1-s2.0-S0268960X01901511-main

8/9/2019 1-s2.0-S0268960X01901511-main

1/15

8/9/2019 1-s2.0-S0268960X01901511-main

2/15

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

8/9/2019 1-s2.0-S0268960X01901511-main

3/15

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

71 2001 Harcourt Publishers Ltd Blood Reviews (2001) 15 , 69–83

8/9/2019 1-s2.0-S0268960X01901511-main

4/15

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


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

8/9/2019 1-s2.0-S0268960X01901511-main

5/15

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



8/9/2019 1-s2.0-S0268960X01901511-main

6/15

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


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

8/9/2019 1-s2.0-S0268960X01901511-main

7/15

8/9/2019 1-s2.0-S0268960X01901511-main

8/15

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

8/9/2019 1-s2.0-S0268960X01901511-main

9/15

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.



8/9/2019 1-s2.0-S0268960X01901511-main

10/15

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


Table 5 General indications for irradiated blood components

Infants

8/9/2019 1-s2.0-S0268960X01901511-main

11/15

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.

References

1. Dodd RY. Current viral risks of blood and blood products.Ann Med

2000; 32: 469–474.

2. Busch MP. HIV, HBV and HCV: new developments related to

transfusion safety.Vox Sang 2000; 78: 253–256.

3. Dodd RY.Transmission of parasites and bacteria by blood

components.Vox Sang 2000; 78: 239–242.

4. Williamson LM,Lowe S,Love EM et al. Serious hazards of

transfusion (SHOT) initiative: analysis of the first two annual

reports. BMJ 1999; 319:16–19.

5. Brand A. Immunological aspects of blood transfusions. Blood Rev

2000; 14: 130–144.

6. Capon SM, Goldfinger D.Acute hemolytic transfusion reaction,a

paradigm of the systemic inflammatory response:new insights into

pathophysiology and treatment.Transfusion 1995;35: 513–520.

7. Solanki D,McCurdy PR. Delayed hemolytic transfusion reactions.An

often-missed entity. Jama 1978;239: 729–731.

8. Moore SB,Taswell HF, Pineda AA, Sonnenberg CL. Delayed hemolytic

transfusion reactions. Evidence of the need for an improved

pretransfusion compatibility test.Am J Clin Pathol 1980;74: 94–97.



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:

[email protected]

8/9/2019 1-s2.0-S0268960X01901511-main

12/15

9. Pineda AA,Vamvakas EC, Gorden LD,Winters JL, Moore SB.Trends

in the incidence of delayed hemolytic and delayed serologic

transfusion reactions.Transfusion 1999;39: 1097–1103.

10. Salama A, Mueller-Eckhardt C. Delayed hemolytic transfusion

reactions. Evidence for complement activation involving allogeneic

and autologous red cells.Transfusion 1984;24: 188–193.

11. Patten E, Reddi CR,Riglin H,Edwards J. Delayed hemolytictransfusion reaction caused by a primary immune response.

Transfusion 1982; 22: 248–250.

12. Davenport RD.The role of cytokines in hemolytic transfusion

reactions. Immunol Invest 1995;24: 319–331.

13. von Zabern I, Ehlers M,Grunwald U, Mauermann K,

Greinacher A. Release of mediators of systemic inflammatory

response syndrome in the course of a severe delayed hemolytic

transfusion reaction caused by anti-D.Transfusion 1998; 38:

459–468.

14. Pineda AA,Taswell HF, Brzica SM, Jr.Transfusion reaction.An

immunologic hazard of blood transfusion.Transfusion 1978;18:

1–7.

15. Vamvakas EC, Pineda AA,Reisner R, Santrach PJ, Moore SB.Thedifferentiation of delayed hemolytic and delayed serologic

transfusion reactions: incidence and predictors of hemolysis.

Transfusion 1995; 35: 26–32.

16. Ness PM,Shirey RS,Thoman SK, Buck SA.The differentiation of

delayed serologic and delayed hemolytic transfusion reactions:

incidence, long-term serologic findings, and clinical significance.

