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incompatible transfusions in which complement fixation
results in formation of the C5b-9 membrane attack complex.
Accordingly, only rarely do delayed reactions cause intravas-
cular hemolysis with associated hemoglobinemia and hemo-
globinuria. 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 medi-ators 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-Jk a, in particu-
lar, is often implicated in these reactions.14 Certain antibod-
ies, 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 transfu-
sions should receive red cells that do not carry the associ-ated antigen, so-called ‘antigen negative’ units. Patients
previously sensitized to red cell antigens must be clearly
identified in blood bank information systems to avoid subse-
quent reactions caused by an anamnestic response to further
exposures. In addition, most blood bank standards demand
that pre-transfusion testing of recently transfused or preg-
nant patients be performed on samples obtained within 3
days of a transfusion.This requirement is based on the fre-
quent observation that these patients develop clinically sig-
nificant red cell antibodies associated with immediate and
delayed hemolysis.17 DHTR are particularly prevalent in
patients with diseases that require frequent red cell transfu-
sion.18
Patients with sickle cell disease (SCD) are at a high risk of DHTR because of differences in red cell antigen frequency
between the donor population and the recipients. For exam-
ple, black SCD patients are often Fy a and Fy b 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 sig-
nificant differences in the Rh system between black and
white individuals.Many centers attempt to avoid these prob-
lems 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 transfu-
sion reactions (HTR) can be particularly dangerous in
patients with sickle cell disease – the ‘sickle cell HTR syn-
drome’.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 antibod-ies 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 reac-
tions 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 (> 1˚C elevation) and shaking chills, and these may be
accompanied by nausea, vomiting, dyspnea, and hypoten-
sion. Oxygen saturation may decrease during rigors, but
should return to baseline as the reaction resolves.The sever-
ity 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 aceta-
minophen [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 transfu-
sion to be maximally effective.Severe rigors can be promptly
Perrotta and Snyder
70Blood Reviews (2001) 15 , 69–83 2001 Harcourt Publishers Ltd
Table 2 Antibodies commonly implicated in delayed
hemolytic reactions
Blood group system Specific antibody
Kidd (Jk) Jk a > Jk b
Rh E > C > c
Kell K
Duffy (Fy) Fya
Glycophorin S > s
Table 1 Non-infectious complications of transfusion therapy
Acute immune hemolytic reactions Metabolic disturbances
Delayed extravascular hemolysis Air embolism
Febrile non-hemolytic reactions Hypothermia
Allergic reactions (urticarial, anaphylactic) Hypotensive reactions and ACE inhibitors
Non-immune red cell hemolysis Red-eye syndrome
Post-transfusion purpura Transfusion-associated sepsisCirculatory overload Transfusion-associated graft-versus-host disease
Iron overload Transfusion-associated acute lung injury
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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 4–6 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 restartedusing 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 recipi-
ent’s 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-α, IL-1, and IL-
6. Direct activity of various biological response modifiers
including cytokines also appear to play a role in these reac-
tions.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 elabo-
ration 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 find-
ing is attributed to reactive substances contained in
the plasma portion of platelet concentrates. In particular,
a strong positive correlation between supernatant IL-1β
and IL-6 levels and the frequency of febrile reactions has
been observed. Similar associations between the durationof 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 toHLA antigens.30 Pre-storage leukoreduction of red cells can
further reduce the likelihood of FNHTR as compared to bed-
side 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 leukore-
duction 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 sub-
stances in donor plasma, are common following plasma,
platelet, and red cell transfusions. Typical cutaneous hyper-
sensitivity reactions present as pruritis and/or urticaria in
the absence of fever. Allergic reactions are classically IgEmediated and symptoms are attributed to histamine release.
