Transfusion-Related Adverse Events
LA Williams, III, University of Alabama at Birmingham, Birmingham, AL, USA
EL Snyder, Yale New Haven Hospital, New Haven, CT, USA
Ó 2014 Elsevier Inc. All rights reserved.
Adverse Event
Definition of an Adverse Event
An adverse event or transfusion reaction is an event as a result
of a blood transfusion. Transfusion reactions are categorized
into noninfectious (also known as noninfectious serious
hazards of transfusion (NISHOT)) and infectious (also known
as transfusion-transmitted diseases (TTDs)) (Hendrickson and
Hillyer, 2009). Reactions can occur immediately, within 24 h of
transfusion (e.g., acute hemolytic transfusion reactions) or
delayed for days or years (e.g., transfusion-transmitted hepa-
titis) (Mazzei et al., 2011). The linkage to transfusion as the
cause may be based on the temporal association with clinical
signs or symptoms or via laboratory testing on the patient,
donor, or blood product.
Recognition of a Transfusion Reaction
Patient management during a transfusion includes patient
monitoring, particularly in the first 15 min when severe acute
reactions may occur. While the specific signs and symptoms of
each reaction will be discussed in more detail later, general
clues to a potential reaction and a differential diagnosis are
included in Table 1.
Initial Management of a Transfusion Reaction
Once a physician or nurse suspects a transfusion reaction, the
first action must be to immediately discontinue the transfusion
Table 1 Signs and symptoms of transfusion reactions
Sign or Symptom
Fever and/or chills, and rigors
Increase in heart rate or blood pressure
Decrease in heart rate and/or blood pressure
Dyspnea, tachypnea, or increased oxygen requirements
Nonproductive cough
Pulmonary edema
Signs of heart failure
Hives, itching, rash
Impending sense of doom, general malaise
Chest or back pain
Nausea and vomiting
Sweating, flushed facial appearance
Diarrhea
Dark urine
Jaundice
Anemia
Thrombocytopenia
Disseminated intravascular coagulation
Abbreviations: AHTR, acute hemolytic transfusion reaction; DHTR, delayed hemolytic transfusion reaction; FNHTR, febrile nonhemolytic transfusion reaction; PTP, Post-
transfusion purpura; TRALI, transfusion-associated acute lung injury; TACO, transfusion-associated circulatory overload; TAD, transfusion-associated dyspnea; TA-GVHD,
transfusion-associated graft vs host disease.
Reference Module in Biomedical Research, 3rd edition http://dx.doi.org/10.1016/B978-0-12-801238-3.00075-1
(transfusions should not be restarted except in the case of a mild
allergic reaction which has resolved or stabilized). Intravenous
(IV) access should be maintained. Second, any life-threatening
symptoms, such as shock, should be treated immediately.
Third, notify the primary physician. Fourth, notify the trans-
fusion service and fill out the appropriate paperwork detailing
the specifics of the reaction, send appropriate samples, and
return blood product with attached tubing and fluids. The
information needed generally includes: start and stop time of
the transfusion; what product was transfused; how much
product was transfused; pre-, intra-, and postvital signs; and
signs or symptoms the patient exhibited. All potential adverse
events should be reported to the transfusion service.
Transfusion Reaction Workup by Transfusion Service
The transfusion service confirms the blood type of the donor
and patient and their compatibility and performs a direct
antiglobulin test (DAT) to investigate for an acute hemolytic
transfusion reaction (AHTR). Other laboratory tests may be
performed depending on the suspected reaction. Common
laboratory findings are detailed in Table 2.
Noninfectious Serious Hazards of Transfusion
Febrile Nonhemolytic Transfusion Reactions
Febrile nonhemolytic transfusion reactions (FNHTRs) are one
of the more common reactions encountered during a blood
Differential Diagnosis
Acute Delayed
AHTR, FNHTR, sepsis, TRALI DHTR, TA-GVHD
TACO
AHTR, anaphylaxis, sepsis, TRALI
AHTR, anaphylaxis, TRALI, TACO, TAD
TACO, TAD
TRALI, TACO
TACO
Allergic TA-GVHD
AHTR
AHTR, anaphylaxis
AHTR, anaphylaxis, sepsis
Anaphylaxis
Sepsis, anaphylaxis TA-GVHD
AHTR
DHTR, transfusion-transmitted hepatitis
AHTR DHTR, transfusion-transmitted babesia or malaria
PTP
AHTR, sepsis
1
2 Transfusion-Related Adverse Events
Table 2 Laboratory and radiographic findings in transfusion
reactions
Type of reaction Common laboratory and radiographic findings
AHTR Visible plasma hemolysis and hemoglobinuria, increased
LDH and bilirubin, decreased hematocrit, positive
crossmatch, positive DAT
DHTR Visible plasma hemolysis, decreased hematocrit from
pretransfusion, increased LDH and bilirubin, positive
antibody screen, positive DAT
FNHTR Negative laboratory findings
Sepsis Positive bacterial cultures in the patient and/or the blood
product
TRALI Bilateral pulmonary infiltrates, positive for recipient
antibodies to donor WBCs; transient posttransfusion
leukopenia
TACO Bilateral pulmonary infiltrates, increased NT-proBNP
PTP Severe thrombocytopenia, platelet antibodies present
TA-GVHD Pancytopenia
Allergic Negative laboratory findings
Anaphylactic Some patients may have IgA deficiency and anti-IgA
Abbreviations: LDH, lactate dehydrogenase; DAT, direct antiglobulin test;
NT-proBNP, N terminal-pro brain natriuretic peptide; RBC, red blood cells; WBC,
white blood cells; IgA, immunoglobulin A.