Transfusion 1990; 30: 688–693.

17. Shulman IA,Nelson JM, Nakayama R.When should antibody

screening tests be done for recently transfused patients?

Transfusion 1990; 30: 39–41.

18. Syed SK, Sears DA,Werch JB, Udden MM, Milam JD. Case reports:

delayed hemolytic transfusion reaction in sickle cell disease. Am J

Med Sci 1996; 312: 175–181.

19. Petz LD, Calhoun L,Shulman IA, Johnson C,Herron RM.The sickle

cell hemolytic transfusion reaction syndrome.Transfusion 1997;37:

382–392.

20. Cullis JO,Win N, Dudley JM, Kaye T. Post-transfusion

hyperhaemolysis in a patient with sickle cell disease: use of steroids

and intravenous immunoglobulin to prevent further red cell

destruction.Vox Sang 1995; 69: 355–357.

21. Heddle NM,Klama LN, Griffith L et al.A prospective study to

identify the risk factors associated with acute reactions to platelet

and red cell transfusions.Transfusion 1993; 33: 794–797.

22. Winqvist I. Meperidine (pethidine) to control shaking chills and

fever associated with non-hemolytic transfusion reactions. Eur J

Haematol 1991; 47:154–155.

23. Perrotta PL, Feldman D, Snyder EL. Biological response modifiers in

platelet transfusion therapy. In: Seghatchian J,Snyder EL, Krailadsiri P,

eds. Platelet therapy (First ed).Amsterdam: Elsevier 2000;227–262.

24. Chambers LA, Kruskall MS, Pacini DG, Donovan LM. Febrile

reactions after platelet transfusion:the effect of single versus

multiple donors.Transfusion 1990;30: 219–221.

25. Riccardi D, Raspollini E, Rebulla P et al. Relationship of the time of

storage and transfusion reactions to platelet concentrates from

buffy coats.Transfusion 1997; 37: 528–530.

26. Heddle NM,Klama L, Singer J et al.The role of the plasma from

platelet concentrates in transfusion reactions. N Engl J Med 1994;

331: 625–628.

27. Sarkodee-Adoo CB, Kendall JM,Sridhara R,Lee EJ, Schiffer CA.The

relationship between the duration of platelet storage and the

development of transfusion reactions.Transfusion 1998; 38:

229–235.

28. Neumuller J, Schwartz DW, Mayr WR.Demonstration by flow

cytometry of the numbers of residual white blood cells and

platelets in filtered red blood cell concentrates and plasma

preparations.Vox Sang 1997; 73: 220–229.

29. Bowden RA,Slichter SJ,Sayers M et al.A comparison of filteredleukocyte-reduced and cytomegalovirus (CMV) seronegative blood

products for the prevention of transfusion-associated CMV

infection after marrow transplant. Blood 1995; 86: 3598–3603.

30. Leukocyte reduction and ultraviolet B irradiation of platelets to

prevent alloimmunization and refractoriness to platelet

transfusions.The Trial to Reduce Alloimmunization to Platelets

Study Group.N Engl J Med 1997; 337: 1861–1869.

31. Federowicz I, Barrett BB,Andersen JW et al.Characterization of

reactions after transfusion of cellular blood components that are

white cell reduced before storage.Transfusion 1996;36: 21–28.

32. Stack G,Snyder EL.Cytokine generation in stored platelet

concentrates.Transfusion 1994;34: 20–25.

33. Kluter H, Bubel S, Kirchner H,Wilhelm D. Febrile and allergictransfusion reactions after the transfusion of white cell-poor

platelet preparations.Transfusion 1999;39: 1179–1184.

34. Domen RE.Adverse reactions associated with autologous blood

transfusion: evaluation and incidence at a large academic hospital.

Transfusion 1998; 38: 296–300.

35. Wilhelm D, Kluter H,Klouche M, Kirchner H. Impact of allergy

screening for blood donors: relationship to nonhemolytic

transfusion reactions.Vox Sang 1995;69: 217–221.

