Complications of Transfusion
MB Pagano, Puget Sound Blood Center, Seattle, WA, USA
AAR Tobian, Johns Hopkins University, Baltimore, MD, USA
ã 2014 Elsevier Inc. All rights reserved.
Glossary
Calculated residual risk It is calculated as the incidence rate
times the infectious window period.
Hemolytic disease of the fetus and the newborn
(HDFNB) It is a condition that develops in a fetus when IgG
antibodies (e.g., anti-D and anti-K) produced by the mother
against red blood cell antigens that the mother does not
express (e.g., D
and K
) pass through the placenta and
attack the fetus’s red blood cells that express the cognate
antigen (Dþ and Kþ). The destruction of fetal red blood
cells by maternal antibodies results in severe hemolysis that
can lead to anemia and erythroblastosis fetalis.
Introduction
Blood transfusion can be a life-saving therapeutic tool for
individuals with blood loss or impaired production. However,
this intervention is not risk-free, and possible complications
must be considered when making the decision to transfuse a
patient. This article is intended to describe the most common
complications of transfusion, with an emphasis on the patho-
physiology and clinical implications.
Historical Perspective
Risks associated with blood transfusion have evolved over time
according to our understanding of blood groups, antibody char-
acteristics, and infectious disease testing. The first recorded
attempts of blood transfusions occurred more than 300 years
ago, soon after the circulatory system was unveiled (Figure 1). In
1628, William Harvey described how blood was pumped from
the heart in a one-way circular course through venous and
arterial circuits, opposite to the prevailing theory that blood
was produced in the liver and reabsorbed throughout the
body. Harvey’s discovery was the initial step in the evolution
of the concept of blood transfusion as a way to replace lost
blood. In the 1600s and 1700s, blood transfusions utilizing
sheep blood or milk were performed, but these practices were
rapidly abandoned. In the early 1800s, the British obstetrician
James Blundell demonstrated with a series of experiments in
dogs that blood transfusions were effective in restoring pulse
and consciousness after exsanguination. Soon after, he per-
formed the first successful human-to-human transfusion in a
patient with a severe postpartum hemorrhage, in which the
patient received her husband’s blood and survived. In this
early stage of transfusion medicine, half of the transfused
patients died almost immediately after a transfusion, most likely
due to acute hemolysis secondary to ABO incompatibility. The
high mortality associated with transfusions drastically changed
after Carl Landsteiner discovered the ABO group in 1901. This
3182 Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms
Incidence The incidence of transfusion-transmissible agents
among blood donors is the number of observed new
infections over the total number of person-years observed.
Infectious window period The period between when an
individual becomes infected and the infection is detected by
laboratory testing. This period is the most critical for risk of
transfusion-transmitted infections.
Prevalence Prevalence reflects the number of confirmed
positive donations for a given transfusion-transmissible
agent over the total number of donations tested.
finding led to the beginning of compatibility testing that
significantly decreased the risk of immediate death. Following
the initial ABO group discovery, more than 300 blood
group antigens and 30 blood group systems were found. These
findings led to an understanding of alloimmune conditions,
such as hemolytic disease of the fetus and the newborn and its
treatment. Overall, advances in immunohematology resulted
in prolonged survival after transfusion, which unveiled a myriad
of other risks associated with the use of blood products.
The first recognized transfusion-transmitted infectious dis-
ease occurred in 1915 when several cases of transfusion-
associated syphilis were reported (Figure 2). The first pre-
transfusion infectious screening test, introduced in 1938, was
designed to detect syphilis. During the following decades,
transfusion-associated hepatitis was recognized as a severe
problem related to the transfusion of blood products. It was
not until the 1970s that screening for the hepatitis B virus (HBV)
was available and blood donations became voluntary. Early in
the 1980s, the first cases of acquired immunodeficiency syn-
drome (AIDS) were reported, and, by 1985, specific testing for
human immunodeficiency virus (HIV) had been developed and
implemented. From the AIDS experience, the transfusion com-
munity became aware of the possibility of unidentified latent
infections in asymptomatic carriers who could transmit the
disease, thus jeopardizing the safety of the blood supply. A
donor questionnaire was introduced in 1990s as the first check-
point in the blood donation screening process, with the intent
of diverting high-risk populations. Over time, the addition of
multiple layers of screening, including the volunteer donation
that results in self-deferral, donor questionnaire, laboratory test-
ing, and the introduction of surveillance mechanisms have
made the blood supply as safe as it has ever been.
Noninfectious Complications
Advances in infectious disease recognition and testing have
resulted in noninfectious complications being much more
http://dx.doi.org/10.1016/B978-0-12-386456-7.06214-6
 Blood Banking | Complications of Transfusion 3183

1600–1800 1900s 1910s 1940s 1960–1970 1990s 2000s 2010s

•Transfusion of •Landsteiner •ATRs described •HDFNB, Rh •Anti-D used for •Universal •Male-only •Hemovigilance
sheep blood, ABO discovery discovery HDFNB leukoreduction in plasma
milk Canada and UK to initiated to
reduce reduce TRALI
alloimmunization
and febrile
nonhemolytic
transfusion
reactions

Figure 1 Noninfectious complications timeline. Description of some of the most relevant historical events in the history of transfusion medicine. ATR:
allergic transfusion reaction; HDFNB: hemolytic disease of the fetus and the newborn; TRALI: transfusion-related acute lung injury.

1930s 1960s 1970s 1980s 1990s 2000s 2010

•Syphilis testing •PTH frequency •HBV testing •HIV testing •Donor •Bacterial culture •Hemovigilance
~30% •Voluntary questionnaire for platelets
donation •HCV testing •WNV testing
•PTH frequency •PTH frequency < 1% •Chagas testing
~10%

Figure 2 Infectious complications timeline. Description of the most relevant events in the history of transfusion medicine. PTH: posttransfusion
hepatitis; HBV: hepatitis B virus; HIV: human immunodeficiency virus; HCV: hepatitis C virus; WNV: West Nile virus.

