1 s2.0 S0268960X01901511 Main

Non-infectious transfusion reactions
Non-infectious
complications of
transfusion therapy
P. L. Perrotta,1 E. L. Snyder 2
1
State University of New York @ Stony Brook, USA
Yale University, USA
Abstract Blood transfusion is considered safe when the

infused blood is tested using state of the art viral assays
developed over the past several decades. Only rarely are
known viruses like HIV and hepatitis C transmitted by
transfusion when blood donors are screened using these
sensitive laboratory tests. However, there are a variety of
transfusion risks which still remain that cannot be entirely
eliminated, many of which are non-infectious in nature.
Predominantly immune-mediated complications include the
rapid intravascular or slow extravascular destruction
(hemolysis) of transfused red cells or extravascular removal of
platelets by pre-formed antibodies carried by the transfusion
recipient.Alternatively, red cells can be damaged when exposed
to excessive heat or incompatible intravenous fluids before or
during the transfusion. Common complications of blood
transfusion that at least partly involve the immune system
include febrile non-hemolytic and allergic reactions.While
these are usually not life-threatening, they can hamper efforts
to transfuse a patient. Other complications include circulatory
overload, hypothermia and metabolic disturbances. Profound
hypotensive episodes have been described in patients on
angiotensin-converting enzyme (ACE) inhibitors who receive
platelet transfusions through bedside leukoreduction filters.
These curious reactions appear to involve dysmetabolism of
the vasoactive substance bradykinin. Products contaminated by
bacteria during blood collection and transfused can cause lifethreatening septic reactions.A long-term complication of blood
transfusion therapy unique to chronically transfused patients is
iron overload. Less common but serious reactions more
specific to blood transfusion include transfusion-associated
graft-versus-host disease and transfusion-associated acute lung
injury. Many of these complications of transfusion therapy can
be prevented by adhering to well-established practice
guidelines. In addition, individuals who administer blood
transfusions should recognize these complications in order to
be able to quickly provide appropriate treatment. 2001
Harcourt Publishers Ltd
INTRODUCTION
odern blood banking procedures have dramatically
reduced the risks of transfusion therapy. For example, screening of donated blood using sensitive
assays has substantially decreased the risk of viral transmission by blood transfusion.1 The most important of these
include tests for human immunodeficiency virus (HIV),
hepatitis C virus (HCV) and hepatitis B virus (HBV).

Nucleotide testing for HIV and HCV, implemented in most
developed countries, has reduced the residual risk of transfusionacquired HIV and HCV to approximately one per
500,000 to 750,000 blood exposures.2 However, other infectious agents not typically screened for including bacteria and
parasites can be transferred more frequently by blood transfusion. Bacterial transmission may be more common than is
recognized, and is a particular problem in platelets, which
are stored at room temperature. Parasites that can be transmitted by blood transfusion include Plasmodium sp, Babesia,
and Ehrlichia.3 Importantly, it should be noted that blood is
not screened for these pathogens.
As the incidence of transfusion-transmitted viral disease
approaches low levels that are difficult to estimate, noninfectious complications of transfusion therapy become relatively more important (Table 1). Immunologic complications,
which include immune hemolytic reactions caused by ABO
incompatible transfusions, still occur despite the development of well-planned transfusion protocols.4
Alloimmunization to antigens carried by red cells,
platelets and plasma proteins can cause accelerated cell
destruction and other untoward effects. More recently, there
is increasing interest in the immunomodulatory effects of
blood transfusion.5 The most controversial of the immunologic issues include possible associations between blood
transfusion and either occurrence or recurrence of cancer
and post-operative infection. For the purposes of this review,
we will assume the transfused red cells are ABO compatible.
Thus, we will not discuss acute intravascular hemolytic reactions and the reader is referred to other reviews.6
DELAYED EXTRAVASCULAR HEMOLYSIS
Delayed hemolytic transfusion reactions (DHTR) are reasonably common and should be suspected in patients who
experience an unexplained post-transfusion drop in hematocrit.7 The frequency of DHTR was originally estimated at
around one per 4000 transfusions.8 However, their incidence
may be increasing as more sensitive methods of antibody
detection are developed.9 DHTR typically occur in a patient
with a negative antibody screen on pre-transfusion testing,
but who then develops a red cell antibody associated with
accelerated destruction of transfused red cells.There is usually a delay of 3 days to 2 weeks between transfusion and
onset of extravascular hemolysis. Additional evidence of a
DHTR includes an unconjugated hyperbilirubinemia, appearance of a newly positive direct antiglobulin test (DAT), and
commonly, a falling haptoglobin. The DAT may reveal IgG
and/or complement coating red cells.10 In most cases, red cell
destruction is caused by an antibody that is initially present in
a titer below the limits of detection on routine screening.The
antibody then rapidly forms on secondary exposure to the
offending antigen.Rarely,DHTR are caused by primary allosensitization in which a patient synthesizes a new antibody
while the sensitizing red cells are still circulating.11 The antibodies typically fix complement only to C3; thus, terminal
complement pathway components are not generated and
hemolysis is extravascular as opposed to intravascular. This
contrasts with acute hemolytic reactions caused by ABO
2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 6983
doi: 10.1054/blre.2001.0151, available online at http://www.idealibrary.com on
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Table 1 Non-infectious complications of transfusion therapy
Acute immune hemolytic reactions
Delayed extravascular hemolysis
Febrile non-hemolytic reactions
Allergic reactions (urticarial, anaphylactic)
Non-immune red cell hemolysis
Post-transfusion purpura
Circulatory overload
Iron overload
incompatible transfusions in which complement fixation

results in formation of the C5b-9 membrane attack complex.
Accordingly, only rarely do delayed reactions cause intravascular hemolysis with associated hemoglobinemia and hemoglobinuria. Cytokines, which play a central role in the
pathophysiology of ABO incompatible reactions, may also
contribute to DHTR.12 This is particularly true in more severe
delayed reactions in which elevations of inflammatory mediators like tumor necrosis factor, IL-6, and IL-8 have been
described.13
Antibodies most commonly implicated in DHTR include
those directed against Kidd (Jk), Rh (E, C, c), Kell (K), and
Duffy (Fy) blood group antigens (Table 2).Anti-Jka, in particular, is often implicated in these reactions.14 Certain antibodies, such as those with Kidd and Duffy specificity, are more
frequently identified in delayed hemolytic reactions in which
the transfused cells are clearly removed.15 Delayed serologic
transfusion reactions are defined as the presence of a new
red cell antibody in a patient, without evidence of red cell
removal.16 Patients with DHTR who require further transfusions should receive red cells that do not carry the associated antigen, so-called antigen negative units. Patients
previously sensitized to red cell antigens must be clearly
identified in blood bank information systems to avoid subsequent reactions caused by an anamnestic response to further
exposures. In addition, most blood bank standards demand
that pre-transfusion testing of recently transfused or pregnant patients be performed on samples obtained within 3
days of a transfusion. This requirement is based on the frequent observation that these patients develop clinically significant red cell antibodies associated with immediate and
delayed hemolysis.17 DHTR are particularly prevalent in
patients with diseases that require frequent red cell transfusion.18 Patients with sickle cell disease (SCD) are at a high risk
of DHTR because of differences in red cell antigen frequency
Table 2 Antibodies commonly implicated in delayed

hemolytic reactions
70
Blood group system
Specific antibody
Kidd (Jk)
Rh
Kell
Duffy (Fy)
Glycophorin
Jka > Jkb

