Transfusion Reactions

Alvin A. Aldea

Introduction

Definition of Transfusion Reaction

A transfusion reaction is defined as any transfusion-related adverse event that occurs during or
after the transfusion of whole blood, blood components, or human-derived plasma products (Ruediger &
Lopez-Plaza, 2012).

Recognition, Evaluation, and Resolution of Transfusion Reaction

Recognition

The initial step involves the transfusionist, and the physician responsible for the patient at the
time of transfusion (Ruediger & Lopez-Plaza, 2012). Having said that, they must be knowledgeable on the
different signs and symptoms of various complications of transfusion of blood and blood products
(Mazzei, Popovsky, & Kopko, 2014). The following are some of the signs and symptoms to be considered,
to wit:

• Fever, generally defined as a greater than or equal to 1 C rise in temperature above 37 C [the most
common sign of an acute HTR (AHTR)].
• Chills with or without rigors.
• Respiratory distress, including wheezing, coughing, and dyspnea.
• Hyper- or hypotension.
• Abdominal, chest, flank, or back pain.
• Pain at the infusion site.
• Skin manifestations, including urticaria, rash, flushing, pruritus, and localized edema.
• Jaundice or hemoglobinuria.
• Nausea/vomiting.
• Abnormal bleeding.
• Oliguria/anuria.

Clinical Evaluation and Management of a Transfusion Reaction

The evaluation and management of transfusion reaction in a patient involves a two-pronged

investigation combining clinical evaluation of the patient with laboratory verification and testing (Mazzei,
Popovsky, & Kopko, 2014; Ruediger & Lopez-Plaza, 2012). The two areas must coordinate with each other
to ensure the optimum recovery of the patient. The steps involved are the following:

• At the Bed Side:

1. Stop the transfusion immediately but keep the line open with saline.
2. Document the clerical recheck between the patient and the component. The labels on the
component, patient records, and patient identification should be examined to detect any
identification errors. Transfusing facilities may require repeat ABO and Rh typing of the
patient using a new sample.
3. Contact the treating physician immediately for instructions on patient care.
 • Transfusion Service Department Involvement:
1. Contact the transfusion service for directions on investigating the cause of the AHTR.
Most transfusion services use a standardized form to document all of the information
available on both the patient and the component.
2. Obtain instructions concerning the return of any remaining component, associated
intravenous fluid bags, and tubing.
3. Identify appropriate samples (blood and urine) to send to the laboratory.

Standard Laboratory Investigation

1. Clerical check of the component bag, label, paper work, and patient sample.
2. Repeat ABO testing on the posttransfusion sample.
3. Visual check of pre- and posttransfusion samples to look for evidence of hemolysis (which may
not be visible if <50 mg/dL of hemoglobin is present).
4. Direct antiglobulin test (DAT) on a posttransfusion sample.
5. Report of findings to the blood bank supervisor or medical director, who may request additional
studies, tests, or quarantine of cocomponents generated from the same donor collection.

In addition to the steps mentioned above, the transfusion service must also retain records of the
patient vis-à-vis to transfusion reaction such as, but not limited to, clinically significant antibodies, or

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special transfusion requirements. Also included are information about special products previously
transfused to the patient (e.g., irradiated or washed components), if any.

Basic Immunohematologic Check on a Post-Transfusion Sample

Initial Check

Initial check on a posttransfusion sample involves the following (Price, 2009). First, a clerical
verification must be performed to check that the information in the post-reaction sample, transfusion
documentation and in the blood bag matches. If it matches, then there is no discrepancy in the clerical
part; but, if there is an anomaly or mismatch, necessary steps must be performed like notifying the
physician, follow up the other patient involved (if any), and/or perform secondary testing if requested.
Second, a visual hemolysis test should be done. If there is hemolysis present, request for a redraw and
examine the same. The redraw serves as a check whether the previous sample’s hemolysis is due to
transfusion reaction or due to error in phlebotomy. If the redraw shows signs of hemolysis, notify the
physician and do appropriated secondary testing if requested. Third, perform DAT to verify if there is a
coating of antibody to RBC in vivo. Whatever the results are, notify the physician and do the necessary
follow up test if requested. Last is the performance of repeat ABO testing. If there is a discrepancy on the
result, request for a redraw and re test. If the redraw and the previous sample show the same result,
notify the physician; if not, do follow up tests if requested.

Secondary Check

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 Secondary follow up steps may be performed to further identify the cause of the transfusion
reaction (Ruediger & Lopez-Plaza, 2012). It can be performed upon the request of the attending physician.

Acute Transfusion Reactions

Acute Transfusion Reaction is defined as a reaction in which signs and symptoms present during
or within 24 hours of a transfusion (Ruediger & Lopez-Plaza, 2012). Most can be grouped according to the
common etiology that gives similar presenting signs and symptoms. Acute transfusion reactions include
hemolysis, both immune and nonimmune mediated; transfusion-related sepsis; TRALI; severe allergic
reactions, including anaphylaxis; TACO; complications of massive transfusion; air embolism; febrile
nonhemolytic transfusion reactions (FNHTRs); and mild allergic reactions, such as urticaria or rash.

Acute Hemolytic Transfusion Reaction

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Definition

Acute hemolytic transfusion reaction (AHTR) consists of acute hemolysis with accompanying
presenting symptoms within 24 hours of transfusion (Ruediger & Lopez-Plaza, 2012). Etiology may be of
immune or nonimmune origin.

Presentation

In the immune mediated acute hemolytic transfusion reaction, accompanying signs and
symptoms include abdominal, chest, flank, or back pain; pain at infusion site; feeling of impending doom;
hemoglobinemia; hemoglobinuria; hypotension; renal failure; shock; and diffuse intravascular
coagulopathy (Ruediger & Lopez-Plaza, 2012). Red or dark urine or diffuse oozing may be the only sign in
the anesthetized patient.

Nonimmune hemolysis most frequently presents as asymptomatic hemoglobinuria, although it

has been occasionally associated with renal dysfunction, and rare related death has been reported
(Davenport, 2002).

Incidence

The incidence of AHTR in clinical practice has never been precisely determined. Historic studies
have estimated their occurrence to be from 1 in 10,000 to 1 in 50,000 transfused blood components
(Pineda, Brzics, & Taswell, Hemolytic transfusion reactions: recent experience in a large blood bank, 1978;
Lichtiger & Perry-Thorton, 1984). Also, other literature came up with 1 in 40,000 AHTR: 1 in 76,000 and 1
in 1.8 million in Fatal HTR (Mazzei, Popovsky, & Kopko, 2014).

