverse events resulting from transfu-
sion, there are multiple mechanisms underlying mild
allergic transfusion reactions. One of the most com-
monly theorized models involves preformed IgE or
IgG class antibodies in the recipient reacting against
proteins present in the donor product.31,32
As a result of
this interaction, the recipient develops a hypersensitiv-
ity response. Proteins, drugs, and even food are among
the various allergens reported in association with aller-
gic reactions.31,32
Of interest, a recipient need not form
an endogenous IgG or IgE antibody to have an allergic
reaction. A report33
was published regarding the passive
transfer of such antibodies via donor plasma, which
then mediate allergic responses in the recipient.
Alternatively, donor units may contain mediators of hy-
persensitivity reactions (eg, histamine and bradykinins)
which can directly induce a hypersensitivity response
in the recipient in the absence of preformed IgE or IgG
class antibodies.55
Based on a report in the literature, 55
the transfer of mediators such as histamine more likely
appears to be associated with a mild allergic reaction,
whereas the involvement of preformed or transferred
antibodies correlates with more severe reactions. Fur-
ther research in this area may better elucidate whether
the mechanism of an allergic reaction can better help
predict its severity.
Diagnosis
Mild allergic reactions are associated with the devel-
opment of urticaria, pruritus, flushing, and occasional
mild wheezing during the 1 to 2 hours after transfusion.
Patients may demonstrate patches of itchy, flushed skin
with occasional hives. Despite these sometimes wor-
risome and widespread manifestations, mild allergic
reactions are not associated with fever, hypotension,
or cardiovascular compromise. A mild allergic reaction
does not require imaging studies and is not typically
associated with any abnormalities in the results of basic
laboratory studies.
On demonstration of signs or symptoms consistent with
a mild allergic reaction, blood-product infusion should
be discontinued. In some cases, the cessation of a
transfusion is the only treatment indicated. However, for
patients with uncomfortable itching, flushing, or hives,
the use of an antihistamine agent, such as diphen-
hydramine, may be indicated. Due to the relatively mild
nature of simple allergic reactions, some facilities allow
a reinitiation of transfusion with the same unit that was
implicated in the reaction. Although this is acceptable,
such a practice should be performed with caution; a
report55
indicates that allergic reactions can become
more severe over time.
Randomized, placebo-controlled trials have shown no
reduction in allergic reactions when diphenhydramine is
provided to transfusion recipients.54
However, patients
who repeatedly demonstrate allergic symptoms and
who require chronic transfusion therapy may benefit
from preinfusion dosage of antihistamines. Of note,
concomitant use of H2 blockers (eg, ranitidine) may be
useful in such settings to promote a more complete
blockade of the histamine receptor; however, this prac-
tice has not been confirmed by clinical trials. At our
institution, patients with recurrent mild-to-moderate al-
lergic reactions are occasionally premedicated with cor-
ticosteroids. However, due to the potential side effects
of corticosteroids, we recommend that this practice be
restricted to patients whose conditions are refractory to