E>C>c
K
Fya
S>s
Blood Reviews (2001) 15, 6983
2001 Harcourt Publishers Ltd
Metabolic disturbances
Air embolism
Hypothermia
Hypotensive reactions and ACE inhibitors
Red-eye syndrome
Transfusion-associated sepsis
Transfusion-associated graft-versus-host disease
Transfusion-associated acute lung injury
between the donor population and the recipients. For example, black SCD patients are often Fya and Fyb negative. This
phenotype is uncommon in white blood donors.Thus, black
patients are very likely to be exposed to Fy positive blood,
and thus, may develop anti-Fy antibodies.There are also significant differences in the Rh system between black and
white individuals. Many centers attempt to avoid these problems by providing antigen matched red cells when possible.
For example, the recipients red cells are typed for Rh and
Kell antigens, after which they receive units that do not carry
antigens that they do not possess. Finally, hemolytic transfusion reactions (HTR) can be particularly dangerous in
patients with sickle cell disease the sickle cell HTR syndrome.19 These may exhibit the typical manifestations of an
acute or delayed hemolytic transfusion reaction. In addition,
patients will have symptoms suggestive of a sickle cell crisis,
marked reticulocytopenia, and may develop a more severe
anemia following transfusion than was previously present.
However, serologic evaluation may not reveal a new red cell
antibody or a newly positive DAT.20 Serologic studies are
often complicated by the presence of other red cell antibodies that were evident before the transfusion. These patients
may be very difficult to transfuse.
FEBRILE NON-HEMOLYTIC TRANSFUSION REACTIONS

Febrile non-hemolytic transfusion reactions (FNHTR) are
most commonly encountered during transfusions of red
cells, platelets, or plasma. They typically occur during the
transfusion, but may present minutes or several hours after
the transfusion is completed. The frequency of febrile reactions is higher following transfusion of platelets (4% to
30%)21 than of red cells (0.5%). Most FNHTRs are self-limited
and not life-threatening. The most common signs include
fever (> 1C elevation) and shaking chills, and these may be
accompanied by nausea, vomiting, dyspnea, and hypotension. Oxygen saturation may decrease during rigors, but
should return to baseline as the reaction resolves.The severity of symptoms can be related to number of leukocytes in
the product and/or the rate of transfusion. Pre-medicating
transfusion recipients with an antipyretic like acetaminophen [Paracetamol] may help to minimize FNHTR.
Antihistamines are not useful in preventing or treating
FNHTR and are not indicated unless there is a clear allergic
component. Corticosteroids may also minimize FNHTRs, but
these should be administered several hours before transfusion to be maximally effective. Severe rigors can be promptly

resolved with intravenous meperidine [Pethidine].22
Intravenous corticosteroids can be considered, but these
will not produce as rapid relief as meperidine. If symptoms
are especially severe or do not resolve within 46 h,
other causes of the fever should be considered, including
transfusion-related sepsis.The transfusion should be stopped
when a FNHTR develops and should not be restarted
using the causative donation/component.This is because the
most common sign of an acute hemolytic reaction is also
fever.
FNHTR are likely related to interactions between a recipients cytotoxic antibodies and HLA and/or leukocyte specific
antigens on donor white blood cells. Formation of leukocyte
antigen-antibody complexes results in complement binding
and release of endogenous pyrogens like TNF-, IL-1, and IL6. Direct activity of various biological response modifiers
including cytokines also appear to play a role in these reactions.23 For instance, FNHTR are seen in patients who have
not been previously transfused or pregnant.24 The higher
incidence of febrile reactions with platelet transfusion may
be related to the duration of storage. When platelets are
prepared by the buffy coat method, there is a progressive
increase in the relative risk of developing predominantly
febrile reactions as platelets are stored for their 5 day
shelf-life.25 During platelet storage, there is continued elaboration of biologically active cytokines by residual white cells.
Reaction rates are as much as double in 3 to 5 day-old
platelets as compared to 1 or 2 day-old products.26 This finding is attributed to reactive substances contained in
the plasma portion of platelet concentrates. In particular,
a strong positive correlation between supernatant IL-1
and IL-6 levels and the frequency of febrile reactions has
been observed. Similar associations between the duration
of storage of non-filtered pooled platelet concentrates
and febrile reactions has been described by other
groups.27
Patients with recurrent febrile reactions to platelet or red
cell transfusions should receive leukoreduced (LR) products
and pre-transfusion antipyretics. In countries which do not
routinely leukocyte deplete all blood components, plasma is
not filtered for white cell reduction, although significant
numbers of white cells can be found in freshly frozen
plasma.28 Third generation leukoreduction filters eliminate
99.9% of the white cells found in a unit of blood. In addition
to reducing the incidence of FNHTR, LR can also decrease
transmission of cytomegalovirus29 and alloimmunization to
HLA antigens.30 Pre-storage leukoreduction of red cells can
further reduce the likelihood of FNHTR as compared to bedside filtration.31 LR decreases the incidence and severity of
FNHTR at least partly by minimizing production of cytokines
by residual leukocytes during storage. In particular, IL-8 levels
of platelets prepared by the platelet-rich plasma method and
leukoreduced shortly after collection are significantly lower
than in non-LR PCs stored for 5 days.32 Prestorage leukoreduction of platelet concentrates, as compared to platelets
leukoreduced at the bedside, does not appear to further
reduce the incidence of FTRs.33 Interestingly, both febrile
nonhemolytic and allergic reactions can follow autologous
blood transfusions.34
ALLERGIC REACTIONS, URTICARIAL AND