Table 1 Noninfectious complications classification

Acute Delayed

Immune-mediated Hemolytic transfusion reaction Hemolytic transfusion reaction

Transfusion-related acute lung injury Transfusion-associated graft versus host disease
Allergic/anaphylactic Posttransfusion purpura
Febrile nonhemolytic
Nonimmune-mediated Transfusion-associated circulatory overload Iron overload

common than infectious complications. In 2012, 38
transfusion-related deaths were reported to the Food and
Drug Administration (FDA) in the United States, and the
three leading causes were transfusion-related acute lung injury
(TRALI) (n ¼ 17, 45%), transfusion-associated circulatory over-
load (TACO) (n ¼ 8, 21%), and non-ABO hemolytic transfu-
sion reactions (HTRs) (n ¼ 5, 13%).
In 2010, the Centers for Disease Control and Prevention, in
collaboration with AABB, launched the Hemovigilance Mod-
ule of the National Healthcare Safety Network. This module
provides specific definitions for different types of transfusion
reactions. The purpose of the hemovigilance network is to
serve as a tool for hospitals to contribute data on adverse events
associated with blood transfusions. Contributions to this net-
work are voluntary, nonpunitive, and independent of regula-
tion; these data are used for public health purposes only.
Noninfectious complications are classified as acute or
delayed, depending on the timing of their presentation—that is,
if they occur before or after 24 h of the transfusion, respectively.
They can also be classified, based on their pathophysiology,
as immune- and nonimmune-mediated reactions (Table 1).
Changes in vital signs or the clinical status of a patient during a
transfusion need to be investigated for a possible transfusion
reaction. The most important step in a transfusion reaction is to
stop the transfusion. Venous access should be available to main-
tain hydration and provide medication. Also, blood and urine
samples should be sent to the blood bank to characterize the
reaction, and the component bag should be sent for culture if a
bacterial infection is suspected.
Acute Transfusion Reactions
Acute Hemolytic Transfusion Reactions
Description
Acute HTRs (AHTRs) often result as a consequence of pre-
formed antibodies present in the recipient reacting against
donor red blood cells (RBCs) with subsequent hemolysis
of the transfused cells. The most frequent blood group associ-
ated with intravascular AHTR is the ABO blood group, but
antibodies from other blood groups, including Duffy, Rh,
Kidd, MNS, and Kell, can also precipitate severe hemolytic
reactions.
3184 Blood Banking | Complications of Transfusion
Pathophysiology
AHTR is due to preformed antibodies in the recipient that bind
donor RBCs (Figure 3(a)). The antibodies can be IgM (against
the ABO blood group) or IgG. IgM antibodies have a pentamer
structure, and a single molecule can efficiently bind comple-
ment in the intravascular space. The antigen–antibody com-
plex binds C1q to initiate the classical complement pathway
generating C3a as anaphylatoxin and C3b to opsonize the
transfused RBC and subsequent assembly of the membrane
attack complex (MAC), resulting in intravascular hemolysis.
The anaphylatoxins C3a and C5a stimulate the release of
vasoactive substances from mast cells, resulting in vasodilation
and hypotension. Tumor necrosis factor-a (TNF-a) increases
early in the reaction, resulting in fever and leukocyte activation.
TNF-a also induces expression of tissue factor from endothelial
cells and decreases thrombomodulin expression, resulting in
a procoagulant state that can lead to disseminated intravascu-
lar coagulation (DIC). Other chemokines including CXCL8
(interleukin-8) and CCL8 (monocyte chemoattractant
protein-1) increase later in the reaction and interact with gran-
ulocytes, lymphocytes, and macrophages. Intravascular hemo-
lysis also results in the release of free hemoglobin into the
circulation, which can bind nitric oxide, decreasing its levels
and resulting in vasoconstriction. The combination of
antigen–antibody complex deposition, free hemoglobin,
hypotension, and vasoconstriction can lead to renal hypoper-
fusion and acute renal failure.
With the exception of IgG1 and IgG3, which can bind and
activate complement, resulting in intravascular hemolysis, IgG
is generally less efficient in activating complement and often
the MAC complex is not generated. In the case of IgG-mediated
hemolysis, the C3b- or IgG-coated RBCs will be removed by
the reticuloendothelial system in the spleen, resulting in extra-
vascular hemolysis (Figure 3(b)).
Incidence
The most common cause for an ABO-incompatible transfusion
is clerical error. Mislabeled specimens, type and screen sample
obtained from the wrong patient, specimen samples reversed
in the laboratory, or incorrect blood component administra-
tion are among the most frequent reasons for ABO AHTR. In a
study performed from 1990 to 1999 in New York State, the
estimated frequency of ABO AHTR was 1 per 76 000 RBC units,
with a mortality of 1 per 1.8 million transfused RBC units.
Barcode technology and systems designed to improve patient
identification decreased errors that result in mistransfusions,
resulting in a consistent decrease of ABO AHTR since 2001. In
2012, there were three cases of ABO AHTR-related deaths
reported to the FDA. However, non-ABO AHTR have increased
in the last several years, with five deaths reported in 2012. The
most common reasons for non-ABO AHTR are limitations on
antibody identification techniques and the emergency release
of RBC units for a patient with unexpected antibodies.
Less frequently, AHTR may result from the transfusion of
plasma containing preformed antibodies against recipient
cells. Although the use of ABO-incompatible platelets is not
optimal, patients often receive out-of-group platelets with
incompatible plasma for inventory management reasons.
Some measures need to be taken to avoid hemolytic reactions
when transfusing incompatible plasma, including the size of
the recipient (pediatric, smaller patients do not tolerate incom-
patible plasma) and the amount of plasma transfused.
Clinical presentation
AHTR occurs within 24 h of the transfusion but most often are
within the first 15 min of initiation of the transfusion. Signs
and symptoms include fever, pain at the infusion site, flank
pain, chest or abdominal discomfort, vomiting, diarrhea,
hemoglobinuria, increase in the bilirubin, hypotension, and
shock. Acute renal failure and DIC can also be present in severe
reactions. The severity of the reaction is related to the amount
of blood transfused, possibly the transfusion rate, antigen
density on the RBC membrane, and immunoglobulin class
and subclass of the recipient and its efficiency on activating
complement.
Treatment of AHTR is mainly supportive and includes
blood pressure support, hydration combined with diuretics to
increase urine output, dialysis in cases of renal failure, and
prompt treatment of DIC.
Febrile Nonhemolytic Transfusion Reactions
Description
Febrile nonhemolytic transfusion reactions (FNHTRs) are
defined as the presence of either fever (temperature  38  C/
100.4  F with a change of at least 1  C/1.8  F from pre-
transfusion value) or chills/rigors during or within 4 h of the
transfusion. FNHTRs are frequently seen with platelet and RBC
transfusions and less frequently with plasma transfusions.
Pathophysiology
FNHTRs are caused by the presence of antibodies (anti-HLA or
anti-leukocytes) in recipient plasma that react against leuko-
cytes present in donor components or the presence of biolog-
ical response modifiers (BRMs) that accumulate in donor
plasma during product storage. In both cases, there is an
increase in circulating cytokines that results in fever, chills, or
rigors (Figure 4(a) and 4(b)).
Numerous BRMs—including cytokines, chemokines, com-
plement fragments, histamine, and lipids—that originate from
platelets or leukocytes accumulate during storage. It is thought
that most FNHTR related to RBC transfusions are the result of
interactions between leukocytes in the unit and antibodies in
the recipient’s plasma, whereas FNHTR that occur with platelet
transfusions are a consequence of BRMs. However, either
mechanism can lead to FNHTRs in platelet or RBC transfu-
sions. It has been shown that prestorage leukoreduction
decreases but does not eliminate FNHTRs after platelet trans-
fusion and that levels of RANTES, sCD40L, and TGFb1 in
leukoreduced apheresis platelet increase during storage. BRMs
levels in RBC units are less prominent when compared to
platelets. Possible explanations for the different BRMs levels
between these products are the presence of different leukocyte
population (lymphocytes and, to a lesser extent, monocytes
predominate in platelets) and storage temperature (4  C for
RBC and 22  C for platelets).
 Blood Banking | Complications of Transfusion 3185