In the Philippines, there is no centralized data for cases of transfusion reaction. However, there
are studies that give estimates per case. In one study, of 18 cases of transfusion reactions in a tertiary
hospital, 44% (8) are of hemolytic reactions (Munarriz, Velarde-Afable, Fajardo, & Lo, 1998)

Pathophysiology

Immune AHTR

Previously formed IgM or IgG antibodies in the recipient recognize the corresponding donor red
cell antigens, immune complexes are formed, the complement cascade is activated, vasoactive amines
and inflammatory mediators are released into the plasma, and the coagulation cascade is activated
(Mazzei, Popovsky, & Kopko, 2014). The activated lytic arm (membrane attack complex) of the
complement cascade causes hemoglobinemia and hemoglobinuria, the hallmarks of intravascular
hemolysis. The secreted vasoactive amines and inflammatory mediators are responsible for most of the
systemic symptoms. The activation of the coagulation cascade causes diffuse intravascular coagulopathy
(DIC) and the consequent bleeding. A combination of the vascular collapse and the DIC-initiated end organ
microthrombi contribute to renal failure. Without the completion of the complement cascade, the red
cell undergoes extravascular hemolysis. This is typical of non-ABO antibodies and delayed hemolytic
transfusion reactions.

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 Less frequently, ABO-incompatibility-related acute hemolytic transfusion reaction may be
observed with the transfusion of plasma containing sufficient quantities of isohemagglutinins (by volume
or antibody titers) against the recipient ABO antigens (Fung, Downes, & Shulman, 2007). This syndrome
has been observed with the transfusion of platelets, mainly group O single donor platelets transfused to
a non-O recipient (Josephson, Mullins, & Van Denmark, 2004).Recent studies have shown that whole
blood–derived pooled platelets may contain similar levels of isohemagglutinins (Cooling, Downs, & Butch,
2004).

Non-immune AHTR

Its pathophysiology is independent of the presence of antibodies (Ruediger & Lopez-Plaza, 2012).
It can be caused by chemical damage or mechanical damage such as improper shipping or storage
temperatures; incomplete deglycerolization of frozen red blood cells; needles used for transfusion with
an inappropriately small bore size; rapid pressure infuser or roller pumps; improper use of blood warmers;
concurrent infusion of unapproved fluids via the transfusion line; and bacterial contamination.

Treatment

The first element of therapy of an AHTR is to stop the infusion of the suspected incompatible
blood (Capon & Sacher, Acute hemolytic transfusion reaction, a paradgim of the systemic inflammatory
response: new insights into pathophysiology and treatment, 1995). It also is critical to maintain
intravenous access for the patient, so the intravenous line should not be removed or sent to the laboratory
for evaluation (Mazzei, Popovsky, & Kopko, 2014). In a suspected reaction, emergency measures may
precede definitive confirmation (Sue Shirey, King, & Ness, 2007). The early management should include
careful monitoring of the vital signs, maintenance of the blood pressure and blood volume, and transfer
of the patient to the appropriate acute care setting (most likely an intensive care unit [ICU]) for aggressive
management, if required. An intensive care specialist or a nephrologist or both should be consulted
because dialysis therapy may be required. If AHTR due to ABO compatibility is confirmed, a pulmonary
artery catheter may be critical for monitoring. Aggressive fluid replacement is subsequently administered,
and vasopressors, such as dopamine, are commonly used in an attempt to mitigate renal complications.
Diuretics such as furosemide are commonly administered to maintain urine output along with fluid
support (Capon & Sacher, Hemolytic transfusion reactions: a review of mechanisms, sequalae, and
management, 1989). If renal failure ensues, however, dialysis should be initiated promptly.

In the event that bleeding ensues or the laboratory confirms that DIC has developed, supportive
therapy with platelet concentrates and plasma products may become important. The use of heparin has
been advocated to prevent or reduce the complications of DIC but may be difficult in the face of surgical
bleeding (Rock, Bove , & Nemerson, 1969). The use of protein C concentrates to interrupt DIC should also
be considered, although clinical trial support is obviously lacking (Rivard, David, & Farell, 1995).

The classic clinical descriptions of AHTR did not include the respiratory failure that can occur and
is now more commonly recognized (Sue Shirey, King, & Ness, 2007). Pulmonary function should be
carefully monitored, with oxygen therapy and ventilator support initiated early by the intensive care
specialists. Whether specific inflammatory inhibitors that have been studied for other chronic

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inflammatory states (inhibitors of IL-1 or TNF) would be useful is not known, but their use in severe
situations appears justifiable.

Transfusion-Associated Sepsis

Definition

Transfusion-associated sepsis (TAS) is an acute nonimmune transfusion reaction presenting with

body temperatures usually 2°C or more above normal and rigors that can be accompanied by hypotension
(Ruediger & Lopez-Plaza, 2012).

Presentation

Fever (particularly a temperature of greater than or equal to 38.5 C or 101 F) and shaking chills
and hypotension during or shortly after transfusion are the most frequent presenting symptoms of
transfusion-related sepsis (Mazzei, Popovsky, & Kopko, 2014). In severe cases, the patient may develop
shock with accompanying renal failure and DIC.

Incidence

Like any other cases of non-infectious complications of blood transfusion, there are no centralized
worldwide data of incidence of TAS. However, there are estimates provided per component. In one study,
the TAS cases for RBCs and platelets are 1:250,000 and 1:50,000 (SDP) & 1:25,000 (PPP), respectively
(Ruediger & Lopez-Plaza, 2012; Mazzei, Popovsky, & Kopko, 2014). Concurrently, there are no recorded
data found for the Philippines.

Causes

Skin flora and, less frequently, gut flora associated with transient bacteremia in an asymptomatic
donor are considered the sources of bacterial contamination (Ruediger & Lopez-Plaza, 2012). Bacterial
endotoxins generated during storage may contribute to TAS-related morbidity and mortality. Not
surprisingly, bacterially contaminated platelets are considered the most frequent component causing TAS,
due to room temperature storage requirements. The contamination rate in association with red blood cell
transfusions is related to the inhibition of the growth and viability of most bacteria at the component
storage required temperatures (1°C to 6°C) and thus the lower risk for TAS.

