Adverse events related to blood transfusion
Abstract
The most significant adverse effects are caused by acute blood transfusion responses.Knowledge of
the numerous clinical aspects of acute and delayed transfusion responses, as well as the capacity to
detect significant reactions in real time, can lead to a better prognosis. Evidence-based medicine has
altered today's clinical practice situation in order to reduce hazardous transfusion responses. New
evidence-based transfusion algorithms and better haemovigilance contribute to preoperative
transfusion avoidance. Recognizing unpleasant outcomes while under anesthesia is often difficult.
Unwanted transfusions of blood can be prevented by using improved blood conservation measures
after surgery and anesthetic treatments that minimize blood loss. Better and more recent blood
screening procedures have reduced infectious consequences to nearly non-existent levels. Most non-
infectious problems can be prevented with universal leukoreduction of red blood cells (RBCs),
screening of suitable donors such as using only plasma from male donors, and restriction of RBC
storage.
Key words: Adverse events, anaesthesia, blood transfusion, complications, non-infectious
Introduction
An unfavorable reaction or event is a negative reaction or effect in a patient that is caused by the
delivery of blood or a blood component.[1] Today, even in industrialized nations, the biggest danger
to the patient is non-infectious transfusion complications, which cause considerable morbidity and
death.[2] Non-infectious adverse events associated with blood transfusions are referred to as non-
infectious adverse reactions to transfusions (NIATRs) in this review. The technical manual of the
American Association of Blood Banks provides recommendations for the detection, diagnosis,
investigation, and categorization of non-infectious transfusion responses, and can be used as a quick
reference for doctors and other health care workers who deal with blood transfusion.[3] The acute
and delayed NIATRs are defined based on the period of manifestation, and the putative aetiology is
further split into immune-mediated and non-immune mediated subtypes. Table 1 provides an
overview of many prevalent NIATRs, including categorization, pathogenesis, clinical manifestations,
and therapy. Figure 1 depicts a differential diagnosis strategy to assist doctors in the case of a
suspected NIATR. The following is a widely recognized categorization of adverse reactions:
Acute Noninfectious Blood Transfusion adverse reactions
They are classed as Acute immune mediated blood transfusion responses and Acute non-immune
mediated blood transfusion reactions if they occur within 24 hours of transfusion. Acute immune-
mediated - blood transfusion responses are further categorized.
Acute haemolytic transfusion reactions
A haemolytic transfusion response occurs when transfusion causes signs and clinical or laboratory
indications of accelerated red cell death. Symptoms of AHTRs (acute haemolytic transfusion
reactions)emerge minutes after the transfusion begins. Haemoglobinemia, haemoglobinuria,
reduced serum haptoglobin, unconjugated hyperbilirubinaemia, elevated serum glutamic-oxaloacetic
transaminase and Lactate dehydrogenase levels, and decreased haemoglobin are all common
laboratory findings. The immunologic basis for AHTRs is the interaction of the recipient's prepared
antibodies with the donor's red cell antigens, which results in the rapid death of the transfused red
cells. Transfusion of ABO-incompatible plasma (e.g., ABO mismatch platelet transfusion) can induce
haemolysis of the patient's red cells in rare cases, especially if donors have a high ABO antibody titer.
Febrile nonhemolytic transfusion reactions
Febrile nonhaemolytic transfusion responses (FNHTRs) are defined by a temperature rise of at least
1°C during or immediately after transfusion that is otherwise unexplained. Antipyretics may disguise
a fever, but they seldom prevent chills and rigors caused by a cytokine-mediated systemic
inflammatory response. Before ruling out FNHTR, other causes of fever should be ruled out. FNHTRs
are more common following platelet transfusion (up to 30% of platelet transfusions) than after red
blood cell (RBC) transfusion because platelets are maintained at room temperature, which enhances
leucocyte activation and cytokine buildup.[5] FNHTRs are treated symptomatically. Laboratory
leucoreduction is more effective and beneficial than bedside leucoreduction.
Reactions to allergens
Symptoms may appear seconds or minutes after the transfusion begins, or they may take several
hours to appear.