CE Update
other forms of premedication therapy. Another option
for prevention of allergic symptoms is the removal of the
supernatant plasma of RBCs and PLTs. However, wash-
ing or saline replacement are recommended only for
patients with repeated reactions whose conditions do
not respond to premedication therapy.
Acute Hypotensive Reactions
A decrease in blood pressure during transfusion is a
relatively uncommon occurrence. Although hypotension
may be understood as a component of sepsis, anaphy-
laxis, and TRALI (Table 2), the occurrence of isolated
decreases in blood pressure during transfusion with a
virtual absence of other signs and symptoms is best
characterized as an acute hypotensive reaction (AHR).56
Overall, these reactions are relatively rare, with no com-
pelling/clear data available on their true incidence, to
our knowledge.
Pathogenesis
Much research on AHRs has focused on the possible
role of bradykinins and their metabolites.57,58
These
peptides have the potential to induce vasodilation and
smooth muscle relaxation in vivo, with a resultant de-
crease in blood pressure. Studies57,58
have shown that
blood products often contain coagulation factor XII and
prekallikreins; on infusion to recipients, these products
can lead to the increased synthesis of bradykinins. In
vulnerable patients, this increased synthesis can cause
acute hypotension. Moreover, the effects of bradykinin
generation may be exacerbated in patients taking angio-
tensin-converting enzyme (ACE) inhibitor antihyperten-
sives because ACE is a key enzyme in the degradation
of bradykinin. Likewise, reports59,60
have been published
of AHRs occurring in patients taking ACE inhibitors.
Diagnosis
Acute hypotensive reactions typically occur with sig-
nificant, isolated decreases in systolic and diastolic
blood pressure.56,59,60
Certain reported cases59,60
have
also included associated flushing and mild dyspnea.
Otherwise, patients are expected to lack symptoms
such as fever, chest pain, flank pain, and nausea. The
results of laboratory and imaging studies are typically
the same as the baseline values. Currently, no helpful
acute-care tests are available to aid in the diagnosis of
AHRs; as a result, AHR remains a diagnosis of exclusion.
Therefore, it is critical to rule out other, more serious
adverse events of transfusion also associated with hy-
potension (Table 2).
Most AHRs will resolve quickly after cessation of trans-
fusion without the need for any specific treatment.60
In
some cases of severe or sustained decreases of blood
pressure, fluid boluses of normal saline may be required.
The use of pressors is highly unusual in the setting of
hypotensive reactions but may be necessary for those
patients whose conditions are refractory to other forms
of intervention. From a preventative standpoint, because
of the well-established association between ACE inhibi-
tors and hypotensive reactions,59,60
patients taking these
medications who demonstrate episodes of hypotension
during transfusion may benefit from a switch to another
antihypertensive agent, particularly if they are expected
to require ongoing transfusion support.
Reporting of Transfusion
Reactions
The evaluation of a transfusion reaction represents an
excellent opportunity for a clinical consultation, from
the laboratory medicine or blood-bank standpoint.
Establishing a viable and useful means of consulta-
tion regarding transfusion reactions raises the visibility
of the blood bank as a source of clinical service and,
ultimately, can improve transfusion safety. Moreover,
few physicians or health care providers have extensive
experience in the evaluation or management of transfu-
sion reactions. The input of a physician experienced in
transfusion medicine can make a meaningful difference
in the treatment and prevention of acute reactions.
At our facility, we have adopted a consultative approach
to the evaluation of transfusion reactions. On notifica-
tion of a reaction, blood-bank staff contacts laboratory
residents and/or fellows covering the service, who are
trained to immediately perform an investigation into the
circumstances of the reaction. Their procedures include
interviewing the patient, notating vital signs, collect-
ing other data, and presenting the case to an on-call
attending physician. After this initial investigation, the
clinical team is informed of the findings; treatment and
management recommendations are made.
Subsequently, a formal Transfusion Reaction Evaluation
note is placed in the electronic medical record within 24