36. Stern A, van Hage-Hamsten M, Sondell K, Johansson SG. Is allergy

screening of blood donors necessary? A comparison between

questionnaire answers and the presence of circulating IgE

antibodies.Vox Sang 1995; 69: 114–119.

37. Sharon R, Kidroni G,Michel J. Presence of aspirin in blood units.

Vox Sang 1980;38: 284–287.

38. Buck SA, Kickler TS,McGuire M,Braine HG,Ness PM.The utility of

platelet washing using an automated procedure for severe platelet

allergic reactions.Transfusion 1987;27: 391–393.

39. Davenport RD, Burnie KL, Barr RM.Transfusion management of

patients with IgA deficiency and anti-IgA during liver

transplantation.Vox Sang 1992; 63: 247–250.

40. Nicholls A. Ethylene oxide and anaphylaxis during haemodialysis. Br

Med J (Clin Res Ed) 1986; 292: 1221–1222.

41. Ryden SE,Oberman HA.Compatibility of common intravenous

solutions with CPD blood.Transfusion 1975;15: 250–255.

42. Staples PJ, Griner PF. Extracorporeal hemolysis of blood in a

microwave blood warmer. N Engl J Med 1971;285: 317–319.

43. Beauregard P, Blajchman MA. Hemolytic and pseudo-hemolytic

transfusion reactions:an overview of the hemolytic transfusion

reactions and the clinical conditions that mimic them.Transfus Med

Rev 1994;8: 184–199.

44. Moss G,Staunton C.Needles and hemolysis.N Engl J Med 1970;

283:598.

45. Mollison PL, Engelfriet CP, Contreras M. Blood transfusion in

clinical medicine (10th ed). Oxford [UK];Malden,MA,USA:

Blackwell Science; 1997.

46. Ma SK,Wong KF, Siu L. Hemoglobinemia and hemoglobinuria

complicating concomitant use of a white cell filter and a pressure

infusion device.Transfusion 1995; 35: 180.

47. Blajchman MA. Reducing the risk of bacterial contamination of

cellular blood components.Dev Biol Stand 2000; 102: 183–193.

Perrotta and Snyder


8/9/2019 1-s2.0-S0268960X01901511-main

13/15

48. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J

Med 1991;324:169–174.

49. Meryman HT, Hornblower M.A method for freezing and washing

red blood cells using a high glycerol concentration.Transfusion

1972; 12: 145–156.

50. Capon SM, Goldfinger D.Acute hemolytic transfusion reaction,a

paradigm of the systemic inflammatory response:new insights intopathophysiology and treatment.Transfusion 1995;35: 513–520.

51. Morrison FS, Mollison PL. Post-transfusion purpura.N Engl J Med

1966; 275:243–248.

52. Waters AH. Post-transfusion purpura.Blood Rev 1989;3: 83–87.

53. Taaning E, Svejgaard A.Post-transfusion purpura: a survey of 12

Danish cases with special reference to immunoglobulin G

subclasses of the platelet antibodies.Transfus Med 1994;4: 1–8.

54. Mueller-Eckhardt C, Lechner K, Heinrich D et al. Post-transfusion

thrombocytopenic purpura: immunological and clinical

studies in two cases and review of the literature. Blut 1980;40:

249–257.

55. Pegels JG,Bruynes EC,Engelfriet CP, von dem Borne AE.Post-

transfusion purpura:a serological and immunochemical study. Br JHaematol 1981;49: 521–530.

56. Chapman JF, Murphy MF, Berney SI et al. Post-transfusion purpura

associated with anti-Baka and anti-PIA2 platelet antibodies and

delayed haemolytic transfusion reaction.Vox Sang 1987; 52:

313–317.

57. Kroll H, Kiefel V, Mueller-Eckhardt C. [Post-transfusion purpura:

clinical and immunologic studies in 38 patients]. Infusionsther

Transfusionmed 1993; 20: 198–204.

58. Zeigler Z,Murphy S, Gardner FH. Post-transfusion purpura: a

heterogeneous syndrome.Blood 1975;45: 529–536.