Intravascular hemolysis

IgM
C1q

C4 – C2
C3 C3a
C3b Anaphylatoxins Vasodilation
C5a Hypotension
C5 Shock
C5b
C5b
C6 Mast cells
C7 MAC complex
C8
C9

TNF-a Immune-mediated Red cell destruction

Cytokine storm hemolysis

Fever Free hemoglobin (Hb)

Leukocyte activation
Thrombosis

Hematocrit Hb/Hp
Haptoglobin (Hp) complex
Disseminated intravascular
LDH Acute kidney failure
coagulation

Bilirubin

Liver
(a)
Extravascular hemolysis

Reticuloendothelial
system

IgG
C3b

Hematocrit
(b) Spleen
Figure 3 (a) Pathophysiology of acute intravascular hemolysis. IgM molecules effectively bind and active complement in the intravascular space,
resulting in immune-mediated intravascular cell destruction. (b) Pathophysiology of acute extravascular hemolysis. IgG is less effective in binding and
activating complement in the intravascular space. Red blood cells coated with IgG and C3b are taken by the Fc receptors expressed in the
reticuloendothelial system in the spleen resulting in a decrease in the hematocrit.
3186 Blood Banking | Complications of Transfusion

Recipient’s HLA or HNA antibodies Donor’s red cells with

leukocytes

C3b Complement
Fever
Chills activation
Rigors
IL-1B
IL-6
TNF
RANTES
CD40L Stimulates patient’s macrophage
(a)
TGFb1
Donor’s platelets
with leukocytes

Lipids prime and activate Leukocytes

Cytokine release
Plasma interacts with plastic bag
Increased C3a and C4a

BRMs increase during storage

Fever
Rigors
Chills

(b)

Figure 4 (a) Pathophysiology of febrile nonhemolytic transfusion reactions. HLA, platelet, or granulocyte antibodies in recipient’s plasma interact with
transfused antigens—for example, donor leukocytes present in RBC units. (b) Pathophysiology of febrile nonhemolytic transfusion reactions.
Biological response modifiers (BRMs) secreted prior to transfusion can precipitate a febrile transfusion reaction.

Incidence Clinical presentation

A recent study performed to evaluate the incidence of FNHTR
after platelet transfusion that included more than 70 000 units
demonstrated an incidence of 0.07% for leukoreduced plate-
lets and 0.20% for nonleukoreduced whole blood platelet
concentrates. A study performed to evaluate the incidence of
FNHTR in RBC that included more than 35 000 units found a
frequency of 0.37% and 0.19% in nonleukoreduced and leu-
koreduced units, respectively.
FNHTRs can present as fever or rigors alone but often are
accompanied by increased blood pressure, headache, and
tachycardia. These reactions are usually self-limited, but the
onset of these symptoms can be worrisome for more severe
conditions. The differential diagnoses of fever or chills during a
transfusion include the underlying medical condition, sepsis
due to bacterial contamination of the blood component,
AHTR, or TRALI.
 Blood Banking | Complications of Transfusion 3187

Treatment
Prestorage leukocyte reduction substantially decreases
FNHTRs. Currently, leukocyte reduction is mandatory in the
United Kingdom and Canada, and, although it is still optional
in the United States, many donor centers have adopted a
universal leukocyte reduction policy. Leukocyte reduction can
be accomplished by filtration before storage or by collection of
the red cell or platelets donations through apheresis.
Allergic Transfusion Reactions
Description
Allergic transfusion reactions (ATRs) are defined by the onset
of urticarial rush, itching, or respiratory symptoms (wheezing
and laryngospasm) within 4 h of a transfusion.
case, histamine release from mast cells and basophil can
result in bronchospasm, headache, flushing, palpitations,
angioedema, hypotension, and rhinitis.
Incidence
ATRs are the most frequent transfusion reactions. There is a
positive correlation between the amount of plasma and the
incidence of ATRs. ATRs have an estimated incidence of 2% of
platelet transfusions versus 0.1–0.5% of RBC transfusions.
Clinical presentation
The severity of the reaction can vary from mild reactions with
only cutaneous manifestations, including itching and hives, to
life-threatening reactions with prominent respiratory symp-
toms, hypotension, and shock.

Pathophysiology
Several mechanisms have been postulated to explain the patho-
physiology of allergic reactions (Figure 5). Recipient, product,
and donor characteristics are all likely involved in the patho-
physiology. Allergic reactions can be precipitated by the pres-
ence of allergens in donor plasma to which recipients may have
IgE antibodies or by passive transfer of donor antibodies against
allergens present in recipient plasma. Specific protein deficien-
cies in the recipient, such as IgA, C4, and haptoglobin, can
promote antibody formation after exposure, resulting in severe
allergic or anaphylactic reactions after reexposure. This IgE–
allergen interaction results in hypersensitivity reaction type 1,
with mast cell/basophil activation and subsequent release of
vasoactive substances such as histamine, leukotrienes, and plate-
let activator factor. Other non-IgE factors, such as IgG, comple-
ment and drugs, can also initiate hypersensitivity type 1 reactions.
These reactions are called anaphylactoid (non-IgE-mediated) to
distinguish them from anaphylactic (IgE-mediated). In either
Treatment
ATRs with mild symptoms usually resolve after the administra-
tion of antihistamines, such as diphenhydramine, and for
severe cases, steroids and epinephrine are usually indicated.
Premedication to prevent allergic reactions with antihista-
minics is a common practice, but several studies have demon-
strated the lack of benefits with this practice.
Strategies to reduce plasma content of platelets are the most
effective means to reduce ATRs. Platelet manipulations to
reduce the plasma include washing or concentrating the plate-
lets. These manipulations result in platelet activation and
decreased recovery and also decrease the shelf life of the unit,
making it difficult to routinely offer these manipulations. More
recently, efforts have been made to develop an additive solu-
tion to replace part of the platelet plasma content during
storage. Recent studies demonstrated that platelet additive
solution reduces allergic reactions. Patients with IgA deficiency