Symptoms and signs include pruritis, erythema, papular
rashes, and weals.Distinguishing allergic and febrile transfu-
sion 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 25–50 mg diphenhydramine or other anti-
histamines. In mild allergic reactions not associated with
fever or vasomotor instability, the transfusion can be contin-
ued 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 aller-gic reactions.It is difficult to predict which patients are a risk
for allergic reactions, but in general, the allergic predisposi-
tion 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 bio-
logic mediators.The most serious symptoms include laryn-
geal 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 pro-tracted 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 mini-
mize allergic reactions, but these procedures usually cause
the loss of significant numbers of platelets.38 Red cells leuko-
reduced 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
Non-infectious transfusion reactions
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can occur. IgA-deficient patients who have had a severe ana-
phylactic 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-defi-
cient 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 candevelop 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 sys-
tem (Table 3). Most of these involve the physical and/or
chemical destruction of red cells. Many medications andintravenous 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 transfu-
sion. 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 50˚C. Accordingly, blood
warmers do not heat blood above 42˚C 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 cryopreserv-
ing 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.44Thus,red cell dam-
age is minimized by using larger diameter needles and slower
infusion rates.45 Significant reactions from mechanical hemoly-
sis are uncommon but must be distinguished from immune or
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 hemoly-
sis.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 (esti-
mated 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 hemoglobin-
uria, 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 unconjugatedhyperbilirubinemia and increased lactate dehydrogenase.
The degree of hemolysis can be exacerbated if a recipient is
concurrently receiving medications like primaquine or nitro-
furantoin.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 hapto-
globin and oxidation to methemoglobin. Frozen stored red
cells contain glycerol to prevent hemolysis during the freez-
ing process. Following thawing, however, these units willcontain some free hemoglobin and more importantly, glyc-
erol. 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 dys-
function. 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 nega-
tive 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, treat-
ment would include measures taken following an acute
intravascular hemolytic reaction caused by an ABO incom-
patible blood transfusion.Vital signs should be closely moni-
tored. 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 proin-
flammatory cytokines (IL-1, TNF-α ), chemokines (IL-8) and
complement fragments (C3a, C5a) play a role in the patho-
physiology of immune hemolytic reactions.50 However, their
role in non-immune mediated hemolysis has not been
Perrotta and Snyder
72Blood Reviews (2001) 15 , 69–83 2001 Harcourt Publishers Ltd
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
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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.
POST-TRANSFUSION PURPURA
Post-transfusion purpura (PTP) is a rare complication of blood transfusion that results in profound thrombocytope-
nia.51 It is characterized by acute thrombocytopenia (platelet
count < 10,000/ µl;10 × 109 /l) occurring 5–10 days following
red cell transfusion.52,53 PTP is often not immediately recog-
nized 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 (PL AI ), 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 pre-
vious blood exposure.58,59 The specificity of the platelet anti-
bodies 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 µl in 4–5 days as described in observa-
tional 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 toplatelet surfaces.63 The beneficial effects of IVIG in antibody-
mediated autoimmune disease have been attributed to the
ability of exogenous IgG to accelerate the rate of IgG catabo-
lism.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 effi-
cacious.65 The role of steroids in treating PTP is unclear,
although patients who develop PTP are often on chemother-
apy 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 anti-
gen 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
obviate prophylactic transfusion before antigen negative
units can be obtained.71
CIRCULATORY OVERLOAD
During acute hemorrhage,it is difficult to overload the circu-
latory system of patients with normal cardiac function.First,the amount of blood lost in severe trauma is often underesti-
mated 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 physio-
logic responses to anemia include increases in cardiac out-
put and increases in 2,3-DPG content of red cells.The latter
shifts the oxygen dissociation curve to the right which facili-
tates the release of oxygen to surrounding tissues.In chroni-
cally anemic patients who have increased their cardiac
output, there is a risk that attempts to raise the arterial oxy-
gen content by transfusion will overload the circulatory sys-
tem.This is particularly true in patients with compromisedcardiac 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 trig-
gers’ 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 fail-
ure, 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 circu-
latory overload include chest tightness and cough and wors-
ening 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 col-
lected blood, the same oxygen carrying capacity is main-
tained 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 vita-
min K has an effect. In the event of Coumarin overdose, large
volumes of plasma may be infused to correct the prothrom-
bin time. Circulatory overload is much less of a problem in
factor VIII or factor IX replacement therapy as highly puri-
fied and concentrated products are used instead of large vol-
umes 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 diure-
sis 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 300–350 mL) to normally-sized
adult patients. However, clinicians occasionally request thatred cells units be ‘split’ so that only one-half unit is infused
over 3–4 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 measure-
ments of central venous pressure, cardiac filling pressures,
and pulmonary vessel pressures,can help to identify impend-
ing circulatory overload. In addition to patients with
impaired cardiac function, patients with neurologic condi-
tions associated with autonomic dysfunction may have diffi-
culty 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, trans-
ferrin may become saturated after only 10–15 units of
blood,74 after which iron may be deposited in tissue
parenchyma.