Differential Diagnosis

The signs and symptoms of TAS may be the same with that of AHTRs, which may lead into
confusion (Mazzei, Popovsky, & Kopko, 2014). In accurately diagnosing TAS, the technologist should check
for the visual changes in the returned blood component for any color changes, especially brown or purple
discoloration, and for the presence of bubbles or frothiness in the platelet concentrate. Also, a culture
and Gram-staining should be performed both in the patient sample and in the blood unit for proper
identification of the causative organism.

Treatment

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If transfusion-related sepsis is suspected, the transfusion should be stopped immediately and supportive
care of the patient should be initiated (Mazzei, Popovsky, & Kopko, 2014). Broad-spectrum antibiotics
may be indicated (Ruediger & Lopez-Plaza, 2012).

Prevention

The prevention of TAS lies upon effective prevention of bacterial contamination from the time of
collection and detecting contamination during processing and before the transfusion of blood unit to the
patient (Ruediger & Lopez-Plaza, 2012). At the time of collection, measures could be implemented such
as, but not limited to, checking the history of donor for any infectious disease, proper phlebotomy
technique, single arm collection technique, and the use of diversion pouch (Vamvakas, Relative safety of
pooled whole blood-derived versus single donor platelets in the United States: A systematic review of
disparate risk, 2009). Also, prior to storage, the following steps to prevent TAS may be done: pre-storage
leukoreduction, pathogen inactivation, and automated culture. Furthermore, visual inspection, checking
for biochemical markers, microscopic, and immunoassay may be performed before the transfusion to
serve as a final barrier for prevention of TAS (Fuller, Uglik, & Savage, 2009).

Febrile Nonhemolytic Transfusion Reaction

An FNHTR is usually defined as the occurrence of greater than or equal to 1C rise in temperature
above 37C that is associated with transfusion and for which no other cause is identifiable (Mazzei,
Popovsky, & Kopko, 2014).

Presentation

The symptoms of FNHTR include shakings, chills, increased respiratory rate, blood pressure
change, and anxiety (Mazzei, Popovsky, & Kopko, 2014). In some cases, the patient may be afebrile but
has all the other symptoms stated above. The said symptoms may take place during the transfusion
process but may also occur four hours after. Most cases are benign albeit, may case discomfort and other
cardiac and respiratory complications.

Incidence

For FNHTR, there are no centralized data worldwide; but, in the Canada, the reported incidence
with red cell products ranges from 0.07 to 6.8 reactions per 100 red cell units transfused (Kleinman, Chan,
& Robillard, Risks associated with transfusion of cellular blood components in Canada, 2003). Also, in the
United States, it was reported that the incidence of FNHTR ranges from 0.1 to 1% (Mazzei, Popovsky, &
Kopko, 2014). In the Philippines, meanwhile, there is no unified national data but in one of the studies of
transfusion reactions in the Philippine General Hospital, more than half (61.1%) of reported transfusion
reaction were FNHTR (Opimo, Mirasol, Balatbat, & Melendres, 2002).

Pathophysiology

At least two mechanisms seem to result in the clinical manifestations of FNHTR. The first
mechanism involves the presence of a white cell alloantibody in the patient’s plasma that interacts with
white cells in the blood product (Brittingham & Chaplin, 1957). Both granulocyte and human leukocyte

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antigen (HLA) antibodies have been implicated in these reactions (Mazzei, Popovsky, & Kopko, 2014). This
antigen-antibody interaction causes release of endotoxins that act on the hypothalamus, resulting in fever
and the other symptoms typical of FNHTR. This mechanism appears to be the primary cause of FNHTR
after the transfusion of red cells but accounts for only approximately 9% of platelet reactions (Heddle,
Klama, & Singer, 1994). The second mechanism involves the generation of leukocyte-derived cytokines
during storage of the product. A variety of cytokines have been detected in stored blood products;
however, the proinflammatory cytokines (interleukin [IL]-1, IL-6, IL-8, and tumor necrosis factor [TNF]-α)
are likely to be the predominant cause of FNHTR (Heddle, Klama, & Singer, 1994).

Differential Diagnosis

The diagnosis of FNHTR is one of exclusion (Mazzei, Popovsky, & Kopko, 2014). Other causes of
fever must be excluded, including other acute transfusion reactions that manifest with fever and clinical
comorbidities and/or medications. Sometimes the timing of the reaction may be helpful in the differential
diagnosis. FNHTRs tend to be dependent on the dose or concentration of leukocytes and/or cytokines
infused and therefore appear toward the end of the transfusion (Mazzei, Popovsky, & Kopko, 2014;
Heddle, Blajchman, & Meyer, A randomized controlled trial comparing the frequency of acute reactions
to plasma-removed platelets and prestorage WBC-reduced platelets, 2002; Brittingham & Chaplin, 1957).
It is atypical for this type of reaction to occur during the initial stage of the transfusion. Clinical experience
has also suggested that the rate of infusion is another important variable that may contribute to these
events (Couban, Carruthers, & Andreou, 2002).

Treatment

When an FNHTR is suspected, the transfusion should be discontinued and a transfusion reaction
work-up initiated (Mazzei, Popovsky, & Kopko, 2014). Treatment of FNHTR consists of the administration
of an antipyretic such as acetaminophen. Severe shaking chills (rigors) may necessitate meperidine
administration. These symptoms resolve with or without treatment and do not typically lead to additional
or long-term adverse sequelae. The decision to stop the transfusion requires clinical judgment based on
the severity of the symptoms, the type of product being transfused, the timing of the symptoms in relation
to the amount of product infused, and the history and clinical state of the patient (Heddle & Kelton, 2001).

Prevention

For red cell reactions, the first line of prevention would include either poststorage or prestorage
leukoreduction (Mazzei, Popovsky, & Kopko, 2014). If reactions still occur to leukoreduced products, other
approaches that may be effective include the transfusion of fresher blood products and or washed blood
products. To prevent FNHTR to platelet transfusions, prestorage leukoreduction has been shown to be
the most effective method (Wang, 2012). For patients who still react to the prestorage leukoreduced
product, other options include removing the residual plasma from the platelet product, washing the
product, or selecting fresher products.