Recipient’s antibodies Recipient’s allergens

Donor’s plasma with allergens
or antibodies

Histamine Stimulates recipient’s

Leukotrienes
mast cells
Chemokines
Cytokines
Itching
Hives
Bronchospasm
Hypotension
Angioedema

Figure 5 Pathophysiology of allergic reactions. Donor and recipient factors are responsible for allergic reactions. Allergens or antibodies present in
recipient or donor plasma can stimulate mast cells and result in allergic reactions.
3188 Blood Banking | Complications of Transfusion
should be transfused with IgA-deficient plasma or washed
cellular products.
Transfusion-Associated Circulatory Overload
Description
TACO is defined as a new onset or exacerbation of respiratory
distress during or within 6 h of the end of the transfusion,
often affecting individuals with congestive heart failure. The
signs and symptoms include acute respiratory distress, left
heart failure, pulmonary edema on chest x-ray, positive fluid
balance and, often, elevation of brain natriuretic peptide.
Pathophysiology
TACO results as a consequence of providing additional volume
to the circulatory system in the context of low ventricular
function, which ultimately precipitates a cardiogenic pulmo-
nary edema.
Incidence
TACO is the second most common transfusion-related fatality,
representing 21% of the total deaths reported in 2012. Its exact
incidence depends on the population being studied, and it has
been reported in  1–8% of elderly orthopedic surgery patients
and 6% of tertiary adult intensive care unit patients. Risks
factors include age (very young and elderly patients are more
susceptible), left ventricular dysfunction, amount of plasma
transfused, cumulative fluid balance, cumulative transfusion
volume, severe anemia, and transfusion rate.
Treatment
Respiratory support and diuresis are the most important ther-
apeutic interventions to treat TACO. In patients with a new
onset of respiratory distress, TACO and TRALI need to be
considered.
Transfusion-Related Acute Lung Injury
Description
TRALI is defined as an acute onset of respiratory failure within
4 h of the transfusion. The respiratory failure is manifested by
hypoxia, bilateral lung infiltrates on the chest x-ray, and no
evidence of volume overload.
Pathophysiology
TRALI is associated with the presence of HLA (classes I and II) or
neutrophil (human neutrophil antigens – HNAs) antibodies in
donor plasma that react against recipient cells, resulting in a
pulmonary insult characterized by neutrophil recruitment and
activation. Donor (presence of antibodies and storage lesion)
and recipient (underlying medical condition and primed neu-
trophils) factors are involved in the pathogenesis of TRALI. The
donor antibodies are the result of sensitization, such as transfu-
sion or pregnancy; female donors are the most significant source
of plasma containing antibodies. Antibodies to HLA class II and
HNA-3a are the most frequently associated with TRALI.
Various mechanisms of antibody–antigen interaction have
been postulated to explain neutrophil activation and rec-
ruitment in the pulmonary circulation. These mechanisms
include anti-HNA and anti-HLA I interacting directly with
the cognate antigen present in neutrophils; anti-HLA I anti-
bodies reacting with the cognate antigen present in endo-
thelial cells, which, in turn, bind with the Fc portion of
neutrophils; and anti-HLA II binding its cognate antigen pre-
sent in monocytes, resulting in cytokine release and neutrophil
activation.
Because RBC units have the least amount of plasma, it is
thought that TRALI in these cases results from non-antibody-
mediated mechanisms. Substances are released during RBC
storage, such as CD40L and lysophosphatidylcholines, that
could directly activate neutrophils. Platelet-induced TRALI
can also result as a combination of multiple mechanisms,
such as antibody and soluble substances present in the plasma
and platelet membrane storage lesions.
With the recognition of HLA and HNA antibodies as the
culprit of TRALI, in 2003, the United Kingdom began using
male-only plasma to avoid sensitized women. In 2006, the
American Red Cross implemented the same change, and
the AABB’s TRALI Working Group recommended implemen-
tation of TRALI mitigation strategies. Although TRALI con-
tinues to be the leading cause of transfusion-related fatalities,
the prevention strategies taken by transfusion services and
blood collection facilities have coincided with a reduction in
TRALI deaths.
Incidence
TRALI is the leading cause of transfusion-associated fatalities,
accounting for 45% (n ¼ 17) of the fatalities reported in 2012.
Its incidence is estimated to be between 0.014% and 0.08% per
blood product transfused. All blood components can poten-
tially trigger TRALI, but high plasma components are associ-
ated with increased risk.
Clinical presentation
Clinical symptoms can vary from mild dyspnea, requiring only
oxygen treatment, to severe dyspnea, requiring mechanical
ventilation and progressing to respiratory failure and death in
up to 20% of the patients. Diagnosis is based on clinical
presentation and radiologic findings since in up to 15% of
the cases, no antibodies are implicated.
Treatment
The main treatment of TRALI is supportive care and respiratory
support. This can be accomplished by oxygen supplementation
alone or mechanical ventilation, according to the severity of
the reaction. Most of the patients will recover within 48–96 h.
It is generally accepted that the patient (i.e., transfusion recip-
ient) is not at risk for future TRALI episodes. However, the
donor’s blood products may continue to lead to additional
TRALI cases. Thus, blood centers evaluate these donors and
potentially eliminate them from the donor pool.
Delayed Transfusion Reactions
Delayed Hemolytic–Serologic Transfusion Reactions
Description
Delayed transfusion reactions are defined by the presence of
RBC alloantibodies between 24 h and 28 days following a
transfusion with evidence of hemolysis (delayed HTR, DHTR)