59. Dainer PM, Canada ED.Post-transfusion purpura and multiple

transfusions. Br Med J 1977; 2: 999.

60. Taaning E,Tonnesen F. Pan-reactive platelet antibodies in post-

transfusion purpura.Vox Sang 1999;76: 120–123.

61. Mueller-Eckhardt C, Kiefel V. High-dose IgG for post-transfusion

purpura-revisited. Blut 1988;57: 163–167.

62. Becker T, Panzer S, Maas D et al. High-dose intravenous

immunoglobulin for post-transfusion purpura.Br J Haematol 1985;

61: 149–155.

63. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous

immunoglobulin in immune thrombocytopenia.Lancet 1983;2:

193–195.

64. Yu Z, Lennon VA. Mechanism of intravenous immune globulin

therapy in antibody-mediated autoimmune diseases.N Engl J Med

1999; 340:227–228.

65. Cimo PL,Aster RH. Post-transfusion purpura: successful treatment

by exchange transfusion.N Engl J Med 1972; 287: 290–292.

66. Cunningham CC, Lind SE.Apparent response of refractory post-

transfusion purpura to splenectomy.Am J Hematol 1989; 30:

112–113.

67. Vogelsang G, Kickler TS, Bell WR.Post-transfusion purpura: a

report of five patients and a review of the pathogenesis and

management.Am J Hematol 1986;21: 259–267.

68. Kekomaki R, Elfenbein G, Gardner R et al. Improved response of

patients refractory to random-donor platelet transfusions by

intravenous gamma globulin.Am J Med 1984; 76: 199–203.

69. Gabriel A, Lassnigg A, Kurz M, Panzer S. Post-transfusion purpura

due to HPA-Ia immunization in a male patient: response to

subsequent multiple HPA-Ia-incompatible red-cell transfusions.

Transfus Med 1995; 5: 131–134.

70. Win N,Peterkin MA,Watson WH.The therapeutic value of HPA-Ia-

negative platelet transfusion in post-transfusion purpura complicated

by life-threatening haemorrhage.Vox Sang 1995;69:138–139.

71. Brecher ME, Moore SB, Letendre L.Posttransfusion purpura: the

therapeutic value of P1A1-negative platelets.Transfusion 1990; 30:

433–435.

72. Hebert PC,Wells G, Blajchman MA et al.A multicenter,randomized, controlled clinical trial of transfusion requirements in

critical care.Transfusion Requirements in Critical Care

Investigators,Canadian Critical Care Trials Group.N Engl J Med

1999; 340:409–417.

73. Couriel D,Weinstein R. Complications of therapeutic plasma

exchange:a recent assessment. J Clin Apheresis 1994; 9: 1–5.

74. Ley TJ, Griffith P, Nienhuis AW.Transfusion haemosiderosis and

chelation therapy. Clin Haematol 1982; 11: 437–464.

75. Marcus RE, Huehns ER.Transfusional iron overload.Clin Lab

Haematol 1985; 7: 195–212.

76. Breuer W, Ronson A,Slotki IN et al.The assessment of serum

nontransferrin-bound iron in chelation therapy and iron

supplementation.Blood 2000;95: 2975–2982.77. Harmatz P, Butensky E, Quirolo K et al. Severity of iron overload in

patients with sickle cell disease receiving chronic red blood cell

transfusion therapy. Blood 2000;96: 76–79.

78. Loebstein R,Lehotay DC,Luo X et al. Diabetic nephropathy in

hypertransfused patients with beta-thalassemia.The role of

oxidative stress. Diabetes Care 1998; 21: 1306–1309.

79. Cunningham-Rundles S,Giardina PJ, Grady RW et al. Effect of

transfusional iron overload on immune response. J Infect Dis 2000;

182 Suppl 1: S115–121.

80. Propper RD, Cooper B, Rufo RR et al. Continuous subcutaneous

administration of deferoxamine in patients with iron overload. N

Engl J Med 1977; 297: 418–423.