ANAPHYLACTIC
Mild allergic reactions, triggered by exposure to soluble substances in donor plasma, are common following plasma,
platelet, and red cell transfusions. Typical cutaneous hypersensitivity reactions present as pruritis and/or urticaria in
the absence of fever. Allergic reactions are classically IgE
mediated and symptoms are attributed to histamine release.
Symptoms and signs include pruritis, erythema, papular
rashes, and weals. Distinguishing allergic and febrile transfusion reactions can be difficult when urticarial symptoms are
accompanied by low-grade fever. Treatment of mild allergic
reactions consists of temporarily interrupting the transfusion
and administering 2550 mg diphenhydramine or other antihistamines. In mild allergic reactions not associated with
fever or vasomotor instability, the transfusion can be continued if the symptoms promptly resolve. If symptoms recur
after the transfusion is restarted, a new unit should be
obtained. Pre-medicating patients with an antihistamine
before blood transfusion may help to minimize milder allergic reactions. It is difficult to predict which patients are a risk
for allergic reactions, but in general, the allergic predisposition of the recipient and/or donor may be important.35
However, screening blood donors for a history of atopy does
not seem warranted.36 Allergic reactions could also occur on
exposure to drugs that a blood donor is taking prior to the
donation.37
Fortunately, severe anaphylactic reactions following
blood transfusion are rare. Anaphylaxis is a severe, systemic
reaction caused by the release of histamine and other biologic mediators. The most serious symptoms include laryngeal edema, lower-airway obstruction, and hypotension.
Reactions are IgE-mediated responses to plasma proteins.
Severe reactions can occur in susceptible individuals on
exposure to latex found in blood containers. Latex is not
found within the plastic bag itself, however, there may be
small amounts of latex in side arms, ports, or caps attached to
the blood container.The supplier of the plastic container in
question should know if latex was used in the manufacturing
process. As in other allergic responses, symptoms are not
dose-related and severe manifestations can occur following
small exposures. Treatment of anaphylaxis includes prompt
administration of epinephrine as epinephrine reverses the
actions of histamine within minutes.Vasopressors and airway
support may be required. An H1-receptor antagonist and
intravenous steroids can be given to reduce the risk of protracted anaphylaxis. Washed red cells in which the residual
donor plasma has been removed and replaced by saline may
benefit patients with repeated or severe allergic reactions.
Plasma can be removed from platelet concentrates to minimize allergic reactions, but these procedures usually cause
the loss of significant numbers of platelets.38 Red cells leukoreduced by filtration do not prevent allergic reactions
because they do not remove the offending soluble stimuli.
The duration of platelet storage, which is related to febrile
non-hemolytic reactions, is not related to increased allergic
reactions.27 Individuals with congenital IgA deficiency may
develop class-specific antibodies to IgA. Upon exposure to
IgA found in blood products,immediate generalized reactions
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can occur. IgA-deficient patients who have had a severe anaphylactic reaction should receive blood components that
lack IgA. These must be obtained from larger blood centers
that maintain a supply of products collected from IgA-deficient donors. If large volumes of red cells are required, they
should be thoroughly washed to remove as much residual
plasma as possible.39 Finally, allergic-type reactions can
develop in individuals who are exposed to ethylene oxide
gas. Ethylene oxide is used to sterilize plastic equipment in
dialysis and apheresis instruments. Rare individuals have
developed IgE antibodies directed against ethylene oxide
and, subsequently, acute hypersensitivity reactions during
hemodialysis or platelet collection by apheresis.40
NON-IMMUNE RED CELL HEMOLYSIS
Red cell hemolysis occurs through a variety of mechanisms,
many of which do not require activation of the immune system (Table 3). Most of these involve the physical and/or
chemical destruction of red cells. Many medications and
intravenous fluids lyse red cells through an osmotic effect
that allows entry of water into cells. Hypotonic fluids such as
5% dextrose in water will cause gross hemolysis on exposure
to red cells.41 Since no hemolysis occurs when red cells are
mixed with normal saline, this is the only fluid that can be
used in intravenous administration tubing during transfusion. Intravenous medications should never be added to a
unit of red cells. Life-threatening hemolysis may occur if
patients are accidentally given large infusions of water by
rapid intravenous injection. Red blood cell damage also may
result from either overheating or freezing blood.Thus, blood
should be warmed only using devices that are specifically
designed for this purpose. Placing red cells in hot water
baths or common microwave ovens is unacceptable and can
produce significant hemolysis.42 Red cells are irreversibly
damaged when warmed above 50C. Accordingly, blood
warmers do not heat blood above 42C when functioning
properly. During refrigerated storage there is lysis of a small
fraction of red cells. However, significant hemolysis occurs if
blood is inadvertently stored frozen without a cryopreserving agent such as glycerol.
Mechanical hemolysis can occur as red cells traverse pumps
used in cardiac bypass surgery and when red cells are forced
through a small-gauge needle or other narrow orifice using a
pressure cuff.43 Factors that influence hemolysis include lumen
diameter, pressure and velocity of the infused blood, shape of
the needle tip, and age of the red cell unit.44 Thus, red cell damage is minimized by using larger diameter needles and slower
infusion rates.45 Significant reactions from mechanical hemolysis are uncommon but must be distinguished from immune or
Table 3 Causes of non-immune red cell hemolysis
Over warming of red cell unit
Infusing larger volumes of older stored red cell units
Adding incompatible intravenous fluids or drugs to red cells
Improper freezing and thawing units of red cells
Mechanical disruption of red cells by extracorporeal instruments
Bacterial contamination of red cells
Pre-existing red cell membrane or enzyme defect in the donor
72
intravascular hemolysis which has more life-threatening

implications. Staff must be trained in the proper use of
equipment (pumps, catheters) used to transfuse blood. Of
practical concern, blood forced through commonly used
leukocyte reduction filters can produce significant hemolysis.46 While bacterial contamination of red cells is reportedly
quite common (on the order of 1 in 2000 units collected),
the incidence of septic reactions to red cells is rare (estimated 1 in 500,000 red cell transfusions).47 Red cell units
that are contaminated by certain bacteria may appear grossly
hemolyzed. Transfusing such units may cause hemoglobinuria, but these effects are often overshadowed by the fever,
hypotension, and pain produced by endotoxins generated by
gram-negative bacteria (see Transfusion associated sepsis).
Uncommonly, a blood donor may have an intrinsic red cell
defect like glucose-6-phosphatase dehydrogenase (G6PD)
deficiency that predisposes the cells to hemolysis. Blood
donors are not routinely screened for these conditions.
Patients transfused with G6PD-deficient red cells may
develop a mild transient hemolysis with an unconjugated
hyperbilirubinemia and increased lactate dehydrogenase.
The degree of hemolysis can be exacerbated if a recipient is
concurrently receiving medications like primaquine or nitrofurantoin.48
Patients who receive hemolyzed blood may or may not
develop the classic signs and symptoms of an immune
hemolytic reaction.The degree of hemolysis encountered in
stored red cells is usually not harmful to the recipient as free
hemoglobin in small quantities is rapidly removed from
plasma through mechanisms involving binding with haptoglobin and oxidation to methemoglobin. Frozen stored red
cells contain glycerol to prevent hemolysis during the freezing process. Following thawing, however, these units will
contain some free hemoglobin and more importantly, glycerol. Glycerol content is decreased by washing the red cells
and resuspending the cells in isotonic saline.49 If red cells are
not adequately deglycerolized, they may lyse on contact with
plasma as water enters cells faster than glycerol can diffuse
out of the cell. Transfusing large amounts of hemolyzed
blood, however, can cause hypotension, shock, and renal dysfunction. Laboratory evidence of non-immune hemolysis
includes hemoglobinuria and plasma-free hemoglobin.
Assuming that the pre-transfusion direct antiglobulin test
(DAT, direct Coombs) was negative, the DAT should be negative as immunoglobulins are not coating red cells.The DAT is
usually reactive following an immune-mediated hemolytic
reaction in which recipient red cell antibodies bind to
incompatible transfused donor red cells. Depending on the
degree of hemolysis and the etiology of the hemolysis, treatment would include measures taken following an acute
intravascular hemolytic reaction caused by an ABO incompatible blood transfusion.Vital signs should be closely monitored. Cardiac and airway support are provided, and urine
output is maintained with a saline diuresis with or without a
loop diuretic. Dialysis should be considered in patients with
renal failure. Biological response modifiers including proinflammatory cytokines (IL-1, TNF-), chemokines (IL-8) and
complement fragments (C3a, C5a) play a role in the pathophysiology of immune hemolytic reactions.50 However, their
role in non-immune mediated hemolysis has not been

extensively studied. Most importantly, non-immune red cell
hemolysis can be prevented by adhering to proper procedures
for collecting, processing, storing, and infusing blood products.
obviate prophylactic transfusion before antigen negative