transfusion. They occur in 0.1–1% of transfusions with leu-
koreduced products. FNHTRs are typically defined as
a temperature rise of 2
F or 1
C from the patient’s baseline
temperature with or without chills/rigors. In FNHTRs, the fever
is caused by a reaction to cytokines either in the blood product
or stimulated by the white blood cells (WBCs) in the product.
In room temperature, WBCs in the blood product (e.g., plate-
lets) release cytokines during storage and the cytokines result in
FNHTR upon transfusion. For other WBC-containing products,
WBCs in the product react with patient’s WBC antibodies,
which results in cytokine release and FNHTR (Mazzei
et al., 2011).
Treatment for FNHTR includes a close observation of vital
signs and clinical status, administration of acetaminophen and,
if severe rigors occur, meperidine. Of note, patients are often
premedicated with acetaminophen (to prevent FNHTRs) and
diphenhydramine (to prevent or lessen allergic reactions)
30 min before the start of a transfusion. However, studies have
shown that this practice does not provide a sufficient risk-to-
benefit ratio (Geiger and Howard, 2007). Importantly, pre-
medication with acetaminophen may mask a true hemolytic or
septic transfusion reaction. If a patient has a preexisting fever
due to an infection or other cause, and develops a fever during
transfusion or immediately posttransfusion, a reaction workup
should be initiated because there is no ability at the bedside to
differentiate between FNHTR, AHTR, or septic transfusion
reaction. The best way to mitigate FNHTRs is to prestorage
leukoreduced blood products, which decreases the numbers of
WBC’s in the blood products (Paglino et al., 2004).
Allergic Transfusion Reactions – Nonanaphylactic
Allergic reactions are the most common reactions, with an
incidence of 1–3% of transfusions. These reactions can vary
from mild itching and hives to anaphylaxis (discussed below).
They can be caused by a multitude of antigens present in the
donor’s plasma, leading to the stimulation/production of IgE,
and resulting histamine release (Grattan, 2012).
For mild reactions, such as those limited to a few hives,
localized rash, and mild urticaria, diphenhydramine is usually
sufficient to relieve the patient’s symptoms in minutes to hours
(Vamvakas, 2007). For more severe or repeated reactions,
diphenhydramine combined with steroid treatment, either as
a preventative measure or as a posttransfusion treatment, is
often utilized with good effect. If the patient has a pattern of
repeated severe allergic reactions, blood banks can consider
washed or volume reduced cellular products or platelets stored
in platelet additive solution to decrease the amount of plasma
in the product.
Allergic Transfusion Reactions – Anaphylactic
Anaphylactic reactions are the most severe type of allergic
reactions, with an incidence of 1:20 000–1:50 000 transfusions
(Domen and Hoeltge, 2003). They may be associated with
selective IgA deficiency where a patient forms an IgG antibody
to IgA (anti-IgA). Exposure to donor IgA causes histamine
release and subsequent anaphylaxis. Other consequences may
include a cytokine storm or amplification of the complement
cascade (Golden, 2007).
Anaphylactic reactions can occur with a small amount of
transfused blood. The patient’s signs/symptoms in severe
cases are typical for anaphylaxis and include respiratory
distress, dyspnea, hypotension, diaphoresis, nausea, vomit-
ing, and chest pain. The transfusion should be stopped
immediately and reaction workup completed. Emergent
treatment for an anaphylactic transfusion reaction includes
respiratory support. In life-threatening reactions, epinephrine
or low dose dopamine, and IV steroids are often required.
If recognized in time, most cases are not fatal, but if there
is a delay in treatment, these reactions can be fatal
(Sandler, 2006).
Prevention of anaphylactic reactions requires a multidisci-
plinary planning. Patients with a history of anaphylaxis should
have their IgA levels measured. If deficient, they should be
tested for the presence of anti-IgA (Vassallo, 2004). If the IgA
levels are below the level of detection, but the patient does not
have detectable anti-IgA and has had a severe allergic reaction,
then he or she should be provided with washed products as
a preventative measure. If the patient has detectable anti-IgA
and is IgA deficient, he or she should receive IgA-deficient
products through product washing or collection from IgA
deficient donors (for plasma products). Another option is
autologous donation (Mazzei et al., 2011).
Delayed Hemolytic Transfusion Reactions and Delayed
Serologic Transfusion Reactions
Together, delayed hemolytic transfusion reactions (DHTRs)
and delayed serologic transfusion reactions (DSTRs) occur in
approximately 1:2500 transfusions. DHTRs are hemolytic
reactions that occur 24 h posttransfusion resulting from post-
transfusion red blood cells (RBCs) alloantibody formation.