81. Wolfe L,Olivieri N, Sallan D et al. Prevention of cardiac disease by

subcutaneous deferoxamine in patients with thalassemia major. N

Engl J Med 1985; 312: 1600–1603.

82. Maurer HS, Lloyd-Still JD,Ingrisano C, Gonzalez-Crussi F, Honig

GR.A prospective evaluation of iron chelation therapy in children

with severe beta-thalassemia.A six-year study.Am J Dis Child

1988; 142:287–292.

83. Kersten MJ, Lange R, Smeets ME et al.Long-term treatment of

transfusional iron overload with the oral iron chelator deferiprone

(L1): a Dutch multicenter trial.Ann Hematol 1996; 73: 247–252.

84. Hoffbrand AV, F AL-R, Davis B et al. Long-term trial of deferiprone

in 51 transfusion-dependent iron overloaded patients.Blood 1998;

91: 295–300.

85. Ware RE,Zimmerman SA, Schultz WH.Hydroxyurea as an

alternative to blood transfusions for the prevention of recurrent

stroke in children with sickle cell disease.Blood 1999;94: 3022–3026.

86. Lichtman SM,Attivissimo L, Goldman IS, Schuster MW, Buchbinder

A. Secondary hemochromatosis as a long-term complication of the

treatment of hematologic malignancies.Am J Hematol 1999; 61:

262–264.

87. Singer ST, Quirolo K, Nishi K et al. Erythrocytapheresis for

chronically transfused children with sickle cell disease: an effective

method for maintaining a low hemoglobin S level and reducing iron

overload. J Clin Apheresis 1999; 14: 122–125.

88. Adams DM, Schultz WH,Ware RE,Kinney TR.Erythrocytapheresis

can reduce iron overload and prevent the need for chelation

therapy in chronically transfused pediatric patients. J Pediatr

Hematol Oncol 1996;18: 46–50.



8/9/2019 1-s2.0-S0268960X01901511-main

14/15

8/9/2019 1-s2.0-S0268960X01901511-main

15/15

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

sepsis after prolonged platelet storage.Am J Med 1986; 81:

405–411.

129. Engelfriet CP, Reesink HW, Blajchman MA et al.Bacterial

contamination of blood components.Vox Sang 2000;78: 59–67.

130. Lozano M, Escolar G, Mazzara R et al. Effects of the addition of

second-messenger effectors to platelet concentrates separatedfrom whole-blood donations and stored at 4 degrees C or -80

degrees C.Transfusion 2000; 40: 527–534.

131. Burstain JM,Brecher ME,Workman K et al.Rapid identification

of bacterially contaminated platelets using reagent strips: glucose

and pH analysis as markers of bacterial metabolism.Transfusion

1997; 37:255–258.

132. Liu HW,Yuen KY, Cheng TS et al.Reduction of platelet

transfusion-associated sepsis by short-term bacterial culture.

Vox Sang 1999;77: 1–5.

133. Lin L, Londe H, Janda JM, Hanson CV, Corash L. Photochemical

inactivation of pathogenic bacteria in human platelet

concentrates.Blood 1994;83: 2698–2706.

134. Corash L. Inactivation of viruses, bacteria,protozoa andleukocytes in platelet and red cell concentrates.Vox Sang 2000;

78:205–210.

135. Goodrich RP.The use of riboflavin for the inactivation of

pathogens in blood products.Vox Sang 2000;78: 211–215.

136. Chiu EK,Yuen KY, Lie AK et al.A prospective study of

symptomatic bacteremia following platelet transfusion and of its

management.Transfusion 1994; 34: 950–954.

137. Yasuura K, Okamoto H,Matsuura A.Transfusion-associated

graft-versus-host disease with transfusion practice in cardiac

surgery. J Cardiovasc Surg (Torino) 2000;41: 377–380.

138. Ohto H,Anderson KC.Survey of transfusion-associated graft-

versus-host disease in immunocompetent recipients.Transfus

Med Rev 1996;10: 31–43.

139. Vogelsang GB,Hess AD. Graft-versus-host disease: new

directions for a persistent problem. Blood 1994; 84: 2061–2067.