75
It is the non-transferrin-bound iron thatappears 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 400–1000 mg/kg body weight. Other suggested
detrimental effects of iron overload include accelerated
development of diabetic nephropathy 78 and increased sus-
ceptibility to infectious disease79 in transfusion-dependent
beta thalassemia. Iron overload is most commonly seen in
conditions that require frequent intermittent red cell transfu-
sion like the thalassemias, hemoglobinopathies, and aplastic
anemias. Periodic blood transfusion, in particular, is being
used more frequently to prevent and treat major complica-
tions of sickle cell disease like cerebrovascular accidents.
Long-term transfusion effectively reduces hemoglobin S lev-
els 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 deferoxam-
ine 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
chelators like deferiprone have been shown to maintain
lower serum ferritin levels in patients with transfusion-
dependent iron overload.83,84 Other alternatives to periodic
blood transfusion like hydroxyurea may reduce the inci-
dence 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 surviv-ing 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 patient’s red cells are efficiently exchanged with
normal donor blood has been examined as an adjunct or
alternative to regular chelation therapy.87 Although erythro-
cytapheresis can reduce total iron burden,the safety and effi-
cacy 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 dam-
age.77 Liver biopsy with quantitative iron determination and
histochemistry remain the reference methods for assessingiron 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 electrolytemonitoring have minimized this complication in the majority
of adult patients.In fact,post-transfusion acidosis and hyper-
kalemia may be more likely related to inadequate resuscita-
tion 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 lev-
els 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-diphospho-
glycerate (2,3-DPG),pH and potassium.Preservative solutions
Perrotta and Snyder
74Blood Reviews (2001) 15 , 69–83 2001 Harcourt Publishers Ltd
Table 4 Changes in red cells and supernatant plasma with
storage
Red cells Supernatant
Decreasing ATP Increasing potassium
Decreasing 2,3-DPG Decreasing pH
Increasing hemolysis Decreasing sodium
Increasing lactate Decreasing glucose
Increasing ammonia
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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 com-monly 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 1–6˚C and are
removed from the refrigerator only at the time of transfusion.
Thus, blood may be transfused ‘ice-cold’ in emergency situa-
tions. Fresh frozen plasma is stored at
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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 break-
down 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 35–42 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 esti-
mate because blood recipients are often immunocompro-
mised and have other risk factors for sepsis. TAS was
implicated in three of 28 deaths in the United Kingdom’s
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 contamina-
tion (BACON) study were likely caused by TAS. Organisms
commonly implicated in septic transfusion reactions (STR)
include gram-positive (Staphylococcus sp.) and gram-nega-
tive (Yersinia, Enterobacter, Pseudomonas sp.) bacteria.122
Yersinia enterocolitica in particular, is capable of growing at
colder temperatures (4–6˚C) 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 short-
lasting, gastroenteritis or mild diarrhea 5–14 days prior to
blood donation. These donors may have a longer than
expected period of asymptomatic bacteria that allows trans-
mission 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 bacte-
rial contamination.
127
Bacterial contamination of platelet concentrates, espe-
cially 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 contam-
inated 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 con-
taminating bacteria which do not produce toxins.There are
no screening tests available at this time to detect contami-
nated units. Commercially available multiple-reagent urine
dipsticks have been used to detect falling glucose levels and
pH in platelet units experimentally contaminated with bacte-
ria.131 However, the sensitivity of reagent strips may be lim-
ited by the normal changes in pH and glucose encountered
during prolonged platelet storage. Short-term bacterial cul-ture of blood products using automated bacterial systems
can detect contaminated blood products,but again this prac-
tice is not widespread.132 Other efforts are underway to
develop both screening tests and means for destroying bac-
teria 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 organ-
isms.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 com-ponents (red cells, platelets). Phase 3 trials are currently
underway in the United States and Europe using psoralen, S-
59 medicated pathogen inactivation of platelet concen-
trates.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, espe-
cially if they become hypotensive. Septic reactions can be dif-ferentiated from more common febrile reactions in that the
latter are generally self-limited and lack profound hypoten-
sion. Clearly, it is critical to distinguish febrile and septic reac-
tions in immunosuppressed patients. A temperature rise of
more than 2˚C following platelet transfusion makes a septic
reaction more likely.136 Rare patients who receive contami-
nated products may develop no, or mild febrile symptoms.