Allergic Reactions

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 Most allergic transfusion reactions (ATRs) are mild, but their spectrum can range from a simple
allergic reaction (urticaria) to life-threatening anaphylaxis (Mazzei, Popovsky, & Kopko, 2014).

Presentation

Urticaria or Hives

Mild allergic reactions are characterized by a localized or confluent red raised itching rash
(urticaria) in the absence of fever (Heddle & Webert, 2007). For a reaction to be classified as
uncomplicated urticaria, no additional symptoms must be present, such as asthma-like attacks, coughing,
difficulty in breathing, or other symptoms associated with anaphylactoid or anaphylactic reactions
(Vamvakas & Pineda, 2001; Perrotta & Snyder, 2001).

Anaphylaxis /Anaphylactoid

Anaphylactic transfusion reactions are severe systemic reactions characterized by hypotension,

bronchospasm or dyspnea, nausea, vomiting, diarrhea, and urticaria (Vamvakas & Pineda, Allergic and
anaphylactic reactions, 2001). The most serious symptoms include lower airway obstruction, laryngeal
edema, and hypotension. Typically, these reactions appear after a small volume (<10 mL) of product has
been infused (Mazzei, Popovsky, & Kopko, 2014; Vamvakas & Pineda, 2001).

Incidence

Several studies have reported that mild allergic reactions occur with approximately 3% of all blood
products transfused (Stephen, Martin, & Bourgeois-Gavardin, 1955; Pineda & Taswell, 1975; Kevy,
Schmidt, & McGinniss, 1962). Other studies report that the incidences of urticarial and anaphylactic
transfusion reactions are 1:100-1:33 (1%-3%) and 1:20,000-1:50,000, respectively (Mazzei, Popovsky, &
Kopko, 2014). The reported frequency of reactions to platelet transfusions has varied from 0.02% to 7.6%
(Heddle, Blajchman, & Meyer, 2002). In the Philippines there is a study reported that there were 2/18
(14%) cases of urticarial reaction (Munarriz, Velarde-Afable, Fajardo, & Lo, 1998).

Pathophysiology

Urticaria or Hives

Urticarial reactions presumably occur as a result of cutaneous hypersensitivity in which the

recipient has been previously sensitized to soluble allergens found in the donor unit (Vamvakas & Pineda,
Allergic and anaphylactic reactions, 2001). The soluble antigen in the donor plasma is bound to
immunoglobulinE (IgE) on mast cells, which causes the release of histamine and the cutaneous symptoms
typically observed. It is important to note that most allergic reactions appear as a spectrum and that
reactions that begin as urticaria may develop into anaphylactoid or anaphylactic reactions, although this
is rare (Heddle & Webert, 2007).

Anaphylactic/Anaphylactoid

Anaphylactic reactions are most commonly due to preformed, class-specific, recipient anti-IgA to
infused donor IgA proteins in patients with IgA deficiency (Pineda & Taswell, 1975). However, other case

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reports have linked anaphylactic reaction to HLA-associated antibodies in platelet transfusion, anti-C4 in
a C4- deficient patient, and antihaptoglobin in an ahaptoglobinemic patient (Take, Tamura, & Sawamura,
1993; Lambin, Le Pennec, & Hauptmann, 1984; Morishita, Shimada, & Watanabe, 2000).

Diagnosis

Urticaria of Hives

Diagnosis of skin-restricted allergy is straightforward and requires recognition of a rash with

associated itching but without additional symptoms (Heddle & Webert, 2007). As soluble plasma antigens
are the cause of these reactions, the reactions tend to be dose dependent, occurring later in the
transfusion. The rash resolves when the transfusion is stopped and/or an antihistamine is given.

Anaphylaxis

Anaphylaxis/anaphylactoid reactions should be recognized immediately when a patient has the

symptoms mentioned above (Mazzei, Popovsky, & Kopko, 2014). When anaphylaxis related to blood
transfusion is suspected, administration of any additional plasma-containing blood product should be
avoided, if possible, until an appropriate diagnostic evaluation can be performed. Differential diagnosis of
transfusion-related anaphylaxis includes hypotensive reactions occurring in patients taking angiotensin-
converting enzyme (ACE) inhibitors, TRALI, and other events unrelated to transfusion, including
myocardial infarction or pulmonary embolus (Vamvakas & Pineda, 2001). When anaphylaxis occurs in
association with blood transfusion, IgA deficiency with concomitant anti-IgA must be investigated. For a
firm diagnosis, this requires demonstration of recipient anti- IgA (Pineda & Taswell, 1975).

The initial investigation may include nephelometry for the detection of IgA (Ruediger & Lopez-
Plaza, 2012). Demonstration of IgA by this method effectively negates a diagnosis of anaphylaxis related
to anti-IgA. If IgA is not detected, additional studies should be performed because some patients have IgA
levels that are below the limit of detection by nephelometry. To detect anti-IgA in these cases, passive
hemagglutination assays (PHAs) utilizing IgA-coated red blood cells are performed. Most often, the IgA
used to coat these red blood cells is from patients with multiple myeloma whose monoclonal protein is
IgA (Pineda & Taswell, 1975).

Treatment

Urticaria

Treatment for uncomplicated urticaria requires temporary discontinuation of the blood-product

infusion and administration of an antihistamine (Ruediger & Lopez-Plaza, 2012). If the symptoms resolve,
the transfusion may be resumed, and a formal transfusion reaction assessment is not required (Mazzei,
Popovsky, & Kopko, 2014). If the symptoms do not resolve or if they progress during treatment or on
continuance of the transfusion, the transfusion should be stopped and a new unit obtained (Vamvakas &
Pineda, 2001).

Anaphylaxis

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 In addition to immediate discontinuation of product infusion, treatment of anaphylaxis includes
prompt administration of epinephrine, which will quickly reverse the action of histamine (Mazzei,
Popovsky, & Kopko, 2014). Other supportive care may include vasopressors and airway support.
Intravenous steroids and an H1- receptor antagonist can be given to reduce the risk of protracted
anaphylaxis (Vamvakas & Pineda, 2001; Perrotta & Snyder, 2001).

Prevention

Urticaria

Premedication with an antihistamine will prevent urticarial reactions in most patients who have
a history of allergic reactions (Mazzei, Popovsky, & Kopko, 2014). If premedication is not effective or if
repeated reactions of increasing severity occur, washed cellular products may be beneficial.