140. Tanei R,Ohta Y, Ishihara S et al.Transfusion-associated graft-

versus-host disease: an in situ hybridization analysis of the

infiltrating donor-derived cells in the cutaneous lesion.

Dermatology 1999;199: 20–24.

141. Yasukawa M. [Treatment of transfusion-associated graft-versus-

host disease]. Nippon Rinsho 1997;55: 2290–2295.

142. Sakurai M, Moizumi Y, Uchida S, Imai Y,Tabayashi K.Transfusion-

associated graft-versus-host disease in immunocompetent

patient: early diagnosis and therapy.Am J Hematol 1998; 58:

84–86.

143. Saigo K,Ryo R.Therapeutic strategy for post-transfusion graft-

vs.-host disease. Int J Hematol 1999;69: 147–151.

144. Nishimura M,Uchida S,Mitsunaga S et al.Characterization of T-

cell clones derived from peripheral blood lymphocytes of a

patient with transfusion-associated graft-versus-host disease:

Fas-mediated killing by CD4+ and CD8+ cytotoxic T-cell clones

and tumor necrosis factor beta production by CD4+ T-cell

clones. Blood 1997; 89:1440–1445.

145. Williamson LM,Warwick RM.Transfusion-associated graft-versus-host disease and its prevention. Blood Rev 1995; 9: 251–261.

146. Grishaber JE,Birney SM,Strauss RG. Potential for transfusion-

associated graft-versus-host disease due to apheresis platelets

matched for HLA class I antigens.Transfusion 1993;33: 910–914.

147. Butson MJ,Yu PK,Cheung T et al.Dosimetry of blood irradiation

with radiochromic film.Transfus Med 1999;9: 205–208.

148. Akahoshi M,Takanashi M,Masuda M et al.A case of transfusion-

associated graft-versus-host disease not prevented by white cell-

reduction filters.Transfusion 1992; 32: 169–172.

149. Grass JA,Wafa T, Reames A et al. Prevention of transfusion-

associated graft-versus-host disease by photochemical

treatment. Blood 1999; 93:3140–3147.

150. Philipps E, Fleischner FG. Pulomonary edema in the course of ablood transfusion without overloading the circulation.Dis Chest

1966; 50: 619–623.

151. Popovsky MA,Moore SB. Diagnostic and pathogenetic

considerations in transfusion-related acute lung injury.

Transfusion 1985; 25: 573–577.

152. Popovsky MA,Chaplin HC,Moore SB.Transfusion-related acute

lung injury: a neglected, serious complication of hemotherapy.

Transfusion 1992; 32: 589–592.

153. Silliman CC.Transfusion-related acute lung injury.Transfus Med

Rev 1999;13: 177–186.

154. Seeger W, Schneider U,Kreusler B et al.Reproduction of

transfusion-related acute lung injury in an ex vivo lung model.

Blood 1990; 76: 1438–1444.

155. Dry SM,Bechard KM, Milford EL,Churchill WH, Benjamin RJ.

The pathology of transfusion-related acute lung injury.Am J Clin

Pathol 1999; 112:216–221.

156. Silliman CC,Voelkel NF,Allard JD et al. Plasma and lipids from

stored packed red blood cells cause acute lung injury in an

animal model. J Clin Invest 1998; 101: 1458–1467.

157. Ramanathan RK,Triulzi DJ, Logan TF.Transfusion-related acute

lung injury following random donor platelet transfusion: a report

of two cases.Vox Sang 1997; 73: 43–45.

158. Densmore TL, Goodnough LT,Ali S,Dynis M,Chaplin H.

Prevalence of HLA sensitization in female apheresis donors.

Transfusion 1999; 39: 103–106.

159. Sazama K. Reports of 355 transfusion-associated deaths: 1976

through 1985.Transfusion 1990;30: 583–590.


83 2001 Harcourt Publishers Ltd Blood Reviews (2001) 15 69–83

1-s2.0-S0268960X01901511-main

Documents

Transcript of 1-s2.0-S0268960X01901511-main