Urticaria
Urticaria is the mildest type of allergic response that appears unexpectedly, causing itching, and can
linger for hours or even days before disappearing. Angioedema may be seen in more severe
instances. Urticaria affects 1-3% of people.[3,6] The transfusion may be restarted after the symptoms
have subsided. Methylprednisolone (one hundred and fifty milligrams intravenously) or prednisone
( fifty milligrams orally) can be used to treat severe responses.
Anaphylaxis
Anaphylaxis is a more severe type of allergic response with a 1:20,000-1:50,000 transfusion rate[7]
that can cause severe hypotension, shock, and loss of consciousness.[8] Anaphylaxis is a frequent
complication in IgA deficient recipients, and it is induced by antibodies to donor IgA. Patient
antibodies against haptoglobin, penicillin, the C4 complement determinant, and ethylene oxide have
all been linked to the cause.[9] The word 'anaphylactoid' refers to responses that have symptoms
similar to anaphylaxis but are not caused by IgE. If the patient is unconscious or in shock, intravenous
adrenaline with cardiac monitoring may be administered.[10]
Transfusion-related acute lung injury
Transfusion-related acute lung injury (TRALI) is a kind of acute lung injury (ALI) that is a leading cause
of transfusion-related morbidity and death. TRALI is defined as follows:[1]
On room air, acute lung injury with hypoxemia and PaO2/FiO2 300 or SpO2 90%
Bilateral pulmonary edema on frontal chest radiograph
No evidence of left atrial hypertension
No pre-existing ALI before transfusion
Onset of symptoms within 6 h of transfusion
No temporal relationship to an alternative risk factor for ALI.
Probable TRALI is additionally identified using the identical parameters as TRALI, but with an
alternate risk factor for ALI. TRALI lung damage is often temporary, with around 80% of patients
recovering within 48-96 hours.[3] Unlike transfusion-associated circulatory overload (TACO), TRALI
pulmonary oedema is noncardiogenic and does not improve with diuretic medication. TRALI is a
clinical diagnosis; laboratory findings may only be used to support it. TRALI is defined as the new
beginning or worsening of pulmonary function with hypoxemia that meets the international criteria
for ALI (PaO2/FiO2<300mmHG) and an X-ray of the chest consistent with pulmonary
edema occurring during or within 6 hours following transfusion.[11] TRALI has been linked to all
plasma-containing components, such as whole blood, RBCs, platelets, cryoprecipitate, and fresh
frozen plasma. TRALI is expected to occur once in every 5000 blood component infusions. After being
exposed to foreign antigens via pregnancy, transfusion, or transplantation, antibodies can build
towards leucocytes (polymorphous neutrophils [PMN]), both for neutrophils and human leucocyte
antigen. Two alternative aetiologies have been postulated.[12] ] It can be a single antibody-mediated
event that involves the administration of anti granulocyte antibodies or anti-HLA to individuals
whose leukocytes exhibit the corresponding antigens. In the vast majority of cases, the source of the
antibody is the donor, not the patient. A two-event model of TRALI mechanism has also been
proposed, which results in neutrophil activation, pulmonary endothelial damage, capillary leakage,
and pulmonary oedema. Clinical improvement can occur within 48-96 hours with early respiratory
assistance.[13]
Consistent transfusion protocols may reduce needless transfusions and their morbidity. Furthermore,
numerous scientists, transfusion medicine practitioners, and the American Association of Blood
Banks urge for the interim exclusion of TRALI donors until leucocyte antibody testing is completed. If
these donors have antibodies to high-frequency leucocyte antigens, they should be barred from
donating plasma or platelets. To ensure the safety of the blood supply, the United Kingdom (UK) has
barred all multiparous females from donating plasma due to the probability that plasma from
females may be a key role in TRALI Washing of cellular components eliminates antibodies, lipids, and
other biologic response modifiers from the plasma fraction for planned major surgical procedures
requiring transfusions. Since there isn't a substantial buildup of PMN priming activity during less
periods of storage for PRBCs and platelet concentrates, respectively, using packed red blood cells
(PRBCs) for less than 14 days and platelet concentrates for less than 2 days may avoid many of the
effects of these compounds that accumulate during storage. Patients at high risk of developing TRALI
may benefit from antiplatelet medications and alternatives to standard blood components such as
prothrombin complex concentrates in the future.[14]
Management of TRALI
The treatment is mostly supportive.Effective TRALI prevention techniques include the use of
primarily male plasma and apheresis platelets. Greater understanding of TRALI's blood component
and patient risk factors will hopefully lead to innovative treatment and preventative options for
lowering the risk of this potentially fatal condition. TRALI treatment is mostly concerned with
avoiding future adverse responses.[15] A patient with TRALI should be reported to the National
Blood Bank for a serological workup on the existence of HLA and HNA antibodies in the recipient and
involved donors. Cross-matching donor plasma against recipient leucocytes determines
incompatibility. A donor who has antibodies that are incompatible with the patient is barred from
donating blood for transfusion products in the future.