or without evidence of hemolysis (delayed serologic transfu-
sion reaction, DSTR). These antibodies can be present on the
RBC surface, evidenced by a positive direct antiglobulin test
and characterized by an elution, or can be present in recipient
serum, evidenced by an antibody panel.
Pathophysiology
The most common cause of a DHTR is the transfusion of an
antigen-positive unit to a patient who lacks the antigen on his
or her RBCs. The recipient has a negative pretransfusion anti-
body screen; after transfusion and reexposure to the antigen,
the recipient develops an anamnestic response with subse-
quent increase in the titers that result in hemolysis. These
antibodies are usually IgG, which are not efficient in binding
complement. IgG-coated cells are removed by the spleen,
resulting in extravascular hemolysis. DHTR should be sus-
pected when a patient has an unexplained drop in his or her
hematocrit at least 24 h after a transfusion. Signs and symp-
toms associated with DHTR include a drop in the hematocrit,
jaundice and, less commonly, fever, chills, back pain, and renal
failure. Duffy, Rh, Kidd, MNS, and Kell antigens are most often
associated with delayed reactions. Kidd antibodies are notori-
ous for an anamnestic response that can result in brisk intra-
vascular hemolysis.
Incidence
The estimated incidence of DHTR and DSTR is 1:6715 and
1:1612 per red cell units transfused, respectively, with a com-
bined incidence of 1:1300.
Sickle cell disease patients are at higher risk for severe
DHTR. These patients have a higher rate of alloimmunization,
estimated to be 25%, versus 0.5–1.5% when compared to non-
sickle cell multiply transfused patients, and can also develop a
hyperhemolysis syndrome. This syndrome is an infrequent but
severe complication that results from simultaneous hemolysis
of donor and recipient red cells.
Treatment
DHTR result in extravascular hemolysis, which is often asymp-
tomatic. Treatment is mainly supportive, but intravenous
immunoglobulin (IVIG) has been used successfully in a lim-
ited number of patients for whom compatible units were not
available.
Transfusion-Associated Graft Versus Host Disease
Description
Transfusion-associated graft versus host disease (TA-GVHD) is
a clinical syndrome that occurs within 2 days to 6 weeks
following a transfusion, characterized by maculopapular skin
rash, diarrhea, fever, hepatosplenomegaly, liver dysfunction,
and aplastic anemia.
Pathophysiology
TA-GVHD is associated with the transfusion of viable lympho-
cytes in cellular blood products. Under normal circumstances,
recipient lymphocytes recognize and eliminate the donor lym-
phocytes. But under some circumstances (often immunosup-
pression), recipient lymphocytes cannot recognize or eliminate
donor lymphocytes, resulting in donor lymphocytes engrafting
Blood Banking | Complications of Transfusion 3189
and reacting against recipient cells, including the bone mar-
row. Recipient clinical conditions that can lead to the develop-
ment of TA-GVHD include congenital immune deficiency,
hematologic malignancies, bone marrow transplant, antineo-
plastic drugs such as purine analogues (fludarabine), and
Hodgkin’s disease. Also, the transfusion of an allogeneic unit
from a donor whose HLA is homozygous for a locus to a
recipient who is heterozygous for the HLA locus can result in
TA-GVHD. In this case, the recipient cannot recognize the
donor lymphocytes as foreign, but the donor lymphocytes
can recognize recipient cells as foreign.
Incidence
TA-GVHD is a rare complication, with two transfusion-related
deaths reported to the FDA during the years 2010–2011.
Treatment
TA-GVHD is universally fatal, with only a few successful reports
of patients treated with steroids, immunosuppressive drugs,
and HSC transplant.
TA-GVHD can be prevented by irradiation of cellular blood
components with gamma rays and x-rays. Gamma radiation is
more commonly used than x radiation. The rationale for irra-
diation is to induce DNA damage and prevent lymphocyte
activation and proliferation.
Posttransfusion Purpura
Description
Posttransfusion purpura (PTP) is defined as the onset of
thrombocytopenia secondary to the presence of platelet-
specific antibodies that react against donor and recipient plate-
lets. This type of reaction is usually underdiagnosed because
the thrombocytopenia can be asymptomatic or because there
are alternative explanations for the thrombocytopenia.
Pathophysiology
The antibody frequently involved in PTP is directed against the
platelet antigen HPA-1a located in the glycoprotein IIIa, from
the IIb–IIIa receptor complex. Platelet-specific antibodies can
be formed after exposure to any blood products containing
platelets, such as RBC, platelets, and plasma, or during preg-
nancy. After reexposure to the platelet antigen contained in the
transfused blood product, most commonly RBC, there is an
anamnestic immune response with an increase in antibody
titers, which results in the destruction of both the donor’s
and the recipient’s own platelets. There are different theories
to explain this phenomenon, including the generation of
immune complex (antibody from donor – antigen from prod-
uct transfused) that binds the Fc platelet receptors, resulting in
platelet clearance by the spleen, the adsorption of soluble
antigen on the platelet surface from donor plasma with subse-
quent antibody binding and splenic sequestration, and possi-
ble autoimmune reactivity of the alloantibody.
Incidence
PTP has been estimated to occur in 1:24 000 blood compo-
nents transfused. Although no PTP-related deaths have been
reported to the FDA since at least 2008, the mortality rate
ranges from 0% to 12.8%.
3190 Blood Banking | Complications of Transfusion
Clinical presentation
Patients often present with purpura, bruising, mucosal, and
gastrointestinal bleeding in the context of thrombocytopenia,
which begins within 4–24 days following a transfusion. PTP is