Anaphylaxis

Prevention of anaphylactic reactions in patients who are determined to be IgA deficient with anti-
IgA antibodies requires avoidance of transfusion with plasma-containing IgA (Mazzei, Popovsky, & Kopko,
2014). Cellular products can be washed to remove the residual plasma containing IgA, or products can be
collected from donors who are known to be IgA deficient (Sandler, Eckrich, & Malamut, 1994). When red
cells are required, autologous donation and frozen blood may also be feasible options (Mazzei, Popovsky,
& Kopko, 2014).

Transfusion-Related Acute Lung Injury (TRALI)

Definition

Transfusion-related acute lung injury (TRALI) consists of an acute transfusion reaction presenting
with respiratory distress and severe hypoxemia during or within 6 hours of transfusion in the absence of
other causes of acute lung injury (e.g., aspiration, pneumonia, toxic inhalation, lung contusion, near
drowning, severe sepsis, shock, multiple trauma, burn injury, acute pancreatitis, cardiopulmonary bypass,
drug overdose) (Popovsky, Tranfusion associated circulatory overload: The plot thickens, 2009; Goldman,
Webert, & Arnold, Towards understandinf of TRALI, 2005).

Presentation

Clinical signs and symptoms of TRALI typically include fever, chills, dyspnea, cyanosis,
hypotension, and new-onset bilateral pulmonary edema (Popovsky & Haley, 2000). An increase in blood
pressure followed by hypotension is not uncommon. TRALI can be life threatening or fatal. Symptoms
arise within 6 hours of transfusion, with most cases becoming evident within 1 to 2 hours after the end of
transfusion to the signs and symptoms traditionally associated with TRALI, there is a growing appreciation
that the disorder can be associated with a dramatic transient neutropenia or leukopenia (Nakagawa &
Toy, 2004).

Incidence

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 The incidence of TRALI is not well defined but has been estimated to occur between 0.014% and
0.08% per allogeneic blood product unit transfused or 0.04% to 0.16% per patient transfused (Popovsky
& Moore, 2001; Silliman, Boshkov, & Mehdizadehkasi, 2003). One study, reported that it is the leading
cause of transfusion related mortality reported to the FDA, with more than 34 cases in 2007 (Li, Daniels,
& Kojicic, 2009). Furthermore, the incidence rates for various blood products vary widely, with estimates
ranging from 1 in 432 to 1 in 88,000 per unit of whole blood platelets, 1 in 1224 per unit of apheresis
platelets, 1 in 4000 to 1 in 557,000 per unit of red blood cells (RBCs), and 1 in 7896 to 1 in 74,000 per unit
of fresh frozen plasma (FFP) transfused (Kleinman, Caufield, & Chan, 2004; Goldman, Webert, & Arnold,
2005). Meanwhile, do centralized data are available for the Philippines.

Pathophysiology

The precise mechanism of lung injury in TRALI has not been determined. TRALI has been
associated with the infusion of antibodies to leukocyte antigens and of biologic response modifiers (BRMs)
(Popovsky & Moore, 1985). Infusions of these antibodies or BRMs are thought to initiate a sequence of
events that results in cellular activation and damage of the basement membrane. Pulmonary edema
occurs secondary to leakage of protein-rich fluid into the alveolar space.

Antibodies to HLA Class I antigens, HLA Class II antigens, and human neutrophil antigens (HNAs)
have been associated with TRALI (Mazzei, Popovsky, & Kopko, 2014). These antibodies can be formed
after exposure to foreign antigens via pregnancy, transfusion, or transplantation. In the majority of TRALI
cases with antibodies, the source of the antibody is the donor, not the recipient.

A two-event model of the mechanism of TRALI has been hypothesized (Silliman, Boshkov, &
Mehdizadehkasi, 2003). In the first event, generation of biologically active compounds activates
pulmonary vascular endothelial cells and primes neutrophils, resulting in sequestration of neutrophils in
the pulmonary microvasculature. This first event can result from a variety of physiologic stressors,
including sepsis, surgery, and massive transfusion, and it predisposes the recipient to develop TRALI if a
second event is experienced. The infusion of BRMs or antibodies is the second event. These stimuli, which
ordinarily do not activate neutrophils, activate the primed neutrophils in the pulmonary microvasculature,
which results in pulmonary endothelial damage, capillary leakage, and pulmonary edema.

Differential Diagnosis

The initial diagnosis of TRALI should be suspected if a blood-product recipient has appropriate
clinical findings (acute onset of hypoxemia, as demonstrated by a ratio of Pao2/Fio2 less than 300 mm Hg
or an oxygen saturation less than or equal to 90% on room air with no evidence of circulatory overload)
within 6 hours of a transfusion, together with the exclusion of other causes of pulmonary edema (Webert,
Kleinman, & Blajchman, 2007). The clinical findings should be corroborated with a radiograph of the chest
demonstrating bilateral infiltrates. It is particularly important to exclude pulmonary edema secondary to
cardiac causes, or volume overload, as these latter conditions are managed very differently from TRALI. It
has been suggested that the determination of brain-derived natriuretic peptide (BNP) levels may help to
differentiate TRALI and the volume overload observed in congestive heart failure (CHF), as elevated levels
of BNP are highly predictive of CHF (Sachs, Hattar, & Weissnan, 2005).

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 After the urgent management of the TRALI patient, laboratory investigations may be performed
to gather information to support the antibody-mediated mechanism of TRALI. In the majority of cases in
most published series, the donor plasma has been found to contain anti-HLA or antineutrophil antibodies
or both (Popovsky, Chaplin, & Moore, 1992). Rarely, the recipient may be shown to have antibodies
reactive with antigens on donor neutrophils (Popovsky, Chaplin, & Moore, 1992). As the diagnosis of TRALI
in the past has typically required the presence of recipient-specific antibodies in the donor plasma, TRALI
cases not associated with alloantibodies may have been underdiagnosed. Although not required for the
diagnosis of TRALI, investigation of associated donors for the presence of anti-HLA class I and class II and
antineutrophil antibodies may be performed to guide donor management (Webert, Kleinman, &
Blajchman, 2007).

Treatment

The treatment of TRALI is primarily supportive (Mazzei, Popovsky, & Kopko, 2014). The patient’s
hemodynamic status should be maintained. Ventilatory supportive care may be required, which may
include oxygenation, intubation, and even mechanical ventilation.