Acute non-immune mediated adverse reactions
Transfusion-related sepsis
Transfusion-related sepsis, while uncommon, can be lethal. Having any of a minimum of one of the
following clinical characteristics leads to the diagnosis:
(1) a fever of 39°C (102°F) or an increase of 2°C (3.5°F); (2) tachycardia (heart rate >120/min, or an
increase of >40/min); (3) shaking chills; and (4) a change in systolic blood pressure (BP) (i.e. >30
mmHg rise or reduction in systolic BP) within 90 minutes of transfusion.[16]
In extreme circumstances, the patient may suffer from shock, renal failure, and DIC (disseminated
intravascular coagulation). The isolation of the same organism from both the patient and the rest of
the bag is helpful in detecting transfusion-related sepsis and distinguishing it from AHTRs and
FNHTRs.[17] Platelets are more vulnerable to bacterial contamination than RBCs since they are
maintained at ambient temperature, posing a larger danger. The odds of transfusion-related sepsis
were higher with random-donor platelets than with an apheresis unit. Broad-spectrum antibiotics, in
addition to routine sepsis therapy, should be given to treat transfusion-related sepsis. The danger can
be reduced by screening platelet units for bacterial contamination and using the "diversion
technique" during blood collection.[18]
In addition to the use of disinfectants, germs can be transferred in the blood container via a skin core
when the blood collection needles is entering the skin (as seen in around 65% of all venepunctures).
With the diversion approach, withdrawing the first 15- 30 mL of whole blood from the main
container may lower the chance of bacterial infection.
Non-immune haemolytic reactions
Nonimmune-mediated causes of red cell hemolysis due to transfusion can also occur; for example,
improper storage temperature, improper use of blood warmer, use of hot water bath and microwave
oven, using a needle with an inappropriately small bore size or employing a rapid pressure infuser,
infusion of RBCs through same tubing with hypotonic solution or some pharmacologic agents. The
management is identical to that of the AHTRs.
Transfusion associated circulatory overload
Transfusion-related circulatory overload is associated with significant morbidity and death.[19]
Patients with renal failure, hypoalbuminaemia, anaemia, congestive heart failure, fluid overload, or a
history of plasma transfusion are at the highest risk of TACO. Dyspnoea, orthopnoea, cyanosis,
tachycardia, jugular venous distension, and pedal oedema are some of the symptoms and indicators.
[20] Increased blood pressure is indicated by a broadening of the pulse pressure. It occurs in 1% of
transfused individuals. Within 6 hours of receiving a blood transfusion, TACO may cause acute
pulmonary oedema. Management consists of optimizing the main cause as well as mechanical
ventilation, fluid restriction, and diuretics.[21]
Transfusion associated dyspnoea
It is distinguished by respiratory distress that occurs within 24 hours following transfusion and does
not satisfy the criteria for TRALI, TACO, allergic response, or other recognized causes.[1]
Acute hypotensive transfusion reaction
This is described as a sudden and unexpected decline in blood pressure with no additional causes of
hypotension. As a result, it may appear as an isolated discovery; nonetheless, it recovers swiftly to
transfusion discontinuation and supportive therapy.[22] Patients who have hypotensive transfusion
responses that are otherwise unexplained should be offered a trial with cleansed blood products.