DSTRs are also due to alloantibody formation, but there is no
laboratory evidence of hemolysis.

Previously, the recipient mounted an immune response to
foreign RBC antigens, most commonly through blood trans-
fusions or via pregnancy (Speiss, 2004). The blood group
antigens most often involved, in decreasing frequency, are
Kidd, Duffy, Kell, and MNS (Mollison et al., 1997). Upon
reexposure to the foreign antigen (e.g., via a second blood
transfusion with antigen positive RBCs), the immune system
increases its production of the antibody, leading to extravas-
cular hemolysis in DHTRs. Extravascular hemolysis does not
involve the release of RBC constituents directly into the circu-
lation, but rather occurs within the confines of the reticuloen-
dothelial system and rarely involves complement. If no
detectable hemolysis is identified, the process is termed
a DSTR. This process often takes anywhere from 2 to 14 days
and can be very subtle in clinical presentation (Petrides, 2007).
Often, DHTRs are clinically suspected due to the lack of an
appropriate response to RBC transfusion. In general, after
transfusion, an adult patient’s hemoglobin and hematocrit
should rise to 1 g dl and 3%, respectively. When this does not
occur and no other cause, such as occult bleeding, is identified,
a possible delayed hemolytic transfusion reaction (DHTR)
should be investigated. Other signs of DHTR include jaundice,
anemia, fever, hemoglobinuria, and renal failure. In cases of
DHTR, the antibody screen and crossmatch tests may be
initially negative and become positive posttransfusion.
DHTRs are identified in the laboratory by a positive anti-
body screen and DAT; other labs may reveal an elevated lactate
dehydrogenase (LDH), elevated bilirubin, and decreased
haptoglobin. Once the responsible alloantibody is identified,
the patient should receive antigen negative RBCs (for the cor-
responding antibody) to prevent future reactions. The patient
may need to be aggressively hydrated to preserve kidney
function, as free hemoglobin and RBC stroma is toxic to renal
tubules (Josephson, 2013).
Acute Hemolytic Transfusion Reactions
Acute hemolytic transfusion reactions (AHTRs) occur in
1:76 000 RBC transfusions (Eder and Chambers, 2007). Fatal
AHTRs occur in 1:1 800 000 transfusions (Vamvakas and
Blajchman, 2009). Typically AHTRs are hemolytic reactions
that occur within 24 h of transfusion and lead to intravascular
(rarely extravascular) hemolysis secondary to ABO incompati-
bility, but may result from other blood group incompatibili-
ties. In contrast, DHTRs typically result in extravascular
hemolysis.
Intravascular hemolysis is caused by RBC antigen interac-
tion with preformed antibodies. Most often these are ABO
(IgM) antibodies; however, sufficient concentrations of pre-
formed IgG can also play a role. Other blood group incom-
patibilities can result in AHTR, such as antibodies to Kidd or
Duffy blood group system antigens. Finally, incompatible
plasma may be transfused to a patient and result in an AHTR.
Most frequently, this occurs secondary to ABO incompatible
platelet transfusion. The degree of hemolysis depends on the
amount and strength (titer) of the ABO antibody.
After the initial antigen–antibody interaction, complement
activation occurs, leading to formation of the membrane attack
complex and eventual destruction of the RBC with the release
of its components into the blood stream. Initially, hemoglobin
Transfusion-Related Adverse Events 3
is bound by haptoglobin and metabolized. When haptoglobin
stores are exhausted, the hemoglobin and other constituents,
such as RBC stroma, may travel to the kidney, leading to tissue
damage due to toxicity. In addition, the RBC constituents can
activate the coagulation cascade and lead to systemic vaso-
constriction and shock (Bellone and Hillyer, 2013).
AHTRs are characterized by fever, back or flank pain, chest
pain, hypotension, shock, and ‘impending sense of doom’ in
the patient. These findings often occur soon after the start of the
transfusion. The transfusion should be stopped immediately;
treatment includes vigorous hydration, furosemide (to main-
tain urine output), as well as support of blood pressure,
disseminated intravascular coagulation, and other clinical
sequelae (Ludens et al., 1968).
A transfusion reaction workup should be initiated quickly
to identify the cause of the reaction. Blood bank testing may
reveal hemolysis, incompatibility between the donor and
recipient, and positive DAT. Other laboratory analysis that may
be helpful includes testing of bilirubin and LDH levels, and
urinalysis (to identify free hemoglobin in the urine).
Human error is the most common cause of AHTRs due to
ABO incompatibility. The error could be made in many places:
during the initial blood draw, issuing of the blood product, and
transfusing product to the wrong patient. When an AHTR
occurs, a root cause analysis is imperative (and mandated by
The Joint Commission) to initiate corrective action and prevent
such occurrences in the future (Bellone and Hillyer, 2013).
Efforts to further decrease the human error component include
computerized matching of patient armband barcodes to blood
product barcodes. Prevention mandates elimination of the
possibility of human error. In contrast, due to low platelet
inventories and short shelf-life of platelets, ABO incompatible
platelet transfusions occur not uncommonly. AHTRs secondary
to platelet transfusions are mitigated by transfusing low titer
platelets or ABO compatible platelets.