Prevention

Plasma products and whole blood collected for transfusion should be from male donors, never-
pregnant female donors, or females who have been tested since their last pregnancy and found to be
negative for HLA antibodies (Levitt, 2014).

Transfusion-Associated Circulatory Overload (TACO)

Definition

Ruediger & Lopez-Plaza (2012) defined TACO as “Transfusion-associated circulatory overload

(TACO) is an acute, nonimmune complication of transfusion presenting with respiratory distress and
hypoxemia that can be accompanied by cough, headache, chest tightness, hypertension, jugular vein
distention, elevated central venous pressure, and elevated pulmonary wedge pressure during or after
transfusion.”

Presentation

Symptoms and signs of TACO include dyspnea that worsens as pulmonary edema progresses,
orthopnea, chest tightness, cough, tachycardia, hypertension, and widened pulse pressure. TACO
generally occurs near the end of administration of the transfusion or within 6 hours of completion (Mazzei,
Popovsky, & Kopko, 2014).

Incidence

The frequency of circulatory overload depends on the patient population being transfused and
the blood product being given; however, in one study, it has been estimated to TACO in 1:707 recipients
of RBCs, and 20% of the affected patients received a single unit of RBCs. In studies of older orthopedic
patients undergoing hip or knee replacement, TACO was found in 1% and 8%, respectively (Popovsky,
Audet, & Andrzejewski, 1996; Bierbaum, Callaghan, & Galante, 1999).Patients at higher risk for TACO

Page 13 of 26
include elderly patients, patients of small stature, patients with compromised cardiac function, and small
children (Mazzei, Popovsky, & Kopko, 2014). Meanwhile, no centralized data nor study was found for the
case of the Philippines.

Pathophysiology

When the infusion volume is too high that what the circulatory system of the patient can
accommodate, especially in patients with heart problems, elderly, and children, pulmonary edema can
occur (Mazzei, Popovsky, & Kopko, 2014).

Diagnosis

TACO is frequently confused with TRALI when it comes to diagnosis but it is important to note
that that in TACO, the event of hypotension is constant throughout the episode. In some cases, especially
in those patients with congestive heart failure, the brain natriuretic peptide (BNP) level is elevated (Zhou,
Giacherion, & Cooling, 2005). However, recent studies show that BNP is mediocre measure when it comes
to distinguishing TACO from TRALI (Li, Daniels, & Kojicic, 2009). Moreover, the physical examination will
reveal the patient to have an elevated jugular venous pulse. Auscultation of the chest will suggest
pulmonary congestion with rales and crackles (Perrotta & Snyder, 2001).

Treatment

As soon as symptoms suggest TACO, the transfusion should be stopped (Ruediger & Lopez-Plaza,
2012). The symptoms should be treated by placing the patient in a seated position, providing
supplementary oxygen, and reducing the intravascular volume with diuretics. If symptoms persist in
confirmed TACO, administration of additional diuretics or therapeutic phlebotomy in 250-mL increments
is appropriate (Mazzei, Popovsky, & Kopko, 2014).

Prevention

In general, blood products may routinely be transfused at a rate of 2.0 to 4.0 mL/kg/hr (Mazzei,
Popovsky, & Kopko, 2014). However, in patients with a previous history of TACO or who are thought to
be at an increased risk of TACO (i.e., the elderly, those with poor cardiac function, small infants), this rate
should be decreased to approximately 1 mL/kg/hr (Heddle & Webert, 2007). Total fluid input and output
must be monitored (Mazzei, Popovsky, & Kopko, 2014).

Complications of Massive Transfusion

Citrate Toxicity

Pathophysiology and Presentation

Blood component bags contain citrate as one of the anticoagulant. When transfused at a high
rate, the plasma citrate levels increase, leading to the increase binding with calcium ions; thus, resulting
to hypocalcemia (Mazzei, Popovsky, & Kopko, 2014). When the patient has a normal liver function, the
said hypocalcemia tends to be transient (Dzik & Kirkley, 1988); however, the same is not the case in

Page 14 of 26
patients who are hypothermic or in shock. A decrease in levels of calcium causes reduced neuronal
excitability, which will affect the overall function of the nervous system (Ruediger & Lopez-Plaza, 2012).
When the central nervous system is affected, both the respiratory and cardiac function will be
compromised, causing abnormalities in their functions.

Treatment and Prevention

When a patient has a high risk for abnormality in his or her citrate metabolism, slowing down the
rate of infusion may be helpfu (Mazzei, Popovsky, & Kopko, 2014)l. Also, monitor the level of calcium in
the blood. If the level falls below 50% or if the symptoms of hypocalcemia occurs, infuse the patient with
calcium replacement solution.

Hyperkalemia and Hypokalemia

Pathophysiology

Increased levels of potassium the plasma of a blood unit occurs as a consequence of shift of
electrolytes during storage. Albeit is rarely causes a problem in most patients, hyperkalemia may be a
problem in patients with renal failure, premature infants, and newborns receiving large transfusions, such
as in cardiac surgery or exchange transfusion; otherwise, hyperkalemia is typically a transient effect during
very rapid transfusions.

Hypokalemia seems to occur more frequently in patients undergoing massive transfusions that
hyperkalemia. This is cause by the absorption of plasma potassium both from the patient and from the
blood unit into the intracellular compartments of RBCs, caused by citrate metabolism. Catecholamine
release and aldosterone-induced urinary loss can also trigger hypokalemia in the setting of massive
transfusion (Wilson, 1994).

Treatment

No treatment or preventive strategy for hypokalemia and hyperkalemia is usually necessary,

provided that the patient is adequately resuscitated from the underlying condition that required massive
transfusion (Collins, 1974). For infants receiving small-volume transfusions infused slowly, units may be
used safely until the expiration date (Liu, Manino, & Lane, 1994).