usually self-limited, lasting for about 2 weeks. The thrombocy-
topenia can be severe, with the platelet count <10 000, and can
result in substantial bleeding.
Treatment
High-dose IVIG provides some benefit in improving the plate-
let count within 4 days. Steroids have been tried but are often
ineffective. There are a few case reports describing the transfu-
sion of antigen-negative units, with an increase in platelet
count in 40% of the patients.
Iron Overload
Pathophysiology
Chronic RBC transfusions can lead to pathologic accumulation of
iron, resulting in organ damage. Total body iron content is regu-
lated by adjustment of intestinal iron absorption. Total body iron
content is  4.3 g in men (hemoglobin in red cells 3 g, liver
storage 1 g, and myoglobin and respiratory enzymes 0.3 g) and
3.1 g in women. There is an average fixed excretion of 1 mg day
1,
but there are no physiologic mechanisms to increase excretion to
remove excess iron. A healthy adult has an approximate iron
intake of 1–2 mg day
1, which provides the iron required for
metabolic functions and to cover the fixed loss.
Patients at risk of developing transfusion-associated iron
overload are those who require long-term transfusion support.
Frequent indications for chronic transfusions include hemo-
globinopathies such as thalassemia major and sickle cell
disease; bone marrow disorders such as aplastic anemia,
Blackfan–Diamond syndrome, and myelodysplastic disorders;
and anemia of chronic renal failure.
The iron content of one unit of PRBC is 200–250 mg (1 ml
of red cells contains 1 mg of elemental iron). It is estimated that
the transfusion of approximately 100 units (20–25 g of iron)
results in clinically significant iron overload. Excess iron initially
is deposited in macrophages of the reticuloendothelial system
and later in parenchymal tissue, leading to end-organ dysfunc-
tion. Ferritin is the major intracellular iron storage protein, with
a normal range of 30–400 mg l
1, and can be used to estimate
the degree of iron stores: 1 mg l
1 ferritin ¼ 7–8 mg stored iron.
Patients with iron overload can present with very high ferritin
levels of 2000–10 000 (14–70 g of stored iron).
The organs most frequently affected are the liver, heart, and
endocrine organs. Liver disease is the most frequent complica-
tion and can manifest initially as hepatomegaly and progress to
cirrhosis, which increases the risks of hepatoma. Iron deposi-
tion in the heart can result in restrictive cardiomyopathy, con-
gestive heart failure, and arrhythmias. Diabetes mellitus and its
associated complications, such as retinopathy, vascular dis-
ease, and nephropathy, are also frequently seen.
Treatment
The goal of treatment is to prevent and remove excess iron.
Chelation therapy for patients at risk for iron overload should
be started after 10–20 transfusions, when the serum ferritin is
greater than 1000 mg l
1, or when liver iron concentration is
> 3–7 mg Fe/g dry weight.
Infectious Complications
Transfusion-transmitted infections have decreased drastically
over the last few decades as the result of the introduction of
multiple safety measures, including volunteer blood donation,
questionnaire screening to exclude high-risk populations, and
the development of more sensitive assays to detect infectious
agents at earlier stages. Some diseases are screened only by the
questionnaire, such as malaria and Creutzfeldt–Jakob disease;
by laboratory testing only, such as West Nile virus (WNV); and
by combined questionnaire and laboratory testing. Such as
HIV, HBV, and hepatitis C virus (HCV).
Donor laboratory screening is currently performed to iden-
tify HIV 1/2, HBV, HCV, human T-cell lymphotropic virus
(HTLV-I/II), syphilis, WNV, and Trypanosoma cruzi. Prevalence
rates for almost all tested infections are higher in first-time
donors than in repeat donors. First-time donors who test pos-
itive will receive notification of their test results and receive
advice about future donations. Repeat donors who test positive
for the first time are also notified about the positive results and
receive advice about future donations, but an investigation of
previous donations will be performed (‘look back’). It is pos-
sible that the period between the previous negative donation
and the first positive donation was actually a donation during
the window period, resulting in a false negative result. Recipi-
ents of previous donations may need to be contacted to inves-
tigate the possibility of a transfusion-transmitted infection.
Additionally, selective serology testing to detect cytomega-
lovirus (CMV) antibodies can be performed to identify donors
without exposure to CMV. CMV infection can have devastating
consequences for recipients with severely impaired immune
systems, such as those for intrauterine transfusions and alloge-
neic bone marrow and lung transplant patients who are CMV-
negative. For these high-risk patients, seronegative CMV blood
products are commonly indicated.
In 1999, a new testing methodology was implemented for
early viral detection. Nucleic acid testing (NAT) was introduced
to detect RNA from HIV and HCV, resulting in significant
safety improvement of the blood supply by decreasing the
infectious window period.
Bacterial Contamination of Blood Products
In 2012, bacterial contamination represented the fourth
most frequent cause of transfusion-related mortality. There
were a total of three reported transfusion-related deaths attrib-
uted to microbial infection. The implicated organisms were
Babesia microti associated with a transfusion of RBC, Staphylo-
coccus aureus associated with a transfusion of apheresis platelets,
and Serratia marcescens associated with a unit of pooled
platelets.
The risk for septic reactions is estimated to be 1 in 75 000
and fatal septic reactions at 1 in 500 000 for apheresis platelet.
Transfusion-associated bacteria can originate from the donor’s
skin or asymptomatic bacteremia. Preventive actions to avoid