Transfusion-Associated Circulatory Overload
Transfusion-associated circulatory overload (TACO) was
thought to occur in 1–8% of transfusions, depending on the
patient’s baseline cardiac status (Popovsky et al., 1996;
Bierbaum et al., 1999); however, a recent prospective study of
plasma recipients utilizing active surveillance after transfusion
reported a 4.8% rate (Narick et al., 2012). TACO is an adverse
clinical reaction due to fluid overload or too rapid infusion of
blood products. It is defined by several criteria including the
presence of dyspnea, rales, cyanosis, hypertension, tachycardia,
nonproductive cough, and evidence of congestive heart failure
(i.e., elevated NT-proBNP levels) (Tobian et al., 2008). Chest
X-ray will often demonstrate new or worsening pulmonary
effusions. For definitive diagnosis, other causes of fluid over-
load should be excluded.
Treatment includes respiratory support; most patients are
also given a diuretic, typically furosemide, to reduce the excess
fluid. Once the patient is given the diuretic, rapid resolution
of the reaction symptoms is normally achieved, unlike
transfusion-associated acute lung injury (TRALI), discussed
below. A preventative measure for TACO during future trans-
fusions is to slow down the infusion rate or decrease the
volume infused over time.
4 Transfusion-Related Adverse Events

Transfusion-Related Acute Lung Injury diagnoses being TRALI, TACO, and allergic reactions. Once
these entities are ruled out, TAD is ruled in based on findings of
The estimated incidence of TRALI is approximately
dyspnea, tachypnea, or a change in the objective signs of
0.81:10 000. Recipients at higher risk for the entity include
respiratory distress, such as O2 saturation below 90% (Centers
those with shock, chronic alcohol abuse, positive fluid balance,
for Disease Control, 2010).
higher peak airway pressure, and current smokers (Toy et al.,
Once the reaction is suspected, transfusion should be
2012). Most cases of TRALI are believed to be a double-hit type
stopped and workup initiated. Additional tests to rule out the
of injury and involve donor antihuman leukocyte and/or
other diagnosis include CBC, NT-pro-BNP, and a chest X-ray
neutrophil antibodies (anti-HLA, anti-HNA), though a small
(see discussions of those diagnoses for expected lab findings).
number of cases are a result of recipient antibodies interacting
The treatment of TAD is respiratory support. Future episodes of
with donor WBCs, resulting in primed neutrophils being acti-
TAD may be prevented by slowing the rate of transfusion and
vated in the lung leads to fluid leakage from damaged capil-
identifying at-risk patients.
laries into the lung. This results in a normal pressure fluid
overload localized to the lungs (noncardiogenic pulmonary
edema) and subsequent respiratory distress (Hendrickson and Septic Transfusion Reactions
Hillyer, 2013). This is different from the systemic fluid over-
Septic transfusion reactions are due to bacterial contamination
load seen with TACO, which is due to increased pulmonary
of the product. Their incidence varies by product type. Due to
capillary pressure.
room temperature storage, platelet products have the highest
TRALI presents as dyspnea and hypotension within 6 h of
risk of bacterial contamination, most commonly from gram
transfusion of a blood product (Toy et al., 2005). Other criteria
positive skin contaminant and gram negative organisms
proposed by the 2005 Canadian Consensus Conference
(Kuehnert et al., 2001). After implementation of automated
include a ratio of PaO2/FiO2  300 or SpO2 < 90% on room
culture screening, approximately 1:107 000 apheresis units
air or other clinical evidence of hypoxia, such as worsening or
result in septic reactions (Benjamin, 2012). Resulting mortality
new bilateral infiltrates on chest X-ray (Triulzi, 2006). The
is low, with only three platelet-associated sepsis-related deaths
spectrum of TRALI ranges from mild cough to respiratory
in 2011 (Food and Drug Administration, 2012a).
failure. Once the reaction is suspected, the transfusion should
Since RBCs are stored refrigerated, approximately 2.6 per
be stopped and reaction workup initiated. A posttransfusion
100 000 units are contaminated with an estimated 1:250 000
complete blood count often reveals a transient leukopenia
resulting in sepsis (Maramica, 2013), and one RBC-associated
because the WBCs migrate and agglutinate within the lung
sepsis-related death in 2011 (Food and Drug Administration,
parenchyma (Marques et al., 2005). In contrast to TACO
2012a). The most common organisms are those that can
patients, TRALI patients have no increase in their NT-proBNP
survive in colder temperatures, such as Yersenia enterocolitica.
levels.
Septic transfusion reactions are associated with fever, chills,
Treatment of TRALI is supportive as the disease is usually
rigors, hypotension, tachycardia, nausea, and vomiting. The
self-limiting. Unlike TACO, diuretics do not help and can be
transfusion should be stopped, and the product, and possible
detrimental by leading to a loss of normal intravascular
bacterial cultures should be returned to the blood bank for
volume. In cases where TRALI is the most likely cause of the
a workup. Additionally, blood cultures should be performed
respiratory distress, the blood center should be notified so the
on the patient and he or she should be started with broad-
donor can be tested for the presence of antileukocyte anti-
spectrum antibiotics.
bodies. Multiparous women are more likely to be implicated
Prevention of septic transfusion reactions includes elimi-
due to exposure to foreign (fetal) WBC antigens during preg-
nating potential septic donors, appropriate drawing and pro-
nancy (Triulzi et al., 2009). If the donor is positive for anti-HLA
cessing of products to eliminate contamination, and testing the
antibodies during a TRALI reaction investigation workup, they
products for potential bacteria (Blajchman et al., 2005).
will be deferred from blood donation.