units can be obtained.71
CIRCULATORY OVERLOAD
POST-TRANSFUSION PURPURA
Post-transfusion purpura (PTP) is a rare complication of
blood transfusion that results in profound thrombocytopenia.51 It is characterized by acute thrombocytopenia (platelet
count < 10,000/l; 10 109/l) occurring 510 days following
red cell transfusion.52,53 PTP is often not immediately recognized because of the interval between the transfusion and
the onset of thrombocytopenia. PTP is considered an
immune thrombocytopenia in which anti-platelet antibodies,
most often with specificity to HPA-la (PLAI), are identified in
the recipient.54 Antibodies directed against other broad
platelet antigens like GPIIb/IIIa are also observed,55 as are
multiple antibody specificities.56 Most patients are women
who have been sensitized to platelets through pregnancies
as described in one of the larger series of cases.57
Sensitization can also occur in men, presumably through previous blood exposure.58,59 The specificity of the platelet antibodies can be determined by platelet-ELISA and monoclonal
antibody-specific immobilization of platelet antigen assay.60
The extent of reactivity may decrease as the platelet count
recovers, however, it is not usually practical or necessary to
follow antibody titers.
Treatment with high-dose intravenous immunoglobulin
(IVIG) is the most common therapy and can increase platelet
counts to > 100,000 l in 45 days as described in observational studies.61,62 As in other diseases in which IVIG is used,
mechanisms of action are believed to involve Fc receptor
blockade and/or non-specific binding of immunoglobulin to
platelet surfaces.63 The beneficial effects of IVIG in antibodymediated autoimmune disease have been attributed to the
ability of exogenous IgG to accelerate the rate of IgG catabolism.64 Plasma exchange, often used to treat diseases thought
to be mediated by pathogenic autoantibodies or immune
complexes, was used to treat PTP before IVIG was found efficacious.65 The role of steroids in treating PTP is unclear,
although patients who develop PTP are often on chemotherapy which may include corticosteroids. Splenectomy has
been performed in very few patients who do not respond to
the primary treatments.66 The disease is usually self-limited
and the prognosis of patients with PTP is good; platelet
counts usually recover within 21 days. Patients are at risk for
significant, e.g. intracranial bleeding, when platelet counts
are extremely low, thus treatment should be considered.67
Platelet transfusions may be given, often before the diagnosis
of PTP is established. Transfused platelets typically survive
poorly, even if they do not carry the implicated antigen. IVIG
therapy may also help the survival of transfused platelets
during the period of severe thrombocytopenia.68,69
Interestingly, recurrence after later red cell transfusions is
uncommon. Transfusion with washed red cells and/or cells
from antigen (HPA-1a) donors has been advocated,70 although
the clear value of these practices is unclear.The HPA-1a antigen is carried by over 95% of blood donors and thus, there are
only small reserves of antigen negative components. In fact,
platelet counts may recover with IVIG therapy to levels that
During acute hemorrhage, it is difficult to overload the circulatory system of patients with normal cardiac function. First,
the amount of blood lost in severe trauma is often underestimated as intravascular volume is maintained by intravenous
fluids and blood products. Second, temporary increases in
blood volume which may cause small increases in venous
pressure are well-tolerated by most patients. Major physiologic responses to anemia include increases in cardiac output and increases in 2,3-DPG content of red cells.The latter
shifts the oxygen dissociation curve to the right which facilitates the release of oxygen to surrounding tissues. In chronically anemic patients who have increased their cardiac
output, there is a risk that attempts to raise the arterial oxygen content by transfusion will overload the circulatory system. This is particularly true in patients with compromised
cardiac status who may not be able to tolerate increased
intravascular volume. Therefore, the risks and benefits of
blood transfusion therapy must be examined before any
transfusion. Most physicians no longer use transfusion triggers to determine when a patient should be transfused and
in general, patients are now transfused at lower hematocrits.
The risk/benefit ratio is less clear in patients with significant
cardiac disease, e.g. post-infarction and congestive heart failure, and the decision to transfuse is more complex. Recent
concerns have been expressed about the risks of under
transfusing patients with coronary disease.72 Specifically,
there is evidence that the hematocrit of patients with cardiac
disease should be maintained close to 30%.
Once cardiac output cannot be maintained, circulatory
overload can result in pulmonary edema. Symptoms of circulatory overload include chest tightness and cough and worsening dyspnea as pulmonary edema progresses. Volume
overload often occurs during or after infusions of both
plasma and red cells.Whole blood, rarely used today, carried
a higher risk of volume overload because of the increased
amount of plasma. By removing most of the plasma from collected blood, the same oxygen carrying capacity is maintained in a smaller total volume. Each unit of red cells
measures between 300 and 350 mL and contains red cells,
some residual plasma, and the anticoagulant/preservative
solution. The volume of each unit of plasma is typically
between 180 and 300 mL. Plasma is often used to emergently
reverse the effects of coumarins (e.g. Warfarin) before vitamin K has an effect. In the event of Coumarin overdose, large
volumes of plasma may be infused to correct the prothrombin time. Circulatory overload is much less of a problem in
factor VIII or factor IX replacement therapy as highly purified and concentrated products are used instead of large volumes of fresh frozen plasma or cryoprecipitate.An additional
benefit of factor concentrates and recombinant products are
decreased risks of transfusion-transmitted viral infections.
The use of plasma in thrombotic thrombocytopenic purpura
should not result in volume overload because plasma
exchange using apheresis instruments is largely isovolaemic.
Patients at risk for circulatory overload may benefit from
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slower rates of transfusion, and may require additional diuresis to minimize excess fluid. The rate of transfusion can be
lowered so that a single red cell unit is transfused over 4 h,
which is the maximum time allowed to infuse a unit. Only
rarely does it seem necessary to infuse volumes smaller than
a single red cell unit (volume 300350 mL) to normally-sized
adult patients. However, clinicians occasionally request that
red cells units be split so that only one-half unit is infused
over 34 h. Diuretics should be considered in patients with
any degree of cardiac or renal failure. Furosemide, or other
diuretics, should never be added directly to red cells or
infused through the same line as the blood product to avoid
hemolysis. Invasive cardiac monitoring, including measurements of central venous pressure, cardiac filling pressures,
and pulmonary vessel pressures, can help to identify impending circulatory overload. In addition to patients with
impaired cardiac function, patients with neurologic conditions associated with autonomic dysfunction may have difficulty regulating their blood pressure during blood
transfusion and plasmapheresis, as can other individuals with
impaired renal function.73
IRON OVERLOAD IN CHRONICALLY TRANSFUSED
PATIENTS
Patients who receive numerous red cell transfusions may
develop iron overload. Each unit of red cells contributes 250
mg iron, whereas daily iron excretion is only about 1 mg in
the absence of bleeding. Excess iron in patients who receive
few red cell transfusion is typically harmless. However, transferrin may become saturated after only 1015 units of
blood,74 after which iron may be deposited in tissue
parenchyma.75 It is the non-transferrin-bound iron that
appears in the serum of individuals with iron overload that
has been implicated in the biologic damage associated with
iron overload.76 Favored sites of iron deposition include the
liver, pancreas and heart. Hepatic iron overload may initially
cause histologic evidence of injury like fibrosis, which may
then progress to overt cirrhosis.77 Cardiac toxicity may cause
a cardiomyopathy and arrhythmias. However, signs of clinical
toxicity are typically not apparent until total body iron
reaches 4001000 mg/kg body weight. Other suggested
detrimental effects of iron overload include accelerated
development of diabetic nephropathy78 and increased susceptibility to infectious disease79 in transfusion-dependent
beta thalassemia. Iron overload is most commonly seen in
conditions that require frequent intermittent red cell transfusion like the thalassemias, hemoglobinopathies, and aplastic
anemias. Periodic blood transfusion, in particular, is being
used more frequently to prevent and treat major complications of sickle cell disease like cerebrovascular accidents.
Long-term transfusion effectively reduces hemoglobin S levels and can prevent recurrent stroke, however, it eventually
will result in iron overload.
Iron-chelating therapy should be considered in these and
other chronically transfused patients to minimize the potential
long-term effects of iron overload. Subcutaneous deferoxamine injections80 can limit, or in some cases reverse, cardiac and
hepatic injury in patients with thalassemia.81,82 This treatment
is most effective when started early. Newer orally active iron
74
chelators like deferiprone have been shown to maintain