Many symptoms are attributed to preformed endotoxins and
cytokines.These include skin f lushing, rigors,and rapidly pro-
gressive 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 gram-
negative 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 compo-
nent. 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 rou-
tinely 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 infec-
tion. Importantly, an acute hemolytic transfusion reaction
should be excluded. Treatment includes broad-spectrum
antibiotics,fluids, and cardiorespiratory support.
Non-infectious transfusion reactions
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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 diffi-
cult to estimate but is related to the number of viable T lym-
phocytes transfused, the recipient’s immune status, and theHLA disparity between donor and recipient.137 Therefore,
multiply transfused patients who receive cells from donors
who share HLA haplotypes (haploidentical) with the recipi-
ent are at greatest risk.The classic scenario for the develop-
ment 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 immunocompe-
tent T and NK cells attack recipient cells because these recip-
ient cells appear foreign due to differences in major or minor
histocompatibility antigens.139 GVHD is usually seen follow-
ing allogeneic bone marrow transplant (BMT),but may alsooccur in immunodeficient or immunosuppressed patients
following blood transfusion.Clinically,TA-GVHD is character-
ized by the acute onset of rash, abdominal pain, diarrhea,
liver function abnormalities, and bone marrow suppression
beginning 2 to 30 days following transfusion. The macu-
lopapular 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 modali-
ties are proposed based on the presumed mechanism of the
disease.143 These strategies are designed to reduce the cyto-
toxic T-lymphocyte mediated tissue injury through apoptotic
pathways, as well as reducing the production of inflamma-
tory cytokines like tumor necrosis factor.144 Fortunately,TA-
GVHD 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.145This radia-tion 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 malig-
nancies, and cancer patients who are marrow/stem cell
transplant candidates or are receiving high-dose chemother-apy (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 dosime-
ter to verify that an effective dose of radiation has been deliv-
ered to the product.147 Leukoreduction is not adequate to
prevent TA-GVHD as there are sufficient residual lympho-
cytes present to cause GVHD.148 Photochemical treatment
(PCT) of blood products using psoralen S-59 and long-wave-
length 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 wereuntreated,gamma irradiated (2500 cGy),or PCT treated (150
µM S-59, 2.1 J/cm2 UVA). Mice that received gamma irradi-
ated 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 asnon-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 pres-
sures and function with hypoxemia and decreased pul-monary compliance. Radiographic findings include diffuse,
fluffy infiltrates characteristic of pulmonary edema. The
etiology of many cases of TRALI appears to involve an
Perrotta and Snyder
78Blood Reviews (2001) 15 , 69–83 2001 Harcourt Publishers Ltd
Table 5 General indications for irradiated blood components
Infants
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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 cap-
illary bed via integrins and other cell adhesion molecules.Ex
vivo animal models of TRALI provide some support for thishypothesis.154 Proteolytic enzymes are then released that
destroy tissue,resulting in a capillary leak syndrome and pul-
monary 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 identi-
fied in many cases of TRALI, suggesting that other mecha-
nisms 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 pul-monary edema without hypervolemia and congestive heart
failure.The identification of HLA and/or granulocyte antibod-
ies in either the donor’s or recipient’s serum is highly sug-
gestive of TRALI in the appropriate clinical context. Ideally,
the corresponding antigens are found on the recipient’s or
donor’s leukocytes.This specialized testing is performed in
few specialized laboratories and will not be available during
the acute episode. Products obtained from donors impli-
cated 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 sensitiza-
tion. Thus, prospective screening of blood donors for HLA
sensitization is not recommended. Unlike acute respiratory
distress syndrome, approximately 80–90% of patients with
TRALI will survive with supportive care consisting of
aggressive respiratory support, supplemental oxygen and
mechanical ventilation when necessary. Based on the pre-
sumed 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 ther-
apy have markedly reduced, but not eliminated, the inci-
dence 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 anability to weigh risk/benefit ratios. In many countries,
informed consent must be obtained by health care person-
nel 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 non-
infectious 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 dif-
fer among individual patients. Cardiac patients are often at
increased risk for volume overload; multiply transfused
patients frequently develop multiple red cell antibodies,andseverely immunocompromised patients may develop TA-
GVHD 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 mecha-
nisms 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.
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