Hemostatic Abnormalities

Pathophysiology

Coagulation abnormalities can develop secondarily to hemodilution or diffuse intravascular

coagulopathy (Ruediger & Lopez-Plaza, 2012). Use of large volumes of asanguineous fluids and packed
red blood cells during resuscitation in hemorrhagic shock will create platelet and coagulation factor
deficiencies. Thrombocytopenia with platelet counts below 50,000/mm3, hypofibrinogenemia, and
coagulation factor levels below 25% generally occur after the replacement of two blood volumes (Hippala,
Myllyla, & Vahtera, 1995). Tissue injury may disrupt the procoagulant-anticoagulant balance, leading to
diffuse intravascular coagulopathy and putting the massively transfused patient at risk of bleeding

Page 15 of 26
secondary to a combination of platelet and coagulation factor consumption and secondary fibrinolysis
(Mazzei, Popovsky, & Kopko, 2014).

Treatment and Prevention

Frequent monitoring of these laboratory values serves to avoid overuse of platelets and plasma
products (FFP and Cryoprecipitated AHF) by anticipating the specific components needed while avoiding
dilutional coagulopathy (Mazzei, Popovsky, & Kopko, 2014). It is imperative that the laboratory provide
results of these tests rapidly. Intraoperative and postoperative laboratory testing, such as
thromboelastography, may be useful.

Air Embolism

Air embolism can happen if blood, in an open system, is infused to the patient under pressure or
if air enters through the central catheter in the midst of blood administration. It can be potentially fatal
for an adult of the air is approximately 100 mL (O'Quin & Lakshminarayan, 1982). Cough, dyspnea, chest
pain, and shock are some of the symptoms to watch for.

If suspected, the patient should be placed on the left side with the head down to displace are
bubble from the pulmonary valve (Mazzei, Popovsky, & Kopko, 2014). Further, aspiration of the air may
be attempted. The measure to prevent this from happening are routine checks of materials used in
transfusion.

Hypothermia

Hypothermia can occur in massive transfusion especially if there is no time available for the units
to come to room temperature. Use of blood warmers may help in preventing hyporthermia. However, the
temperature provided by the blood warmer should be monitored to eliminate the risk of overheating; for
this, a warning system may be used (Levitt, 2014).

Delayed Transfusion Reactions

Ruediger & Lopez-Plaza (2012) defined delayed transfusion reactions as “reactions in which signs
and symptoms present after 24 hours of a transfusion and represent a diverse etiology.”

Delayed Hemolytic Transfusion Reaction (DHTR)

Definition

Delayed serologic/hemolytic transfusion reaction (DSHTR) is defined as the detection of “new”

red cell antibodies after 24 hours of transfusion. It usually occurs secondarily to an amnestic response but
can also occur during a primary immune response and may (delayed hemolytic) or may not (delayed
serologic) be associated with shortened survival of the transfused cells (Ness, Shirey, & Thoman, 1990).

Presentation

Page 16 of 26
 The unique feature of DHTR is the presence of fever and anemia days or weeks after transfusion
of RBC component (Mazzei, Popovsky, & Kopko, 2014). Since the hemolysis occurs extravascularly, renal
function and DIC are usually not compromised. Similarly, the patients with DHTR present with unexplained
anemia or do nor experience hemoglobin increase following transfusion.

Incidence

DHTR usually occurs more compared to AHTRs, with an estimate of approximately 1:2500
(Vamvakas, Pineda, & Reisner, 1995). Meanwhile, there is no data found in the case of the Philippines.

Pathophysiology

During pregnancy or transfusion, exposure to non-ABO antigens may stimulate the development
of antibodies in the recipient (Mazzei, Popovsky, & Kopko, 2014). Primary immune response stimulates
IgM antibody production, followed by a switch to IgG production. The primary immune response is usually
asymptomatic and becomes apparent by immunohematology testing within weeks to months after
transfusion. With time, these antibodies may diminish to undetectable levels when repeat
immunohematology testing is performed. In such cases, a subsequent exposure to incompatible red cells
elicits a secondary immune response with rapid production of IgG becoming detectable between 2 days
to 2 weeks after the reexposure (Eder & Chambers, 2007). The degree of accelerated red cell destruction
will depend on the characteristics of the implicated antibody such as antibody specificity (usually
antibodies directed against the Rh, Kidd, Duffy, and anti-Kell antigens), thermal activity range, and the
ability to fix complement. Most frequently, the red cell destruction occurs as extravascular hemolysis.

Diagnosis

In the diagnosis of DHTR, both the clinician and the transfusion service must recognize the
characteristics. In the clinician side, he or she may recognize fevers with decrease in hemolysis days after
transfusion. He or she must refer this to the transfusion service. The transfusion service, meanwhile,
checks for the laboratory manifestation of DHTR. The serologic findings in classic cases of DHTR include
the development of a post-transfusion positive DAT that may have a mixed-field appearance because of
the presence of IgG antibody–sensitized donor RBCs interspersed with DAT-negative autologous RBCs and
the presence of a newy identified alloantibody in the red cell eluate or plasma studies or both
approximately 3 to 10 days (or usually by 20 days) after the index transfusion (Shirey & Ness, 1991). If the
serologic and clinical findings, coincide with that of DHTR, then the patient should be observed further
and the physician must be notified.

Treatment

Then primary treatments to be used in cases of confirmed DHTR patient monitoring and provision
of supportive care (Mazzei, Popovsky, & Kopko, 2014). Next should be the identification of the implicated
antibody and transfusion of antigen negative units.

Prevention

Page 17 of 26
 If transfusion is requested for the patient in the future, a proper checking of transfusion records
is recommended to take note of the alloantibodies identified (Mazzei, Popovsky, & Kopko, 2014). If the
alloantibodies identified are indicated in the patient transfusion record, antigen-negative blood units
should be transfused to him or her.

Transfusion-Associated Graft VS Host Disease (TAGVHD)

Definition

Transfusion-associated graft-versus-host disease (TA-GVHD) is defined as a delayed immune

transfusion reaction due to an immunologic attack by viable donor lymphocytes contained in the
transfused blood component against the transfusion recipient (Ruediger & Lopez-Plaza, 2012).

Presentation

The clinical manifestations of TA-GVHD typically begin 8 to 10 days after transfusion, although
symptoms can occur as early as 3 days and as late as 30 days. Signs and symptoms include a maculopapular
rash, fever, enterocolitis with watery diarrhea, elevated liver function test results, and pancytopenia. The
rash begins on the trunk and progresses to the extremities. In severe cases, bullae may develop (Ruhl,
Bein, & Sachs, 2012).