lower serum ferritin levels in patients with transfusiondependent iron overload.83,84 Other alternatives to periodic
blood transfusion like hydroxyurea may reduce the incidence of iron overload in sickle cell disease by reducing
transfusion needs.85 Iron overload can also present problems
for chronically transfused oncology patients who are surviving longer with newer therapies.86 Massively transfused
patients with hemorrhagic blood loss are at a much lower
risk for iron overload because transfused iron is balanced
with iron lost by bleeding. Periodic erythrocytapheresis in
which the patients red cells are efficiently exchanged with
normal donor blood has been examined as an adjunct or
alternative to regular chelation therapy.87 Although erythrocytapheresis can reduce total iron burden, the safety and efficacy of this treatment as compared to standard chelation
therapy is unclear.88 In some cases, measurements of iron
stores like ferritin may not accurately predict end-organ damage.77 Liver biopsy with quantitative iron determination and
histochemistry remain the reference methods for assessing
iron overload. In general, liver iron contents over 15 mg/g
dry weight are associated with a high risk of cardiac disease.
Non-invasive measurements of body iron status like MRI
have been used to accurately quantify liver hemosiderosis in
multiply transfused thalassemic patients.89 However, MR
imaging is extremely sensitive, and iron deposition can be
seen in the hearts and livers of transfused patients before
there is clear evidence of organ dysfunction.90
METABOLIC DISTURBANCES
Electrolyte imbalances may develop in massively transfused
patients. Modern fluid replacement strategies and electrolyte
monitoring have minimized this complication in the majority
of adult patients. In fact, post-transfusion acidosis and hyperkalemia may be more likely related to inadequate resuscitation from shock than to blood administration. However,
potentially dangerous metabolic changes can occur in small
children and neonates. Electrolyte disturbances that are most
commonly cited include elevated potassium or ammonia levels and acidosis (Table 4). Many metabolic problems related
to red cell transfusion are attributed to changes that occur
during red cell storage. These changes include increases in
plasma potassium and hemoglobin related to red cell lysis
that progress during refrigerated storage. Specific changes in
red cells termed the storage lesion include decreasing
intracellular adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG), pH and potassium. Preservative solutions
Table 4 Changes in red cells and supernatant plasma with

storage
Red cells
Supernatant
Decreasing ATP
Decreasing 2,3-DPG
Increasing hemolysis
Increasing lactate
Increasing ammonia
Increasing potassium
Decreasing pH
Decreasing sodium
Decreasing glucose

are designed to maintain red cells by sustaining ATP and as
used today allow red cell storage for up to 42 days.Adenine is
used to increase ATP and dextrose is provided as a cell nutrient. Hyperkalemia can occur during massive blood transfusion.The risk may be higher in infants, and markedly elevated
potassium levels have been described in infants who receive
large volumes of irradiated blood.91 Detrimental effects of
red cell storage increase over time. However, red cell survival
is considered acceptable, even after the longer storage times.
The majority of liquid red cells collected are utilized long
before their outdate because of the often tenuous blood supply. Some additive/preservative solutions contain higher levels of glucose and contain mannitol as a stabilizing agents.
The concerns over the use of these solutions (Adsol,AS-1 red
cells), especially in children, may not be warranted.
Specifically, a hemorrhagic shock animal model could not
demonstrate hyperglycemia or inappropriate osmotic diuresis using such solutions.92
Citrate toxicity and hypocalcemia

Transfusing large volumes of citrated blood components can
transiently decrease levels of ionized calcium. The most
important effects of hypocalcaemia are on the cardiovascular
system and concerns have been expressed over the potential
negative effects of citrate anticoagulants on cardiac contractility.93 An animal model of massive transfusion has suggested
that transfusing citrated whole blood may alter calcium concentrations, and these changes may adversely affect myocardial function.94 However, the risk of clinically significant
hypocalcaemia in adults who receive large volumes of blood
appears very small. Normothermic adults normally can tolerate the infusion of one unit of red cells every 5 min without
requiring supplemental calcium. In most cases, intravenous
calcium infusions should not be given to overcome infusionrelated citrate effects, and in fact these infusions can be dangerous.95 Thus, it is generally considered unnecessary to
administer exogenous calcium during massive transfusion,
with the possible exception of exchange transfusions of children.96 Even in the latter setting, symptoms and signs of
hypocalcaemia cannot be identified despite low serum
Ca2+.97 Calcium levels promptly return to normal levels the
day after the red cell exchange.
Citrate is metabolized by the liver and most recipients
with normal hepatic function tolerate large amounts of citrated blood. However, patients with end-stage liver disease
are more prone to citrate toxicity which may be related to
transient hemodynamic depression.98 This is particularly true
during liver transplants, especially during the anhepatic
phase of the procedure.99 Blood anticoagulated with citrate
cannot be transfused through administration sets that contain Ringer-lactate solution. Ringer-lactate contains calcium
which can overcome the effects of citrate, leading to potentially dangerous clot formation.100 Ionized magnesium
(Mg2+), like Ca2+, is chelated by citrate. Mg2+ has been associated with cardiovascular dysfunction, however, the clinical
significance of decreases in Mg2+ in massive transfusion situations is unclear.101 Symptomatic hypocalcemia caused by citrate is more commonly encountered during apheresis. This
includes plateletpheresis of volunteer donors and therapeutic
plasma exchange. Methods have been devised to minimize

uncomfortable and potentially dangerous citrate reactions in
platelet donors without forming platelet clumps in the collected product.102 Measuring Ca2+ during apheresis procedures provides no information because there is a poor
correlation between this measurement and symptomatology.103 Higher amounts of citrate are used during the collection of peripheral blood progenitor cells by apheresis to
prevent clotting of the stem cells in suspending plasma.
Thus, these patients are more prone to citrate toxicity and
may require supplemental calcium during the procedure.104
Obviously, intravenous calcium gluconate must be provided
through a separate catheter to avoid clotting of returned
blood.
AIR EMBOLISM
Iatrogenic air embolism (AE) occurring during blood transfusion is much less of a threat since glass bottles were replaced
with plastic collection and administration sets.When whole
blood was collected and transfused using glass bottles, air
was often pumped into the bottle in order to increase the
rate of flow. Plastic bags into which blood is collected today
contain no air and, thus, blood donors are not at risk for AE.
Additionally, plastic administration sets do not contain junctions through which air can enter. However, small amounts
of air can enter the circulation during transfusion for example, by failing to expel air from transfusion tubing. AE may
also occur if blood is infused under pressure in an open system or if air enters the circuit when containers or blood
administration sets are changed. Perioperatively recovered
blood (PRB) may pose a risk of air embolism if improperly
performed. Morbidity and mortality attributed to PRB are
typically attributed to reinfusing recovered blood under
pressure.105 Thus,AE can be avoided by properly using infusing pumps, apheresis devices, blood recovery systems and
tubing couplers.
Bubbles of air that enter the arterial circulation will travel
with flowing blood until they are blocked by smaller diameter vessels. The pathologic manifestations of AE result from
this mechanical obstruction which leads to ischemia and
inflammatory reactions.The incidence of iatrogenic AE is difficult to estimate because many accidents are not recognized. Clinical manifestations of AE vary greatly but often
involve the neurologic and cardiovascular systems.
Cardiopulmonary symptoms may include dyspnea, chest
pain, cough and in severe cases, shock. Neurologic impairment may be of sudden onset. Treatment of AE must be
started immediately after the diagnosis is confirmed. First,
the source of air must be identified and removed as vital
signs are controlled. Placing the patient on their left side
with the head down may help to displace air bubbles from
the pulmonary valve. Pure oxygen by face mask or mechanical ventilation should be initiated. Hyperbaric oxygen therapy should be considered when larger amounts of air have
entered the circulation. However, the specialized pressure
chambers needed to perform this treatment are not readily
available. Blood substitutes like perfluorocarbon emulsions
may eventually serve as an alternative treatment for more
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Perrotta and Snyder