Although prestorage leucofilters have been involved in acute hypotensive transfusion reactions,
bedside leucoreduction filters have been implicated more often.[23]
Metabolic and haemostatic derangement
Acute metabolic and hemodynamic problems may arise as a result of large transfusion. AHTRs may
also have haemostatic problems. Dilutional coagulopathy, DIC, and altered liver and platelet
functions are all frequent haemostatic disorders found with heavy transfusion. Each center should
have a major transfusion procedure in place, which includes the use of recombinant factor VIIa. A
viscoelastic point-of-care test (thromboelastography) may help in monitoring coagulation state and
blood component requirements.
Citrate toxicity
When high amounts of citrate-containing blood components are quickly transfused, increased
plasma citrate bonds with calcium ions, resulting in hypocalcaemia and accompanying symptoms. In
most cases, hypocalcaemia induced by citrate overload may be addressed by lowering the infusion
rate. Calcium replacement is indicated in patients who have been heavily transfused, particularly
those with severe liver disease or who have significant hypocalcaemia symptoms.[24]
Hyperkalemia
Because of quick dilution, redistribution into cells, and excretion, the total extracellular potassium
burden, which is 0.5 mMol for fresh RBC units and only 5-7 mMol for units after expiration, seldom
causes issues in the recipient.[3] Transfusion-associated hyperkalemia is defined as an excessively
high potassium level within an hour following transfusion.[1] Irradiation increases potassium leakage.
Hypokalemia
Because donor red cells re-accumulate the ion intracellularly, and citrate metabolism stimulates
additional migration of potassium into the cells, hypokalemia is more prevalent than hyperkalemia
following transfusion. Catecholamine release and aldosterone urine loss can potentially cause
hypokalemia with a big transfusion. In most cases, no treatment or preventative approach is
required.
Coagulopathy
Coagulopathy can be seen in heavy transfusions, especially when two blood volumes are lost and
replenished with red cells and fluids, causing platelets and clotting components to be diluted. In
addition to dilution, consumption coagulopathy is a significant component.
Hypothermia
It might be caused by a substantial amount of cold blood products being transfused. It can induce
cardiac arrhythmias and disrupt platelet function, clotting factor interaction, and bleeding time.[25]
Hypothermia can be avoided by using blood warmers. However, blood should never be heated with
equipment that is not properly built for this purpose, as heat damage to blood cells and proteins
might have fatal consequences.
Air embolism
The introduction of plastic blood bags has significantly reduced the frequency of air embolism.
Nonetheless, air can enter through a central catheter while blood administration equipment or blood
bags are being replaced, or while blood is infused under pressure in an open system.[26]
Delayed reactions (occurring after 24 h or up to month/ years after transfusion)
Delayed immune mediated reactions
Delayed haemolytic transfusion reactions
The rate of delayed haemolytic transfusion responses (DHTRs) is predicted to be one in every 6000
units transfused.[27] The presence of DHTRs is related to the reactivation of pre-existing antibodies
against antigens on transfused red cells. Symptoms may appear days to weeks after receiving an
apparently cross-matched compatible RBC transfusion. Patients with DHTR may experience
unexplained anemia or exhibit no increase in hemoglobin after transfusion. Because the haemolysis
is largely extravascular (implicated antibodies do not fix complement except in a few cases), acute
renal failure and DIC do not develop, however haemoglobinuria may occur in rare cases. There are
situations when there are no clinical or laboratory signs of haemolysis, yet an alloimmune red cell
antibody is identified. DSTR stands for delayed serologic transfusion response. In order of decreasing
frequency, blood group antibodies related with DHTRs/DSTRs include those of the Kidd, Duffy, Kell,
and MNS systems.[20] Because red cell death happens gradually as antibody manufacturing rises, the
majority of DHTRs do not require therapy. Antigen negative blood, on the other hand, may be
necessary for a bleeding patient with low hemoglobin.