Unlike GVHD after allogeneic marrow transplantation, TA-GVHD leads to profound marrow
aplasia, with a mortality rate higher than 90% (Mezzei, Popovsky, & Kopko, 2014). The time course of the
reaction is very rapid; death typically occurs within 1 to 3 weeks of the first symptoms.

Incidence

The incidence of TA-GVHD is rare (Mezzei, Popovsky, & Kopko, 2014).

Pathophysiology

TA-GVHD is a condition wherein viable T-lymphocytes from the transfused blood component (i.e.
with cellular products) multiply and react against the patient (US Food and Drug Administration, 2000).
The disease is usually implicated in patients with cellular immunodeficiencies such as, but not limited to,
congenital cellular immunodeficiencies (DiGeorge syndrome, severe combined immunodeficiency
syndrome), immaturity of the immune system (intrauterine transfusions, very-low-birthweight infants),
disease-associated immunodeficiencies (Hodgkin lymphoma) & therapy-associated cellular
immunodeficiencies (hematopoietic progenitor cell transplantation, fludarabine treatment (Elkins,
Davenport, & Mintz, 2017). Also, TA-GVHD is implicated in cases wherein the host does not recognize
donor lymphocytes as “foreign”, but donor lymphocytes may recognize host as foreign, as in the case of
first degree relatives wherein HLA-heterozygous recipient gets blood from an HLA-homozygous donor,
and the homozygous HLA allele is shared (Mezzei, Popovsky, & Kopko, 2014).

Treatment

Page 18 of 26
 Treatment using immunosuppressive agents is almost always fatal although some successful
treatments were recorded with the use of stem cell treatment (Mezzei, Popovsky, & Kopko, 2014). The
emphasis is in the prevention f the disorder.

Prevention

The only reliable way to prevent TA-GVHD is through the irradiation of cellular blood components
(Mezzei, Popovsky, & Kopko, 2014).

Post-Transfusion Purpura

Definition

Post-transfusion purpura (PTP) is a delayed immune complication of transfusion that presents

with profound thrombocytopenia, frequently accompanied by bleeding, 1 to 24 days after a blood
transfusion (McFarland, 2007).

Presentation

PTP manifests as sudden and severe thrombocytopenia (platelet count <10 × 109/L) and purpura
occurring within 5 to 10 days (range, 1–24 days) of red cells, plasma, or platelet transfusions (McFarland,
2007). Fevers and chills may occur during the implicated transfusion.

Incidence

The risk of PTP is unknown, but approximately 300 cases are reported in some literature (Heddle
& Webert, 2007). Other literature reported its incidence as rare (Mezzei, Popovsky, & Kopko, 2014). In
the Philippines, there are no data found.

Pathophysiology

PTP is generally thought to be caused by recipient alloantibodies directed against donor platelet
antigens that the recipient lacks (Mazzei, Popovsky, & Kopko, 2014). The alloantibodies are IgG
immunoglobulins (Taaning & Svejgaard, 1994). The most common platelet alloantibody identified in
patients with PTP occurs in patients who are homozygous for human platelet-specific alloantigen 1b (HPA-
1b) and is directed against HPA-1a, although antibodies of other specificities have been identified (Ertel,
Al-Tawil, & Santoso, 2005). The platelet destruction that occurs includes the transfused platelets as well
as the autologous platelets, leading to a profound thrombocytopenia.

Female patients are approximately 5 times more likely to develop PTP after transfusion than are
male patients, because of sensitization during previous pregnancies (Taaning & Svejgaard, 1994).

Treatment

The current treatment of choice for this reaction is intravenous immunoglobulin (IVIG) at a dose
of 1 g/kg for 2 days (McFarland, 2007).

Prevention

Page 19 of 26
 The platelet or other components to be transfused to the patient with a history of PTP should be
from antigen-matched donors. Autologous donations and directed donations from antigen-matched
donors and family members may also be appropriate (Mezzei, Popovsky, & Kopko, 2014).

Iron Overload

Definition and Presentation

Iron overload is a delayed, nonimmune complication of transfusion, presenting with multiorgan

(i.e., liver, heart, endocrine organs) damage secondary to excessive iron accumulation (Ruediger & Lopez-
Plaza, 2012).

Incidence

The incidence of iron overload is rare (Mezzei, Popovsky, & Kopko, 2014)

Pathophysiology

Each unit of red cells contains approximately 200 to 250 mg of iron. When the patient is transfused
of 10 to 15 units of RBCs, the iron begins to be stored in the liver parenchymal cells, myocardium, and
endocrine organs (Ruediger & Lopez-Plaza, 2012). Chronic iron overload leads to liver dysfunction, heart
failure, skin pigmentation, and endocrine disorders such as diabetes mellitus. The toxic manifestations of
excess iron stores depend on such factors as (1) the amount of excess iron, (2) the rate of iron
accumulation, (3) the ascorbate level, (4) alcohol use, and (5) viral hepatitis infection (Merson & Oliver,
2002; Olivieri & Brittenham, 1997).

Diagnosis

The iron content of different organs may be estimated or measured directly. The serum ferritin,
although commonly performed, is a poor measure of total body iron, as it is affected by other variables,
such as inflammation (Heddle & Webert, 2007). Hepatic storage iron has been demonstrated to correlate
with total body iron stores (Angelucci, Muretto, & Nicolucci, 2002). Liver iron can be measured after liver
biopsy or by supraconducting quantum interface device (SQUID) or by magnetic resonance imaging (MRI).
Patients with liver iron levels greater than 15 mg of iron per gram of liver are at increased risk for hepatic
fibrosis and other complications (Brittenham, Griffith, & Nienhuis, 1994). Cardiac iron may be indirectly
measured by using MRI. Other measures of iron status include the measurement of non–transferrin-
bound iron and urine iron excretion. Patients with iron overload should also have the function of
potentially affected organs assessed: the heart, liver, and endocrine glands.

Treatment and Prevention

The chelating agents bind to iron in the tissues, helping its removal through the urine and feces.
Currently, there are three chelating agents available: parenteral deferoxamine, oral deferiprone, and oral
deferasirox (Mezzei, Popovsky, & Kopko, 2014). In certain chronic red cell transfusion patient populations,
red cell exchange transfusion may be used as an alternative to transfusion therapy and may help delay
transfusion-related iron accumulation, preventing associated organ damage (Kim, Dugan, & Silber, 1994).

Page 20 of 26
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