CE Update
hours of the initial call. This note is typically written by
the trainee using data collected from his or her investi-
gation; it is edited by the attending physician.
The presence of a formal note in the patient’s medical
record can serve many purposes. First and foremost,
it can provide detailed guidance on the management
of a reported reaction. Often, information provided via
telephone may not be effectively communicated, nor is
it always passed down accurately among shifts. Hence,
important details regarding patient management after
a reaction could be lost without appropriate documen-
tation. Also, a Transfusion Reaction Evaluation note is
available for review in the future. This feature, particu-
larly for electronic records, brings the history of reac-
tions to the attention of any other health care providers
and may allow more readily for preventative measures
to be performed before the onset of a reaction.
Summary
Transfusion reactions remain a significant risk associ-
ated with blood-product administration. From severe,
life-threatening reactions to benign side effects, pa-
tients are exposed to a number of hazards when receiv-
ing blood products. However, with knowledge of these
reactions, blood banks and transfusion services are
uniquely positioned to provide guidance regarding their
diagnosis, treatment, and prevention. LM
Acknowledgements
This material results from investigation supported with
resources and the use of facilities at the VA Connecticut
Healthcare System, West Haven, Connecticut. Also,
the writing and publication were made possible in part
by Clinical and Translational Science Awards grant UL1
RR024139 from the National Center for Research Re-
sources (NCRR), a component of the National Institutes
of Health (NIH). Its contents are solely the responsibility
of the authors and do not necessarily represent the of-
ficial view of the NCRR or the NIH.
References
1. Vamvakas EC, Blajchman MA. Blood still kills: Six strategies to further
reduce allogeneic blood transfusion–related mortality. Transfus Med
Rev. 2010;24:77-124.
2. U.S. Food and Drug Administration. Fatalities Reported to FDA
Following Blood Collection and Transfusion. Available at: http://
www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailablility/
ReportaProblem/TransfusionDonationFatalities/UCM129521.pdf.
Accessed March 17, 2012.
3. Shaz BH, Stowell SR, Hillyer CD. Transfusion-related acute lung
injury: From bedside to bench and back. Blood. 2011;117:1463-1471.
4. Sachs UJH, Wasel W, Bayat B, et al. Mechanism of transfusion-
related acute lung injury induced by HLA class II antibodies. Blood.
2011;117:669-677.
5. Silliman CC, Moore EE, Kelher MR, et al. Identification of lipids that
accumulate during the routine storage of prestorage leukoreduced
RBCs and cause acute lung injury. Transfusion. 2011;51:2549-2554.
6. Kleinman SH, Triulzi DJ, Murphy EL, et al, for the National Heart,
Lung, and Blood Institute Retrovirus Epidemiology Donor Study–II
(REDS-II). The Leukocyte Antibody Prevalence Study–II (LAPS-II):
A retrospective cohort study of transfusion-related acute lung
injury in recipients of high–plasma-volume human leukocyte
antigen antibody–positive or –negative components. Transfusion.
2011;51:2078-2091.
7. Goldman M, Webert KE, Arnold DM, et al; TRALI Consensus Panel.
Proceedings of a consensus conference: Towards an understanding
of TRALI. Transfus Med Rev. 2005;19:2-31.
8. Wiersum-Osselton JC, Middelburg RA, Beckers EAM, et al. Male-
only fresh-frozen plasma for transfusion-related acute lung injury
prevention: Before-and-after comparative cohort study. Transfusion.
2011;51:1278-1283.
9. Chapman CE, Stainsby D, Jones H, et al. Ten years of hemovigilance
reports of transfusion-related acute lung injury in the United Kingdom
and the impact of preferential use of male donor plasma. Transfusion.
2009;49:440-452.
10. Linden JV, Wagner K, Voytovich AE, et al. Transfusion errors in
New York State: An analysis of 10 years’ experience. Transfusion.
2000;40:1207-1213.
11. Tormey CA, Stack G. The persistence and evanescence of blood
group alloantibodies in men. Transfusion. 2009;49:505-512.
12. Pineda AA, Vamvakas EC, Gorden LD, et al. Trends in the incidence
of delayed hemolytic and delayed serologic transfusion reactions.
Transfusion. 1999;39:1097-1103.
13. Strobel E. Hemolytic transfusion reactions. Transfus Med Hemother.
2008;35:346-353.
14. Davenport RD. Pathophysiology of hemolytic transfusion reactions.
Semin Hematol. 2005;42:165-168.
15. Kim HH, Park TS, Oh SH, et al. Delayed hemolytic transfusion
reaction due to anti-Fyb caused by a primary immune response:
A case study and a review of the literature. Immunohematology.
2004;20:184-186.
16. Tormey CA, Stack G. Delayed intravascular haemolysis following
multiple asymptomatic ABO-incompatible red blood cell transfusions
in a patient with hepatic failure. Vox Sang. 2008;95:232-235.
17. Tormey CA, Stack G. Estimation of combat-related blood group
alloimmunization and delayed serologic transfusion reactions in U.S.
military veterans. Mil Med. 2009;174:503-507.
18. Li G, Rachmale S, Kojicic M, et al. Incidence and transfusion risk
factors for transfusion-associated circulatory overload among
medical intensive care unit patients. Transfusion. 2011;51:338-343.
19. Gajic O, Gropper MA, Hubmayr RD. Pulmonary edema after
transfusion: How to differentiate transfusion-associated circulatory
overload from transfusion-related acute lung injury. Crit Care Med.
2006;34:S109-S113.
QR code generated on http://qrcode.littleidiot.be
To read this article online, scan
the QR code.