Preventive measures have decreased the risk of TRALI by
70%, particularly for plasma transfusions. These measures Transfusion-Associated Graft vs Host Disease
include evidence-based transfusion practice, elimination of
Transfusion-associated graft vs host disease (TA-GVHD) occurs
high-risk donors for plasma containing products (platelets and
when viable donor lymphocytes engraft in transfusion recip-
plasma) by using all male donors, never pregnant female
ient, then mount an attack against the recipient’s cells, resulting
donors, and female donors with negative anti-HLA antibody
in near uniform death (Ruhl et al., 2009). Recipients at risk are
screens (Shaz et al., 2011).
those who are immunocompromised, those who receive blood
products from close relatives and granulocytes, and those who
Transfusion-Associated Dyspnea
receive HLA-matched products (Petz et al., 1993).
Transfusion-associated dyspnea (TAD) is a relatively new Examples of immunocompromised patients include
transfusion reaction classification as per the National Health hematopoietic stem cell transplant recipients, patients with
Safety Network (NHSN) manual and the incidence is not yet leukemia, lymphoma, and congenital immunodeficiency
well established. TAD is defined as respiratory distress that syndromes, and patients receiving purine analogue and other
occurs within 24 h of transfusion. It often occurs in patients anti-T-cell medications, such as fludarabine (Francis, 2013).
who are at risk of developing respiratory distress, such as These immunocompromised patients are at risk because their
premature infants or patients with underlying lung disease. immune system is incapable of defending itself against
TAD is largely a diagnosis of exclusion with differential the donor lymphocytes. In contrast immunocompetent

individuals may not recognize the donor lymphocytes as
foreign, such as blood from close relatives and HLA matched
(Ruhl et al., 2009).
TA-GVHD presents 3–30 days posttransfusion with fever,
rashes, diarrhea, pancytopenia, hepatitis, and infections.
Common laboratory findings include pancytopenia and an
elevation in hepatic enzyme levels (Ruhl et al., 2009).
There is no effective treatment for TA-GVHD; therefore,
prevention via irradiation or pathogen inactivation of blood
components is paramount (Carson, 2011). Irradiation or
pathogen inactivation alters the DNA of lymphocytes so that
they are unable to proliferate (BCSH Blood Transfusion Task
Force, 1996). Both clinicians and blood bankers must be dili-
gent in identifying at-risk patients and maintaining records to
ensure that these patients receive irradiated and/or pathogen-
inactivated blood products.
Posttransfusion Purpura
Posttransfusion Purpura (PTP) is a rare transfusion compli-
cation, occurring in approximately 1:300 000 transfusions
that results in marked destruction of both donor and recipient
platelets 8–10 days posttransfusion. PTP usually occurs in
patients who lack human platelet antigen-1 (HPA-1). Expo-
sure to the antigen via transfusion causes the recipient to
develop a platelet alloantibody (Perrotta and Snyder, 2001).
The reason for autologous platelet destruction is not well
understood, but theories include production of a cross-
reactive antibody; adsorption of donor-derived, soluble
platelet glycoprotein on autologous platelets; and immune
response including an autoimmune component
(McFarland, 2007).
Patients will present with bruising and mucous membrane
bleeding, due to severe thrombocytopenia. Multiparous
women and recipients of multiple transfusions are at increased
risk. In suspected cases, the patient should undergo HPA anti-
body screening. Treatment with IVIG is usually successful
(Ziman et al., 2002). The disease is usually self-limited with
recovery within 21 days without treatment. Recurrence with
future transfusions is uncommon (Grindon, 2009).
Transfusion-Transmitted Diseases
Hepatitis B Virus
Hepatitis B virus (HBV), a DNA virus, is spread by contact with
blood, semen, or vaginal secretions. Risk factors for contracting
HBV include unprotected sex, sharing or reusing needles during
intravenous drug abuse (IVDA), and sharing a razor blade with
an infected person. The virus can also be passed from a mother
to baby during child birth (Pungpapong et al., 2007).
Decreased risk is due to donor screening via questionnaire and
testing, and vaccination programs for those at risk (e.g., health
care workers) as well as universal vaccination programs.
Symptoms of nausea, vomiting, jaundice, abdominal pain,
dark urine, and clay-colored stools usually present around
90 days after infection and can last anywhere from 6 weeks to
6 months. Without any treatment, approximately 90% of
patients recover in this time frame. If the symptoms last longer
than 6 months, the infection is considered to be chronic.
Transfusion-Related Adverse Events 5
The long-term effects of chronic infection include cirrhosis and
hepatocarcinoma (Pungpapong et al., 2007).