severe air embolism based on their ability to improve tissue
oxygenation.106
HYPOTHERMIA
Hypothermia may occur when large volumes of cold blood
components are transfused over a short period, most commonly in the emergency department or operating room.
Transfusion-related hypothermia is also dangerous to small
children and newborns who undergo exchange transfusion.
Red cells are stored in the liquid state at 16C and are
removed from the refrigerator only at the time of transfusion.
Thus, blood may be transfused ice-cold in emergency situations. Fresh frozen plasma is stored at <18C and is less of a
problem because it is thawed in a waterbath at 3037C or a
microwave device specifically designed for this purpose
immediately prior to transfusion. Hypothermia can adversely
effect oxygen transport and tissue oxygenation based on the
increased affinity of hemoglobin for oxygen at lower temperatures.These effects are further exacerbated by alkalosis
and reduced 2,3-DPG in transfused red cells. Each will contribute to the increased metabolic rate, metabolic acidosis,
and hypoglycemia, which may result in further hypoxia and
hypotension. Hypothermic patients may also have a bleeding
diathesis and increased susceptibility to wound infections.107
Blood may not clot normally when core temperature is
below 35C and platelet function may be impaired. In addition, the liver metabolizes citrate more slowly at lower temperatures, which prolongs the anti-calcaemic effects of this
anticoagulant (see section on Metabolic disturbances).
Adult patients can experience ventricular arrhythmias
when transfused with massive volumes of cold blood. The
risk may be higher when the blood is infused through a central catheter which puts the blood in close proximity to the
cardiac conducting system.108 Detrimental cardiac effects
may be exacerbated by coexisting hypocalcemia and hyperkalemia. Operative patients are at particular risk as operating
rooms are usually cold, and normal thermoregulatory mechanisms may be disturbed by the anesthesia or the procedure
itself.109 The effects of transfusion-related hypothermia can
be minimized by slowing the infusion rate and using an inline blood warming device.These devices do not heat blood
over 40C to avoid hemolyzing red cells. Blood warmers
must be properly maintained and used only by trained personnel.Additionally, warm saline solutions are routinely provided to further minimize the hypothermic effects of blood
transfusion.
by the lack of profound hypotension as the predominant

sign in these other reactions. Clinically, the decreased blood
pressure began shortly after the infusion began, but quickly
subsided once the transfusion was stopped and supportive
measures were initiated. Most patients had respiratory symptoms which were milder than those encountered in TRALI.
Concurrent IgA deficiency was excluded in these patients by
their ability to tolerate additional blood components without
blood pressure changes or anaphylaxis.
The presumed mechanism of these reactions appears to
involve the vasodilatory peptide bradykinin which is generated when blood contacts certain negatively charged artificial surfaces.112 Bradykinin (BK) release occurs following
activation of the kallikrein-kinin cascade.113 Normally, BK is
rapidly degraded to inactive products through pathways that
involve ACE.Thus, patients on ACE inhibitors will be less able
to degrade BK and its active metabolites, which may lead to
hypotension. In vitro studies have documented bradykinin
levels ranging from 6794 to 28,800 pg/ml after filtering
platelets through negatively charged filters.114 BK levels have
also been directly measured in patients receiving platelet
concentrates through positively and negatively charged
leukoreduction filters.115 Consistent with the hypothesis,
bradykinin levels in transfused patients significantly increase
during the first 5 min of platelet transfusion through a negatively charged filter (PL-50H, Pall, Glen Cove, NY), and BK levels were particularly high in two patients with diminished
ACE inhibitors activity. BK levels did not rise when platelets
were transfused through a positively charged filter (Sepacell
PLS-5A, Asahi, Tokyo, Japan). However, similar hypotensive
episodes have been described in five patients not on ACE
inhibitors who received platelets through leukoreduction filters.116 Four of these reactions were associated with negatively charged, and one was associated with a positively
charged filter. These cases suggest that other factors could
contribute to these reactions. More recently, a metabolic
abnormality that affects the degradation of des-Arg9-BK has
been identified in several patients with severe hypotensive
transfusion reactions.117 Des-Arg9-BK is an active metabolite
of BK that is primarily inactivated by ACE and the metallopeptidase aminopeptidase P. In the presence of ACE inhibition, the half-life of des-Arg9-BK, not BK, was significantly
higher in patients with severe hypotensive transfusion reactions as compared to control patients.Thus, inherent characteristics of the blood recipient that further impair the ability
to metabolize active vasodilatory peptides could contribute
to hypotensive reactions.
RED EYE SYNDROME
HYPOTENSIVE REACTIONS ASSOCIATED WITH ACE

INHIBITORS
In the early 1990s, a series of severe hypotensive reactions following blood transfusion were retrospectively reviewed.110 The
most serious reactions occurred in patients on angiotensinconverting enzyme (ACE) inhibitors who received platelets
transfused through negatively-charged bedside leukocyte
reduction filters.111 These reactions were clinically distinguished from severe allergic reactions, hemolytic transfusion
reactions, and transfusion related acute lung injury (TRALI)
76
More than 100 peculiar acute ocular reactions to blood transfusion have been reported to the United States Centers for
Disease Control and Prevention (CDC).118 These peculiar
reactions occur within 24 h of transfusion and are characterized by bilateral erythema (redness) of the conjunctiva and
eyelids.119 Other symptoms include conjunctival hemorrhage, eye pain, headache, and periorbital edema. Symptoms
usually resolve within 5 days. The incidence is difficult to
estimate as they are likely underreported.The cause of these
reactions is unclear but most cases reported to the CDC