CE Update
20. Li G, Daniels CE, Kojicic M, et al. The accuracy of natriuretic peptides
(brain natriuretic peptide and N-terminal pro-brain natriuretic) in the
differentiation between transfusion-related acute lung injury and
transfusion-related circulatory overload in the critically ill. Transfusion.
2009;49:13-20.
21. Zhou L, Giacherio D, Cooling L, et al. Use of B-natriuretic peptide
as a diagnostic marker in the differential diagnosis of transfusion-
associated circulatory overload. Transfusion. 2005;45:1056-1063.
22. Eder AF, Goldman M. How do I investigate septic transfusion
reactions and blood donors with culture-positive PLT donations?
Transfusion. 2011;51:1662-1668.
23. Eder AF, Kennedy JM, Dy BA, et al; American Red Cross Regional
Blood Centers. Limiting and detecting bacterial contamination of
apheresis platelets: Inlet-line diversion and increased culture volume
improve component safety. Transfusion. 2009;49:1554-1563.
24. Eder AF, Kennedy JM, Dy BA, et al; American Red Cross Regional
Blood Centers. Bacterial screening of apheresis platelets and the
residual risk of septic transfusion reactions: The American Red Cross
experience (2004-2006). Transfusion. 2007;47:1134-1142.
25. Jacobs MR, Good CE, Lazarus HM, et al. Relationship between
bacterial load, species virulence, and transfusion reaction with
transfusion of bacterially contaminated platelets. Clin Infect Dis.
2008;46:1214-1220.
26. Benjamin RJ, Dy B, Warren R, et al. Skin disinfection with a single-
step 2% chlorhexidine swab is more effective than a two-step
povidone-iodine method in preventing bacterial contamination of
apheresis platelets. Transfusion. 2011;51:531-538.
27. Dumont LJ, Kleinman S, Murphy JR, et al. Screening of single-donor
apheresis platelets for bacterial contamination: The PASSPORT study
results. Transfusion. 2010;50:589-599.
28. McClaskey J, Xu M, Snyder EL, et al. Clinical trials for pathogen
reduction in transfusion medicine: A review. Transfus Apher Sci.
2009;41:217-225.
29. Pineda AA, Taswell HF. Transfusion reactions associated with anti-
IgA antibodies: Report of four cases and review of the literature.
Transfusion. 1975;15:10-15.
30. Sandler SG, Mallory D, Malamut D, et al. IgA anaphylactic transfusion
reactions. Transfus Med Rev. 1995;9:1-8.
31. Shimada E, Tadokoro K, Watanabe Y, et al. Anaphylactic transfusion
reactions in haptoglobin-deficient patients with IgE and IgG
haptoglobin antibodies. Transfusion. 2002;42:766-773.
32. Jacobs JF, Baumert JL, Brons PP, et al. Anaphylaxis from passive
transfer of peanut allergen in a blood product. N Engl J Med.
2011;364:1981-1982.
33. Arnold DM, Blajchman MA, Ditomasso J, et al. Passive transfer of
peanut hypersensitivity by fresh frozen plasma. Arch Intern Med.
2007;167:853-854.
34. Paglino JC, Pomper GJ, Fisch GS, et al. Reduction of febrile but not
allergic reactions to RBCs and platelets after conversion to universal
prestorage leukoreduction. Transfusion. 2004;44:16-24.
35. Gonzalez CE, Pengetze YM. Post-transfusion purpura. Curr Hematol
Rep. 2005;4:154-159.
36. Rosenberg N, Dardik R. Post-transfusion purpura—when and why?
Isr Med Assoc J. 2006;8:709-710.
37. Shtalrid M, Shvidel L, Vorst E, et al. Post-transfusion purpura: A
challenging diagnosis. Isr Med Assoc J. 2006;8:672-674.
38. Rozman P. Platelet antigens: The role of human platelet alloantigens
(HPA) in blood transfusion and transplantation. Transpl Immunol.
2002;10:165-181.
39. Mueller-Eckhardt C, Kiefel V. High-dose IgG for post-transfusion
purpura–revisited. Blut. 1988;57:163-167.
40. von Baeyer H. Plasmapheresis in immune hematology: Review of
clinical outcome data with respect to evidence-based medicine and