The window period for serologic testing is around 50 days
(Zou et al., 2009). Serologic testing includes HBsAg (HBV
surface antigen), IgG, and IgM anti-HBc (antibody to HBV core
antigen). During the initial stages of infection, anti-HBs (anti-
body to HBV surface antigen) will be negative. The appearance
of anti-HBs and the disappearance of HBsAg signal the devel-
opment of immunity (Bertoletti and Gehring, 2006). Nuclei
acid testing (NAT) testing, done in pools, detects HBV DNA and
reduces the window period by approximately 12 days (Zou
et al., 2009). The residual risk of transfusion-transmitted HBV
is approximately 1:290 000 (Zou et al., 2012).
Hepatitis C Virus
Hepatitis C virus (HCV) is an RNA virus that is transmitted via
exposure to blood. This exposure can be via transfusion, needle
sticks (including occupational and recreational, such as
tattoos), or needle-sharing during IVDA (Galel, 2011).
The symptoms of HCV are similar to those described above
for HBV. The difference is approximately 80% of those infected
have no signs or symptoms indicative of acute infection. 80%
of infected individuals will develop chronic HCV. Of that 80%,
up to 20% will develop cirrhosis and 5% will develop hepatic
carcinoma (Missiha et al., 2008).
Prevention of transfusion-transmitted HCV includes donor
history questionnaire, anti-HCV, and NAT testing, which
reduced the window period to 7.4 days. The risk of transfusion-
transmitted HCV is approximately 1:1.7 million recipients
(Zou et al., 2012). Currently, no vaccine exists for HCV.
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) is an RNA retrovirus
that is transmitted via blood or other bodily fluids or secre-
tions, such as breast milk. Risk factors include high-risk sexual
activity and IVDA. An infected individual may remain asymp-
tomatic for years, or they may develop flulike symptoms a few
weeks after viral transmission. After the flulike symptoms
resolve, the infected individual may go many years before
noticing any more signs or symptoms (Stevenson, 2003).
Once transmitted, HIV replicates, infects, and then destroys
CD4þ T cells that the body uses to fight infection. Once
a sufficient number of these cells are infected and destroyed,
the body loses its ability of fight off infections. This leads to the
clinical syndrome known as acquired immunodeficiency
syndrome (AIDS) (Sierra et al., 2005). Without targeted anti-
viral medications, these individuals die from resulting
infections.
Prevention of transfusion transmission is by donor
screening and testing. NAT testing reduced the window
period to approximately 9 days (Busch et al., 2005; Zou
et al., 2010). In addition to NAT testing, serological testing
for anti-HIV-1 and anti-HIV-2 is also utilized (LaPerche et al.,
2003). HIV-2 is usually not seen outside of Africa and has
lower infectivity, but its infection leads to AIDS, therefore
testing is required (Horsburg and Holmberg, 1988). The
approximate residual risk for transfusion-transmitted HIV is
1:1 500 000.
6 Transfusion-Related Adverse Events
West Nile Virus
West Nile virus (WNV) is an RNA virus in the Flaviviridae family.
The virus is usually transmitted to humans via mosquitoes, with
birds as the intermediate host, or blood transfusion (Katz and
Dodd, 2013; Samuel and Diamond, 2006). In most people, the
resulting infection is asymptomatic and results in no short- or
long-term consequences. However, some individuals, after
3–14 days incubation period develop clinical manifestations
that range from a fever to a mild flulike illness to full-blown
encephalitis with fever, headache, confusion, nausea and vom-
iting, and asymmetric paralysis. Neonates, elderly, and immu-
nocompromised patients are at the greatest risk of developing
significant infection (Shaz, 2009).
In symptomatic patients, the disease manifestations resolve
within 60 days with no treatment or only supportive treatment,
as there is no specific antiviral effective against WNV. In
the more severe cases, irreversible neurological damage leads
to permanent neurologic disability or death (Hayes and
Gubler, 2006).
Prevention of transfusion-transmitted WNV is through
mini-pool NAT and in active areas individual NAT testing
(Food and Drug Administration, 2009). This has substantially
decreased the risk of transfusion-transmitted infection to four
cases from 2004 to 2008.
Human T-Cell Lymphotrophic Viruses I and II
Human T-cell lymphotrophic viruses (HTLVs) I and II are RNA
retroviruses. The endemic areas are Japan, Africa, and the
Caribbean, but the disease is also prevalent in the southern
United States. HTLV I infection is known to be associated with
HTLV-associated myelopathy (HAM), which is also known as
tropical spastic paraparesis (TSP), and adult T-cell lymphoma/
leukemia (ATLL) (Stricker and Kumar, 2010). HTLV is trans-
mitted by transfer of infected T cells via blood or body fluids,
including breast milk. Risk factors include high-risk sexual
activities, IVDA, and occupational exposure (Shaz, 2009).