bacterial contamination from skin flora include the use of
defined protocols to decontaminate the skin at the site of the
venipuncture and the use of the diversion pouch to exclude the
first 10–40 ml of blood during blood collection. In the United
States, the most frequent bacteria associated with platelet
transfusion-associated infections are Coagulase-negative staphy-
lococci, Escherichia coli, and S. aureus, whereas the most frequent
bacteria associated with RBC transfusion-associated infections
are Coagulase-negative staphylococci, Serratia liquefaciens, and
S. marcescens.
Clinical Presentation
Patients receiving a unit of blood contaminated with bacteria
can present with a variety of symptoms ranging from asymp-
tomatic to mild symptoms, including fever, chills and rigors, to
severe symptoms, including hypotension, shock, and death. It
is important to investigate any abrupt change in the general
health of a patient who receives a blood product and immedi-
ately stop the transfusion. Gram stain and cultures from the
unit bag and the patient need to be obtained every time there is
a concern for bacterial contamination, and communication
with the clinical team is critical to evaluate the need to start
antibiotic therapy.
Testing
Bacteria can grow during storage in RBC and platelet units, but
the risks of bacterial contamination are greater in platelet units
since they are stored at 20–24  C in a rich plasma environ-
ment, in contrast to RBCs, which are stored at 4  C and have
minimal plasma. There is no post-donation testing for bacte-
rial contamination of RBC units before transfusions since most
of the bacteria are not able to grow in the cold environment.
The AABB has stated in the Standard for Blood Banks and
Transfusion Services the need for blood banks to have methods
to limit and detect or inactivate bacteria in all platelet compo-
nents. There are currently two FDA-approved culture-based
methods to detect bacteria. The first is an automated culture
system in which an aliquot of 4–10 ml of the platelet unit,
obtained at least 24 h after the collection to allow for bacteria
growth, is incubated in a broth bottle with a colorimetric
sensor sensitive to CO2 concentrations. In the second culture
method, a sample is obtained through a pouch in which a total
of 5–6 ml is passed through a filter that removes platelets and
white cells into the incubation bag. The sample is incubated for
at least 24 h, after which changes in the oxygen concentration
are measured, as evidenced by bacterial growth. An additional
test can be performed before transfusion of the platelet unit.
This is an immunoassay method that detects bacterial antigens
in 30 min. It can be used for testing apheresis platelets that
have already passed the culture method just prior to
transfusion or for testing pooled whole blood-derived platelets
just prior to transfusion.
Human Immunodeficiency Virus
HIV is a retrovirus that can be transmitted through body
fluids, including blood, semen, vaginal fluids, and breast
Blood Banking | Complications of Transfusion 3191
milk. Acute infection can be asymptomatic or result in an
nonspecific viral syndrome characterized by fever, lymphade-
nopathy, and night sweats. Infected individuals can remain
asymptomatic for several years before the AIDS-defined ill-
ness develops. HIV targets CD4 þ cells, resulting in progres-
sive decline of CD4 þ T lymphocytes and risk for
opportunistic infections.
Based on the analysis of donations performed in 2008 at
the American Red Cross, HIV prevalence among allogenic
donations is 1 in 35 886 donations. The estimated residual
risk, calculated as the incidence rate times the infectious
window period, is 1 in 1 860 883 when an infectious window
of 9.1 days was used. From 2000 to 2012, there were a total
of four reported cases in the United States of HIV transfusion-
transmitted infection, the last one having been reported
in 2008. Each year, there are approximately 11 million
blood donations, so a rough calculation of the true risk of
HIV transfusion-transmitted infection based on case reports
would result in a risk of 1 in 33 million donations.
The difference between the estimated residual risk (1 in 1.8
million) and the true risk based on case reports (1 in 33
million) may be due to the estimated residual risk overesti-
mating the true risk, HIV transfusion-transmitted cases being
underrecognized and underreported, or, most likely, a
combination.
Testing for the HIV virus includes a donor questionnaire,
which excludes high-risk donor populations, ELISA testing to
detect anti-HIV 1/2, and NAT to detect HIV RNA by reverse-
transcription polymerase chain reaction (RT-PCR). The FDA
developed specific testing algorithms for testing, interpreting,
and reporting HIV test results.
Hepatitis B Virus
HBV is a DNA virus that can be transmitted through body
fluids, including blood, semen, and vaginal fluids, as well as
perinatally. Clinical manifestation of acute infection most
often results in no symptoms initially, but between 30%
and 50% of individuals will present with jaundice, fever,
nausea, and vomiting. Less than 1% of individuals will
develop a fulminant acute infection that results in death.
Most adults with an acute infection will clear the disease,
while most of the perinatal transmissions will result in
chronic infection of the child. Chronic HBV infection can
be asymptomatic or can evolve to cirrhosis and hepatocellular
carcinoma.
Based on the analysis of donations performed in 2008 at
the American Red Cross, the HBV prevalence (number of con-
firmed positive donations) among allogenic donations is 1 in
12 866 donations. The estimated residual risk is 1 in 366 509,
with an assumed infectious window of 38 days.
Testing for HBV includes the detection of HBsAg (HBV
surface antigen) and anti-HBc IgM and IgG (antibodies
directed against the virus capsid). The exact window period is
not known, but it is estimated to be between 30 and 38 days.
HBV NAT is available, but its use is not mandatory since it has
not been shown to have benefits over the detection of the
antigen and the antibodies.
3192 Blood Banking | Complications of Transfusion
Hepatitis C Virus
HCV is an RNA virus that is transmitted primarily by blood.
Vertical transmission (mother to child) occurs in 10% of
pregnancies. Sexual transmission is controversial. The major-
ity of infected individuals remain asymptomatic, and  80%
of the cases will develop a chronic infection. Between 10%
and 30% of chronically infected individuals will develop
cirrhosis, and 1–3% will develop hepatocellular carcinoma.
Historically, HCV was a major cause of posttransfusion
hepatitis and was initially named non-A non-B hepatitis
until its characterization and cloning in 1989, when it was
renamed HCV. In 1990, the first test to detect antibodies
against HCV was developed and introduced for donor
screening.
Based on the analysis of donations performed in 2008 at
the American Red Cross, the HCV prevalence among allo-
genic donations is 1 in 2997 donations. The estimated resid-
ual risk is 1 in 1 657 722 when an infectious window of 7.4
days is used.
Testing for the HCV virus includes evaluating for anti-HCV
IgG, which is a late marker of infection with a window period
of approximately 2 months; and NAT to detect HCV RNA by
RT-PCR with an estimated window period of 7.4 days.
Human T-Cell Lymphotropic Virus I/II
HTLV types I and II are two closely related RNA viruses that
can be transmitted through body fluids. Both viruses infect
primary lymphocytes. Individuals infected with either of
these viruses usually remain asymptomatic for 20–30 years,
after which  2–5% of HTLV-I infected individuals develop
adult T-cell leukemia/lymphoma. HTLV-I is also the causative
agent of a rare neurologic disorder called HTLV-I-associated
myelopathy/tropical spastic paraparesis or HAM/TSP, which is
characterized by chronic and progressive weakness, stiff mus-
cles, muscle spasms, sensory disturbance, and sphincter dys-
function. HTLV-II was first described in a patient with hairy cell
leukemia, but its association with specific diseases is less clear.
The exact risk of transmission for HTLV is uncertain since
the window period for current testing is unknown, and there
is no confirmatory test to measure the true positive reactive
donors. Based on the analysis of donations performed in
2008 at the American Red Cross, the prevalence among allo-
genic donations is 1 in 35 313 donations. The estimated
residual risk is 1 in 3 394 086 when a window period of 51
days is used.
Testing for HTLV-I and HTLV-II viruses includes the detec-
tion of IgG-specific antibodies.
Trypanosoma cruzi: Chagas Disease
T. cruzi is a parasite that results in Chagas disease. Chagas
disease is transmitted through a triatomine bug vector, the
reduviid bug, or from blood transfusions. Most people with
Chagas disease in the United States acquired their infections in
endemic countries, where infected triatomine bugs reside.
Although there are triatomine bugs in the United States, only
rare vector-borne cases of Chagas disease have been documen-
ted. Acute infections are usually asymptomatic and, in some
cases, there can be a small lesion at inoculation site on the skin
called chagoma. Following the acute phase, most infected peo-
ple enter into a prolonged asymptomatic phase, during which
few or no parasites are found in the blood. During this time,
most people are unaware of their infection. Many people may
remain asymptomatic for life and never develop Chagas-
related symptoms. An estimated 20–30% of infected people
will develop debilitating and sometimes life-threatening med-
ical problems affecting the heart, esophagus, and colon.
Based on the analysis of donations performed in 2008 at
the American Red Cross, the prevalence of Chagas disease
among allogenic donations is 1 in 79 986 donations. Testing
for T. cruzi includes the detection of IgG-specific antibodies.
Since true autochthonous cases (cases infected through the
vector) are rare in the United States, the FDA recommends a
one-time-only screening for every donor.
Treponema pallidum: Syphilis
Syphilis is a sexually transmitted infection caused by Treponema
pallidum. It is manifested by a painless cutaneous lesion in the
genital area in primary syphilis (acute infection), mucocutane-
ous lesions in secondary syphilis, and no symptoms in latent
stages. About 15% of people who have not been treated for
syphilis develop late-stage syphilis, which can appear 10–30
years after infection began; it is manifested by neurologic
symptoms, including difficulty coordinating muscle move-
ments, paralysis, numbness, gradual blindness, and dementia.
Based on the analysis of donations performed in 2008 at
the American Red Cross, the prevalence of syphilis among
allogenic donations is 1 in 4405 donations. No window period
data are available for the T. pallidum antibody to estimate the
residual risk.
Testing for syphilis can be performed with two different
assays. The first assay is a nontreponemal serologic assay that
tests for the presence of reagin antibodies directed against
cardiolipins that are present in a variety of tissues and clinical
situations, including syphilis infection (e.g. rapid plasma
reagin). The confirmatory assay involves a treponemal assay
that tests for the presence of IgG þ IgM antibodies to T. palli-
dum. Syphilis testing has been performed on blood donors
since 1938, and the last case of transfusion-transmitted syphilis
was reported in 1969. The indications and benefits of syphilis
testing are currently being reevaluated since there does not
appear to be any current risk of transfusion-transmitted syph-
ilis. Furthermore, current studies suggest that testing for syph-
ilis has limited value either in preventing transfusion
transmission of syphilis or in serving as a surrogate marker
for high-risk behavior.
West Nile Virus
WNV is an RNA virus that can be transmitted to humans through
a mosquito bite, with birds being the primary WNV reservoir.
Infection from WNV was first detected in the United States in