clinical experience. Ther Apher Dial. 2003;7:127-140.
41. Loren AW, Abrams CS. Efficacy of HPA-1a (PlA1)–negative platelets in
a patient with post-transfusion purpura. Am J Hematol. 2004;76:258-
262.
42. Win N, Matthey F, Slater NGP. Blood components—transfusion
support in post-transfusion purpura due to HPA-1a immunization. Vox
Sang. 1996;71:191-193.
43. Kleinman S, Chan P, Robillard P. Risks associated with transfusion
of cellular blood components in Canada. Transfus Med Rev.
2003;17:120-162.
44. Webb IJ, Anderson KC. Transfusion-associated graft-versus-
host disease: Further reading. In: Popovsky MA, ed. Transfusion
Reactions. 2nd ed. Bethesda, MD: AABB Press;2001:171-186.
45. Ohto H, Anderson KC. Survey of transfusion-associated graft-versus-
host disease in immunocompetent recipients. Transfus Med Rev.
1996:10;31-43.
46. BCSH Blood Transfusion Task Force. Guidelines on gamma
irradiation of blood components for the prevention of transfusion-
associated graft-versus-host disease. Transfus Med. 1996;6:261-271.
47. Tormey CA, Sweeney JD, Champion MH, et al. Analysis of transfusion
reactions associated with prestorage-pooled platelet components.
Transfusion. 2009;49:1242-1247.
48. Pruss A, Kalus U, Radtke H, et al. Universal leukodepletion of
blood components results in a significant reduction of febrile non-
hemolytic but not allergic transfusion reactions. Transfus Apher Sci.
2004;30:41-46.
49. Heddle NM, Klama LN, Griffith L, et al. A prospective study to identify
the risk factors associated with acute reactions to platelet and red
cell transfusions. Transfusion. 1993;33:794-797.
50. Selbst M, Ross R, Tormey CA. Complications associated with the
serological evaluation of febrile transfusion reactions. Conn Med.
2010;74:85-89.
51. Heddle NM. Pathophysiology of febrile nonhemolytic transfusion
reactions. Curr Opin Hematol. 1999;6:420-426.
52. Oberman HA. Controversies in transfusion medicine: Should a febrile
transfusion response occasion the return of the blood component to
the blood bank? Con. Transfusion. 1994;34:353-355.
53. Widmann FK. Controversies in transfusion medicine: Should a febrile
transfusion response occasion the return of the blood component to
the blood bank? Pro. Transfusion. 1994;34:356-358.
54. Kennedy LD, Case LD, Hurd DD, et al. A prospective, randomized,
double-blind controlled trial of acetaminophen and diphenhydramine
pretransfusion medication versus placebo for the prevention of
transfusion reactions. Transfusion. 2008;48:2285-2291.
55. Domen RE, Hoeltge GA. Allergic transfusion reactions: An evaluation
of 273 consecutive reactions. Arch Pathol Lab Med. 2003;127:316-
320.
56. Hume HA, Popovsky MA, Benson K, et al. Hypotensive reactions:
A previously uncharacterized complication of platelet transfusion?
Transfusion. 1996;36:904-909.
57. Cyr M, Hume HA, Champagne M, et al. Anomaly of the des-
Arg9
-bradykinin metabolism associated with severe hypotensive
reactions during blood transfusions: A preliminary study. Transfusion.
1999;39:1084-1088.
58. Cyr M, Eastlund T, Blais C Jr, et al. Bradykinin metabolism and
hypotensive transfusion reactions. Transfusion. 2001;41:136-150.
59. Quillen K. Hypotensive transfusion reactions in patients taking
angiotensin-converting–enzyme inhibitors. N Engl J Med.
2000;343:1422-1423.
60. Kalra A, Palaniswamy C, Patel R, et al. Acute hypotensive transfusion
reaction with concomitant use of angiotensin-converting enzyme
inhibitors: A case report and review of the literature. Am J Ther.
2012;19:e90-e94.

transfusion risks

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (20)

Similar to transfusion risks

Similar to transfusion risks (20)

Recently uploaded

Recently uploaded (20)

transfusion risks