Once a person becomes infected with HTLV, approximately
1% will develop HAM/TSP and approximately 2–5% will
develop ATLL (Galel, 2011). In HAM/TSP, the T cells mount
a response against the virus; however, once across the blood-
brain barrier, the myelin is subject to bystander damage from
the activated T cells, leading to progressive central nervous
system damage. In ATLL, the proposed mechanism is HTLV,
which is passed from T cell to T cell and over many years the
T cells become mutated. The mutations cause unchecked
proliferation, thus leading to a monoclonal T-cell population
(Grassman et al., 2005). HAM/TSP and ATLL take decades to
manifest. However, once manifested, the disease is debilitating
in cases of HAM/TSP and fatal in cases of ATLL (Shaz, 2009).
Prevention of transfusion-transmitted HTLV is via donor
screening, donor testing with anti-HTLV I/II, and leukor-
eduction (Centers for Disease Control and Prevention, 1993).
Residual risk of transfusion-transmitted HTLV is approximately
1:270 000 (Zou et al., 2012).
Syphilis
Syphilis is a disease caused by a spirochetal or treponemal
organism. It is usually transmitted by sexual contact with an
infected person (Lanford and Lukehart, 2006). The organism is
killed within 3 days in the cold environment (1–6
C) in which
RBC products are stored (Petrides, 2007). Syphilis testing
consists of screening and confirmatory testing for treponemal
and nontreponemal antibodies. If positive by confirmatory
testing, the donor will be deferred for at least 12 months (Food
and Drug Administration, 1991). Due to screening and storage
conditions of blood products, there have only been no reported
cases of transfusion-associated syphilis infections since 1966
(Aberle-Grasse et al., 1999).
Trypanosoma cruzi (Chaga’s Disease)
Trypanosoma cruzi (Chaga’s disease) is a protozoan infection that
is transmitted to humans via the bite of an infected reduvid bug
(the kissing bug). The disease has a high prevalence in Mexico,
South America, and Central America (McAdam and Sharpe,
2010). Most acute infections are asymptomatic and resolve on
their own. However, the protozoan remains in the blood
stream, at low levels, for the remainder of the person’s life. In
20–40% of those infected, the parasite leads to the development
of cardiac (e.g., dilated cardiomyopathy) or gastrointestinal
disease years later (Shaz, 2009; Martins-Melo et al., 2012).
Transfusion transmission is prevented by donor question-
naires and screening for antibodies to T. cruzi (American
Association of Blood Banks, 2006). Before this screening was
implemented, seven cases of transfusion-transmitted T. cruzi
were reported.
Cytomegalovirus
Cytomegalovirus (CMV) is a DNA virus in the herpes virus
family. The virus is transmitted by donor leukocytes in sero-
positive individuals. It is estimated that anywhere from 20 to
80% of the population is CMV seropositive. Transmission of
the virus can occur in utero, during transfusions, and during
transplants; the virus is also transmitted by casual contact with
persons who are newly infected and shedding the virus (Lehner
and Wilkinson, 2001).
In most persons, the infection is asymptomatic and causes
no long-term morbidity or mortality. The virus is not destroyed
by the body’s immune response and infectivity is life long. In
fetuses or neonates, transplacental infection can lead to hearing
loss, microcephaly, retinitis, low birth weight, and mental
retardation. In immunocompromised individuals, acute
infection or viral reactivation can lead to multiorgan failure
and death (Shaz, 2009).
Steps to prevent transfusion transmission of CMV to sero-
negative individuals, high-risk recipients, include transfusing
CMV antibody negative or leukoreduced products (Vamvakas,
2005; Bowden et al., 1995). The residual risk of transfusion
transmission is 1–4%.
Babesiosis
Babesiosis is caused by an intracellular parasite which is
transmitted to humans via a tick bite or transfusion. Risk is
highest in endemic areas, such as the Northeast and Midwest
United States (Herwaldt et al., 2011). The risk of acquiring
transfusion-transmitted babesia in the United States is

currently unknown, but it is estimated that the risk may be as
high as 1 in 1800 in Connecticut (Shaz, 2009).
Acute infection with babesia produces a spectrum of clinical
manifestations: asymptomatic to fever, nausea, vomiting, and
hemolytic anemia (Vannier and Krause, 2012). In immuno-
compromised patients and especially asplenic patients, the
infection can lead to shock, multiorgan failure and death
(Galel, 2011).
Babesia is diagnosed by visualizing the intracellular para-
sites on a blood smear and serologic or molecular tests (Krause
et al., 1996; Persing et al., 1992).
Prevention of transfusion-transmitted babesiosis is through
donor questionnaire. If donors state that they have been
diagnosed with babesia in the past, they are indefinitely
deferred from donating. Currently, there is no licensed test for
screening babesia in blood donors, but tests are in develop-
ment (Katz and Dodd, 2013).
Malaria
Malaria is another parasitic disease that is transmitted by
mosquitoes and transfusions. Once the parasite is transmitted,
it quickly enters the liver where it undergoes a part of its life-
cycle and is then released to attach and enter RBCs (Eljigiri and
Sinnis, 2009). Eventually, the parasite will hemolyze the RBCs
and the clinical consequences often depend on how many
RBCs are infected and destroyed at once (McAdam and
Sharpe, 2010).
Malaria is caused by four different Plasmodium species:
Plasmodium ovale, Plasmodium vivax, Plasmodium malariae,
and Plasmodium falciparum. The incubation period of
Plasmodium spp. is estimated to be 12–30 days. The classic
symptoms of malaria include a relapsing and remitting fever
that occurs every 2–3 days as the parasite goes through its
lifecycle and causes destruction of RBCs (Shaz, 2009).