1999 and follows a seasonal epidemic during summer and
autumn. WNV infection is asymptomatic in 80% of the cases,
presents with mild viral illness in 20% of the cases, or results
in severe neuroinvasive disease such as meningoencephalitis
in < 1% of the cases.
Based on the analysis of donations performed in 2008 at
the American Red Cross, the prevalence of WNV among allo-
genic donations is 1 in 43 440 donations.
Testing for WNV was implemented in 2003, after a
transfusion-transmitted case was recognized in 2002. It is per-
formed by viral RNA detection by transcription-mediated
amplification or PCR. Initial WNV testing is performed by
pooling several samples from different donors (mini-pool).
Samples from reactive mini-pools are tested individually, and
those that are positive are not released for transfusion.
Plasmodium species: Malaria
Malaria is a mosquito-borne disease caused by the infection
of Plasmodium species, including P. falciparum, P. malariae,
P. vivax, and P. ovale. The merozoite forms replicate in RBC,
resulting in hemolysis and infection of other RBCs. P. falciparum
infection results in more-severe clinical forms, and chronic infec-
tion can be seen in P. malariae. Acute infection results in fever,
chills, headache, hemolytic anemia, and splenomegaly.
Transfusion-transmitted infection is usually due to P. falciparum
and rarely fatal.
Malaria donor screening is performed exclusively by donor
questionnaire, and no laboratory testing is currently performed
to detect the presence of Plasmodium parasites in blood donors.
The FDA developed screening guidelines for accepting or defer-
ring donors who are currently in or have been in malaria-
endemic areas. Malaria transmitted through blood transfusion
is rare in the United States and occurs at a rate of < 1 in 1
million units of blood transfused.
Babesia microti: Babesiosis
Babesiosis, a tick-borne disease that results from the infection
with B. microti, is endemic in areas of the Northeast and Upper
Midwest United States. Recent studies demonstrated the pres-
ence of antibodies in 1% of studied donors in Connecticut and
2% of studied donors in Minnesota. More than 159 cases of B.
microti infection transmitted by blood transfusion occurred
between 1979 and 2009. B. microti infects RBC, resulting in
hemolysis and fever. Transfusion-transmitted disease can
develop 1–4 weeks after transfusion, resulting in fever and
hemolysis that can lead to severe hemolytic anemia, renal
failure, and coagulopathy. Individuals who are asplenic,
elderly, or immunocompromised are at higher risk for severe
or fatal infection. There is currently no FDA-approved donor
screening test for B. microti infection.
Further Reading
Alter, H.J., Klein, H.G., 2008. The hazards of blood transfusion in historical perspective.
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Brecher, M.E., Hay, S.N., 2005. Bacterial contamination of blood components. Clin.
Microbiol. Rev. 18, 195–204.
Brecher, M.E., et al., 2013. Survey of methods used to detect bacterial contamination of
platelet products in the United States in 2011. Transfusion 53, 911–918.
Davenport, R.D., 2005. Pathophysiology of hemolytic transfusion reactions. Semin.
Hematol. 42, 165–168.
Ellis, H., 2007. James Blundell, pioneer of blood transfusion. Br. J. Hosp. Med. (Lond.)
68, 447.
Fontaine, M.J., Mills, A.M., Weiss, S., Hong, W.-J., Viele, M., Goodnough, L.T., 2012.
How we treat: risk mitigation for ABO-incompatible plasma in plateletpheresis
products. Transfusion 52, 2081–2085.
Heddle, N.M., 1999. Pathophysiology of febrile nonhemolytic transfusion reactions.
Curr. Opin. Hematol. 6, 420–426.
Heddle, N.M., et al., 1999. A randomized controlled trial comparing plasma removal
with white cell reduction to prevent reactions to platelets. Transfusion 39, 231–238.
Hod, E.A., Zimring, J.C., Spitalnik, S.L., 2008. Lessons learned from mouse models of
hemolytic transfusion reactions. Curr. Opin. Hematol. 15, 601–605.
King, K.E., Shirey, S., Thoman, S.K., Bensen-Kennedy, D., Tanz, W.S., Ness, P.N.,
2004. Universal leukoreduction decreases the incidence of febrile nonhemolytic
transfusion reactions to RBCs. Transfusion 44, 25–29.
Kleinman, S.H., et al., 2011. 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 51, 2078–2091.
Pineda, A.A., Vamvakas, E.C., Gorden, L.D., Winters, J.L., Moore, S.B., 1999. Trends in
the incidence of delayed hemolytic and delayed serologic transfusion reactions.
Transfusion 39, 1097–1103.
Reid, M., Shine, I., 2012. The Discovery and Significance of the Blood Groups, first ed.
SBB, Cambridge, MA.
Roback, J.D., Grossman, B.J., Harris, T., Hillyer, C.D., 2011. Technical Manual,
seventeenth ed. American Association of Blood Banks, Bethesda, MD.
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Savage, W.J., et al., 2012a. Allergic agonists in apheresis platelet products are
associated with allergic transfusion reactions. Transfusion 52, 575–581.
Savage, W.J., Tobian, A.A.R., Savage, H.J., Wood, R.A., Schroeder, J.T., Ness, P.M.,
2012b. Scratching the surface of allergic transfusion reactions. Transfusion 53,
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to transfusion safety. Transfusion 49 (Suppl. 2), 1S–29S.
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Tobian, A.A., Savage, W.J., Tisch, D.J., Thoman, S., King, K.E., Ness, P.M., 2011.
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Wang, R.R., Triulzi, D.J., Qu, L., 2012. Effects of prestorage vs poststorage
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Relevant Websites
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5941a3.htm (last accessed June 13,
2013).
http://www.fda.gov/downloads/biologicsblood%20vaccines/
guidancecomplianceregulatoryinformation/guidances/blood/ucm210270.pdf (last
accessed June 13, 2013).
Transfusion/Donation Fatalities > Fatalities Reported to FDA Following Blood
Collection and Transfusion: Annual Summary for Fiscal Year 2012 (last accessed
June 13, 2013).