occurred in patients who received red cells in which white
cells were removed using specific lots of the LeukoNet
Prestorage Leukoreduction Filtration System (Hemasure,
Marlborough, Massachusetts). Possible explanations include
allergic responses to unidentified allergens in the filtration
system, or other reactions to a chemical, material, or breakdown product contained in the leukoreducing system.
Reports of acute periocular reactions decreased after these
leukoreduction filters were removed from inventories.
TRANSFUSION-ASSOCIATED SEPSIS
Bacterial sepsis is a long-recognized complication of blood
transfusion therapy. Blood products may be contaminated by
bacteria if a donor is bacteremic during the blood collection
or if the arm is improperly prepared before venipuncture.120
Use of single-use, closed, sterilized collection systems and
limiting the duration of red cell storage to 3542 days has
contributed to the low incidence of bacterial contamination.
However, there remain occasional reports of severe, often
fatal reactions related to bacteria in a blood component.The
risk of transfusion-associated sepsis (TAS) is difficult to estimate because blood recipients are often immunocompromised and have other risk factors for sepsis. TAS was
implicated in three of 28 deaths in the United Kingdoms
serious hazards of transfusion study (SHOT)121. In the United
States, 10 fatal transfusion reactions reported from January
1998 through June 1999 as part of the bacterial contamination (BACON) study were likely caused by TAS. Organisms
commonly implicated in septic transfusion reactions (STR)
include gram-positive (Staphylococcus sp.) and gram-negative (Yersinia, Enterobacter, Pseudomonas sp.) bacteria.122
Yersinia enterocolitica in particular, is capable of growing at
colder temperatures (46C) and elaborated endotoxins can
cause shock.123 Blood donors must be in good health on the
day of donation. This requirement, however, does not
exclude asymptomatic donors who may have had a shortlasting, gastroenteritis or mild diarrhea 514 days prior to
blood donation. These donors may have a longer than
expected period of asymptomatic bacteria that allows transmission of organisms on donation.124,125 Other less common
blood contaminants like Serratia liquefaciens consistently
cause severe morbidity and are associated with a high death
rate.126 Autologous transfusion does not protect againt bacterial contamination.127
Bacterial contamination of platelet concentrates, especially by gram-positive microorganisms, is more common
because platelets are stored at room temperature.128,129 For
this reason, platelets are stored for a maximum of 5 days.
Storing platelets at lower temperatures will reduce bacterial
growth, however, platelets are damaged when refrigerated
and efforts to use cryoprotectants to protect platelet during
cold storage continue.130 Similarly, antibiotics cannot be
added directly to platelet concentrates because they will
damage cell membranes.Transfusing blood products contaminated by bacteria is dangerous and may cause profound
hypotension and shock. However, fatal STR are relatively
rare.This may be explained by the slow growth of many contaminating bacteria which do not produce toxins.There are
no screening tests available at this time to detect contaminated units. Commercially available multiple-reagent urine
dipsticks have been used to detect falling glucose levels and
pH in platelet units experimentally contaminated with bacteria.131 However, the sensitivity of reagent strips may be limited by the normal changes in pH and glucose encountered
during prolonged platelet storage. Short-term bacterial culture of blood products using automated bacterial systems
can detect contaminated blood products, but again this practice is not widespread.132 Other efforts are underway to
develop both screening tests and means for destroying bacteria within individual blood units. Several approaches to
pathogen inactivation are in pre-clinical or clinical trials.
Most involve use of chemicals or photochemical methods to
destroy blood pathogens by targeting nucleic acids.133
Although originally designed to inactivate viruses like HIV,
they are also effective against bacteria and parasitic organisms.The efficacy of pathogen inactivation systems is usually
first determined in non-cellular products (plasma), and if
results are promising, studies are extended to cellular components (red cells, platelets). Phase 3 trials are currently
underway in the United States and Europe using psoralen, S59 medicated pathogen inactivation of platelet concentrates.134 Alternative photochemical treatments that utilize
riboflavin are also being developed to inactivate bacteria.135
Although most bacteria are effectively inactivated by these
techniques, some bacteria can survive decontamination.
Leukodepletion of blood components may decrease the
growth of some, but not all bacteria, and is not considered an
effective means of eliminating septic transfusion reactions.
Blood cultures should be drawn from patients who
develop high fevers during or following transfusion, especially if they become hypotensive. Septic reactions can be differentiated from more common febrile reactions in that the
latter are generally self-limited and lack profound hypotension. Clearly, it is critical to distinguish febrile and septic reactions in immunosuppressed patients. A temperature rise of
more than 2C following platelet transfusion makes a septic
reaction more likely.136 Rare patients who receive contaminated products may develop no, or mild febrile symptoms.
Many symptoms are attributed to preformed endotoxins and
cytokines.These include skin flushing, rigors, and rapidly progressive cardiovascular collapse. Symptoms may ensue during,
or minutes to hours after the transfusion is completed.Clinical
severity is related to the elaboration of endotoxins by gramnegative organisms and other virulence factors that permit
bacterial growth. The load of bacteria infused is directly
related to the time of storage and the volume of the component. Host characteristics including concomitant antibiotic
administration, degree of immunosuppression and overall
medical status of the patient will also influence clinical
severity. Gram stains of suspected products may help when
organisms are seen. Blood component bags are not routinely retained at most hospitals, but suspected units
should be cultured if possible. The patient should also be
cultured to confirm that the infection was caused by the
blood transfusion and to exclude other sources of infection. Importantly, an acute hemolytic transfusion reaction
should be excluded. Treatment includes broad-spectrum
antibiotics, fluids, and cardiorespiratory support.
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Perrotta and Snyder

TRANSFUSION-ASSOCIATED GRAFT VERSUS HOST
DISEASE
Transfusion-associated graft versus host disease (TA-GVHD)
is a rare complication of blood transfusion that is fatal in
approximately 90% of patients.The risk of TA-GVHD is difficult to estimate but is related to the number of viable T lymphocytes transfused, the recipients immune status, and the
HLA disparity between donor and recipient.137 Therefore,
multiply transfused patients who receive cells from donors
who share HLA haplotypes (haploidentical) with the recipient are at greatest risk.The classic scenario for the development of TA-GVHD in immunocompetent individuals is
homozygosity of the donor for an HLA type shared by the
recipient.138 Thus, TA-GVHD is more common in societies
like Japan where there is a higher likelihood for HLA
homozygosity.TA-GVHD occurs when donor immunocompetent T and NK cells attack recipient cells because these recipient cells appear foreign due to differences in major or minor
histocompatibility antigens.139 GVHD is usually seen following allogeneic bone marrow transplant (BMT), but may also
occur in immunodeficient or immunosuppressed patients
following blood transfusion. Clinically,TA-GVHD is characterized by the acute onset of rash, abdominal pain, diarrhea,
liver function abnormalities, and bone marrow suppression
beginning 2 to 30 days following transfusion. The maculopapular rash seen is similar to that observed in acute
GVHD following BMT. Biopsy of the skin can confirm the
diagnosis. Immunohistochemical studies of skin biopsies will
show an infiltrate of CD3+ T lymphocytes, and populations
of T lymphocyte subsets (CD4+, CD8+) that are donor
derived.140 Pancytopenia in TA-GVHD may be severe and is
attributed to destruction of recipient marrow stem cells by
donor lymphocytes.
Immunosuppressive therapy using corticosteroids,
cyclosporine A and anti-CD3 monoclonal antibody (OKT3)
has been used in cases of TA-GVHD.141,142 The benefits of
these treatments are unclear, however, therapeutic modalities are proposed based on the presumed mechanism of the
disease.143 These strategies are designed to reduce the cytotoxic T-lymphocyte mediated tissue injury through apoptotic
pathways, as well as reducing the production of inflammatory cytokines like tumor necrosis factor.144 Fortunately, TAGVHD can be prevented by irradiating products prior to
transfusion. Specifically, irradiating cellular blood products
with 2500 cGy inactivates donor lymphocytes and is the
most effective method for preventing TA-GVHD.145 This radiation dose is required to completely inactive T cells found in
blood collected and stored in common plastic containers
used today. Platelets and granulocytes are not damaged by
this radiation dose, but red cells sustain detectable damage.

For this reason, the maximum storage time for irradiated red
cells is 28 days. Patients who should receive irradiated blood
components include neonates who may have immature or
abnormal immune systems, patients with hematologic malignancies, and cancer patients who are marrow/stem cell
transplant candidates or are receiving high-dose chemotherapy (Table 5). Directed donations from first-degree relatives
must be irradiated, although most blood centers will extend
this requirement to all blood relatives. For the same reason,
apheresis platelets matched for HLA class I antigens should
be irradiated.146 Radiochromic film can be used as a dosimeter to verify that an effective dose of radiation has been delivered to the product.147 Leukoreduction is not adequate to
prevent TA-GVHD as there are sufficient residual lymphocytes present to cause GVHD.148 Photochemical treatment
(PCT) of blood products using psoralen S-59 and long-wavelength ultraviolet light has been shown to prevent TA-GVHD
in a murine parent to F1 transfusion model.149 In this study,
mice received allogeneic splenic leukocytes that were
untreated, gamma irradiated (2500 cGy), or PCT treated (150
M S-59, 2.1 J/cm2 UVA). Mice that received gamma irradiated or PCT treated leukocytes did not develop clinical or
histologic evidence of TA-GVHD, whereas those that received
untreated leukocytes developed clear evidence of TA-GVHD.
As PCT is also effective in inactivating contaminating viruses
and bacteria and is being developed for this purpose PCT
may also provide protection against TA-GVHD.
TRANSFUSION-RELATED ACUTE LUNG INJURY