P. falciparum, however, is highly pathogenic and leads to more
severe infections because it can infect RBC’s of any age, thus
leading to a larger parasite load and resultant hemolysis. Other
characteristics of P. falciparum that contribute to its pathoge-
nicity is its ability to cause RBCs to stick together, thus causing
clots in the microcirculation of many organs, it also stimulates
the release of cytokines that suppress RBC production and
worsen the severity of fevers, and lastly, it has the ability to
perform antigenic switching, where it alters its surface proteins
in order to avoid the host’s immune response. Infections with
P. falciparum can quickly lead to multiorgan failure and death
(McAdam and Sharpe, 2010).
Worldwide, over 200 million people were infected in 2010
and over 650 000 of those cases were fatal. There are approx-
imately 99 endemic areas for malaria around the world,
including areas in South America, Asia, and sub-Saharan Africa
among others. Efforts to develop a vaccine or adequate
mosquito control have been unsuccessful (Centers for Disease
Control and Prevention, 2012).
In the United States, transfusion-transmitted malaria is due
to immigrants or people who have traveled to endemic areas
and become infected. Prevention is through donor screening
and deferrals as no screening test is available. The deferral
periods vary depending on the extent of stay or if the person
was infected (Spencer et al., 2009). If infected, as of 2012, the
Transfusion-Related Adverse Events 7
FDA recommends an indefinite deferral until treatment is
complete and reviewed by the medical director of the collection
facility (Food and Drug Administration, 2012b). The risk of
transfusion transmission is 1:4 million (Petrides, 2007; Seed
et al., 2005).
Creutzfeldt–Jakob Disease
Creutzfeldt–Jakob disease (CJD) is a prion disease that has
been recognized over the past 30 years. A prion is a unique
infectious agent that is composed of a misfolded protein. Once
introduced into an organism, the misfolded protein serves as
a template to cause misfolding of normal proteins in the
organism leading to the deposition of pathologic plaques in
the brain. There are four classifications of the disease including
sporadic, familial, transmitted, and variant (vCJD) (Sikorska
et al., 2012).
In 1996, vCJD was identified in humans due to the
ingestion of infected meat products. This was nearly 10 years
after bovine spongiform encephalopathy was first described
in cows. In contrast to classical CJD, vCJD affects much
younger patients yet leads to a similarly devastating and fatal
neurologic disease within 3 years of diagnosis (Shaz, 2009).
There have been four documented transfusion-associated
transmissions in the United Kingdom. Currently, there is no
screening test for the organism and no effective treatment
(Galel, 2011).
vCJD is prevented by donor screening and indefinite
deferral of at risk persons as no laboratory test or other meth-
odology is approved. In Europe, a filter is in development to
remove the protein.
Future Direction and Developing Technologies
For TTDs
Though the safety of the blood supply is the highest it has ever
been, emergence of a new infectious agent could present
a danger to the blood supply. Potential improved safety is
through pathogen reduction technology and blood produced
in an in vitro culture system in a laboratory (Giarratana et al.,
2011).
See also: Blood Products; Chagas; Hepatitis B and C; HIV/AIDs;
HTLV; Malaria; Syphilis; Transfusion Medicine-Donor
Eligibility, Testing and Collection.
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Further Reading
Dienstag, J.L., 2010. Chronic viral hepatitis. In: Mandell, J.E., et al. (Eds.), Mandell,
Douglas, and Bennett’s Principles and Practice of Infectious Diseases, seventh ed.
Churchill Livingstone Elsevier, Philadelphia, PA.
Hillyer, C.D., Shaz, B.H., Zimring, J.C., Abshire, T.C., 2009. Transfusion Medicine and
Hemostasis: Clinical and Laboratory Aspects. Elsevier, London.
Kumar, K., Abbas, A., DeLancey, A., Malone, E. (Eds.), 2010. Robbins and Cotran
Pathologic Basis of Disease, eighth ed. Saunders, Philadelphia.
Roback, J.D., Grossman, B.J., Harris, T., Hillyer, C.D. (Eds.), 2011. AABB Technical
Manual, seventeenth ed. AABB Press, Bethesda, MD.
Shaz, B.H., Hillyer, C.D., 2009. Transfusion-associated graft-versus-host disease. In:
Murphy, M., Pamphilon, D. (Eds.), Practical Transfusion Medicine, third ed.
Blackwell Synergy, Oxford.
Stramer, S.L., 2007. Current risks of transfusion-transmitted agents – a review. Arch.
Pathol. Lab. Med. 131, 702–707.
Vamvakas, E.C., Blajchman, M.A., April 2010. Blood still kills: six strategies to further
reduce allogeneic blood transfusion-related mortality. Transfus. Med. Rev. 24 (2),
77–124.
Relevant Websites
http://www.aabb.org/resources/bct/pages/bloodfaq.aspx.
http://www.cdc.gov/bloodsafety/bbp/diseases_organisms.html.
http://www.redcrossblood.org/learn-about-blood.