Transfusion-related acute lung injury (TRALI) is a rare but
serious complication of blood transfusion that presents as
non-cardiogenic pulmonary edema.150 It typically occurs
within 6 h of transfusion and is clinically similar to the adult
respiratory distress syndrome. The most common clinical
findings include the rapid onset of dyspnea, tachypnea,
cyanosis, fever, and hypotension.151 The incidence of TRALI is
unclear because it is often overlooked or not reported, but
the estimated frequency is one in 5000 transfusions.152 Lung
auscultation reveals diffuse crackling and decreased breath
sounds. Invasive hemodynamic monitoring may be required
to differentiate TRALI from pulmonary edema secondary to
cardiac failure or volume overload and to guide therapy.
Specifically, cardiac monitoring shows normal cardiac pressures and function with hypoxemia and decreased pulmonary compliance. Radiographic findings include diffuse,
fluffy infiltrates characteristic of pulmonary edema. The
etiology of many cases of TRALI appears to involve an
Table 5 General indications for irradiated blood components

Infants <1250 g
Intrauterine blood transfusions
Exchange transfusions in neonates
Neonates on extracorporeal membrane
oxygenation (ECMO)
Congenital immunodeficiency
78
Autologous and allogeneic bone marrow/stem cell transplant patients and candidates
Hematologic malignancies (leukemia, lymphoma, aplastic anemia)
Solid tumor with high-dose chemotherapy (neuroblastoma, medulloblastoma, rhabdomyosarcoma)
First-degree relative directed donation

immune-mediated reaction of HLA antibodies or other
leukoagglutins with white cells.153 According to this model,
granulocytes are first activated in the peripheral circulation
by HLA or other Ag-Ab complexes.Activated leukocytes then
migrate to the lungs where they bind to the pulmonary capillary bed via integrins and other cell adhesion molecules. Ex
vivo animal models of TRALI provide some support for this
hypothesis.154 Proteolytic enzymes are then released that
destroy tissue, resulting in a capillary leak syndrome and pulmonary edema. Massive pulmonary edema with granulocyte
aggregation within the pulmonary microvasculature and
alveolar extravasation have been noted in patients who die
of TRALI.155 However, antibody specificity cannot be identified in many cases of TRALI, suggesting that other mechanisms are involved. More recently, reactive lipid products
released from donor cell membranes have been associated
with the development of TRALI using an isolated, perfused
rat lung model.156
TRALI should be suspected in patients with rapid onset
respiratory distress following transfusion therapy, or pulmonary edema without hypervolemia and congestive heart
failure.The identification of HLA and/or granulocyte antibodies in either the donors or recipients serum is highly suggestive of TRALI in the appropriate clinical context. Ideally,
the corresponding antigens are found on the recipients or
donors leukocytes. This specialized testing is performed in
few specialized laboratories and will not be available during
the acute episode. Products obtained from donors implicated in TRALI should not be used for blood transfusion,
although their plasma is suitable for fractionation and for
producing plasma-free components.157 It has been suggested
that transfusing products obtained from female blood donors
who are sensitized to HLA antigens by pregnancy may
increase the risk of TRALI. However, cases of TRALI could not
be found in a large series of platelet transfusions using
apheresis platelets collected from woman,158 despite the fact
that 17% of the female donors demonstrated HLA sensitization. Thus, prospective screening of blood donors for HLA
sensitization is not recommended. Unlike acute respiratory
distress syndrome, approximately 8090% of patients with
TRALI will survive with supportive care consisting of
aggressive respiratory support, supplemental oxygen and
mechanical ventilation when necessary. Based on the presumed pathogenesis of TRALI, leukoreduced blood products
could potentially decrease the incidence of TRALI. Drugs
used to treat TRALI have included corticosteroids and
diuretics, but there are no controlled studies demonstrating
the efficacy of these or other agents versus supportive care
alone.
CONCLUSIONS
Vast improvements in each phase of blood transfusion therapy have markedly reduced, but not eliminated, the incidence of adverse events. Significant technologic innovations
in the equipment used to collect, process, and store blood
products have paralleled our increased understanding of the
physiology of transfusion. Despite many safeguards and
a clear understanding of red cell immunology, hemolytic
reactions caused by transfusing ABO incompatible blood
remain the most common cause of immediate fatality. Less

common fatal reactions attributed to blood transfusion
include septic transfusion reactions, transfusion associated
graft-versus-host disease (TA-GVHD), and transfusion related
acute lung injury.159 Therefore, decisions to transfuse a
patient should be made by individuals with a knowledge of
the most relevant risks of blood component therapy and an
ability to weigh risk/benefit ratios. In many countries,
informed consent must be obtained by health care personnel who are able to communicate these risks before blood
products are transfused. Most patients are concerned about
contracting HIV or hepatitis C from donor blood. However, it
is difficult for patients to understand that the risk of viral
infection is exceedingly small. In some respects, the noninfectious risks of blood transfusion are even more difficult
to quantify because they are often related to the training and
experience of the transfusion team. In many cases, risks differ among individual patients. Cardiac patients are often at
increased risk for volume overload; multiply transfused
patients frequently develop multiple red cell antibodies, and
severely immunocompromised patients may develop TAGVHD if blood is not irradiated. Despite technological
advances in warming devices, hypothermia continues to
adversely affect massively-transfused patients. Autologous
blood often considered quite safe does not eliminate all
risks of transfusion therapy such as bacterial contamination
and fluid overload. A better understanding of the mechanisms leading to the described non-infectious complications
of blood component therapy has lead to strategies designed
to reduce, eliminate, and treat these adverse effects.
However, continued vigilance is needed to prevent the most
avoidable untoward reactions.
Correspondence to: P. L. Perrotta, State University of New York @ Stony
Brook, University Hospital, Laboratory Administration L3-532, Stony Brook,
NY 11794, USA.Tel.: +1 631 444 2601; Fax: +1 631 444 2653; E-mail:
pperrotta@notes.cc.sunysb.edu
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Non-infectious transfusion reactions

State University of New York @ Stony Brook, USA

Yale University, USA

Abstract Blood transfusion is considered safe when the

hepatitis C virus (HCV) and hepatitis B virus (HBV).

Perrotta and Snyder

incompatible transfusions in which complement fixation

Table 2 Antibodies commonly implicated in delayed

Blood group system

Jka > Jkb

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

FEBRILE NON-HEMOLYTIC TRANSFUSION REACTIONS

Non-infectious transfusion reactions

ALLERGIC REACTIONS, URTICARIAL AND

2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 6983

Perrotta and Snyder

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

intravascular hemolysis which has more life-threatening

Non-infectious transfusion reactions

obviate prophylactic transfusion before antigen negative

Perrotta and Snyder

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

chelators like deferiprone have been shown to maintain

Table 4 Changes in red cells and supernatant plasma with

Non-infectious transfusion reactions

Citrate toxicity and hypocalcemia

plasma exchange. Methods have been devised to minimize

Perrotta and Snyder

by the lack of profound hypotension as the predominant

HYPOTENSIVE REACTIONS ASSOCIATED WITH ACE

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

Non-infectious transfusion reactions

Perrotta and Snyder

this radiation dose, but red cells sustain detectable damage.

TRANSFUSION-RELATED ACUTE LUNG INJURY

Table 5 General indications for irradiated blood components

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

Non-infectious transfusion reactions

remain the most common cause of immediate fatality. Less

2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 6983

Perrotta and Snyder

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

development of transfusion reactions.Transfusion 1998; 38:

Non-infectious transfusion reactions

2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 6983

Perrotta and Snyder

Papakonstantinou O, Kostaridou S, Maris T et al. Quantification

Blood Reviews (2001) 15, 6983

2001 Harcourt Publishers Ltd

Hume HA, Popovsky MA, Benson K et al. Hypotensive reactions:

Non-infectious transfusion reactions

Anderson KC, Lew MA, Gorgone BC et al.Transfusion-related

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