Alloimmunisation
ABO antibodies are naturally occurring antibodies (IgM); however, the majority of clinically important
antibodies to red cells are IgG, which is formed in response to vaccination by antigen-positive red
cells after transfusion, organ donation, or foeto-maternal hemorrhage during pregnancy. It has been
observed that about 2-3% of individuals who are exposed to foreign red cell antigens develop
alloantibodies to one or more of these antigens. Alloantibodies have been found in up to 30-40% of
sickle cell anemia patients and 9% of thalassemia major patients.[28] When sickle cell and
thalassemia patients are repeatedly transfused, they might develop an abrupt life-threatening
anemia (hyper haemolysis syndrome).[29] In the absence of an antigenic stimulation, antibody
synthesis declines and, in most cases, ceases over time.[30] Patients who have a history of pregnancy
or who have received non-leukocyte depleted transfusions develop alloantibodies against HLA, which
lead to the largest proportion of alloimmune-mediated platelet transfusion refractoriness. About 20-
70% of multitransfused thrombocytopenic individuals have a lower-than-expected rise in platelet
count. The experiment to lower alloimmunisation to platelets study group discovered that leucocyte
reduction, rather than donor exposure number, was significant in changing the rate of sensitisation.
[31] Transfusion of HLA- and/or HPA-matched platelets is necessary in refractory individuals to lower
the risk of hemorrhage.[32]
Transfusion associated immunomodulation
Transfusion related immunomodulation (TRIM) is the down-regulation of the recipient's cellular
immune response produced by allogeneic blood transfusion.[33] The clinical consequences of TRIM
include a higher risk of post-operative infections and cancer recurrence, as well as the possibility of a
transfusion-related syndrome with multiple organ dysfunction.[34] Allogeneic leucocytes or their
soluble products are thought to mediate TRIM. One of the proposed causes is immunological
deviation towards T-helper lymphocytes type 2 cytokines, as seen by increased secretion of
interleukin (IL)-4, IL-5, and IL-10 cytokines and decreased secretion of T-helper lymphocytes type 1
cytokines such as IL-2, IL-12, and interferon-. The use of autologous blood or prestorage leucofiltered
blood can help to reduce the negative effects of TRIM.[35]
Transfusion-associated graft versus host disease
Transfusion-associated graft versus host disease (TA-GVHD) is a clinical syndrome characterized by a
high temperature, maculopapular rash progressing to haemorrhagic bullae, enterocolitis with watery
diarrhoea, elevated liver function tests, pancytopenia, and findings of characteristic histological
appearances on biopsy that typically begin 8-10 days after transfusion.[36] In TA-GVHD, viable
transfused T-lymphocytes launch an immunologic attack on the immunocompromised transfusion
recipient, who is unable to reject the immunocompetent cells. TA-GVHD can also arise following a
blood transfusion from a blood related donor who is homozygous for an HLA haplotype to a
heterozygous receiver (one-way haplotype match).[37] Chimerism can be detected and diagnosed
using HLA typing and other molecular tests. Although it is uncommon, it has a 90% fatality rate. As a
result, there is a focus on preventing TA-GVHD by irradiating all cellular blood components (RBCs,
platelets, and granulocytes), particularly in individuals at risk of TA-GVHD.[38]
Posttransfusion purpura
Posttransfusion purpura (PTP) is a very infrequent transfusion complication with a female
predominance. It happens from 1 to 24 days following transfusion, with a 9-day average.[39] Patients
often appear with a purpuric rash with thrombocytopenia (platelet counts frequently exceeding
10,000/L), leading in bleeding from mucosal membranes, the gastrointestinal tract, and the urinary
tract. The most common cause of death is cerebral hemorrhage. PTP has been linked to the
transfusion of RBCs or whole blood, but it has also been linked to the transfusion of plasma
and platelets . In most cases, antibodies to HPA-1a are to blame, but antibodies to HPA-1b, other
platelet antigens, and HLA antigens are also involved. PTP is now treated with high-dose intravenous
immune globulin.[40] In these individuals, platelet transfusions are frequently ineffectual at
increasing platelet counts.
Delayed non-immune mediated reactions
Iron overload
Patients who are chronically transfused for disorders such as thalassemia, sickle cell disease, and
other chronic anemias are more vulnerable to iron excess. RBCs contain around 250 mg of iron per
unit. Because red cells are killed, the bulk of the iron released cannot be eliminated and is instead
stored in the body as haemosiderin and ferritin. After administering 10-15 units of RBCs to a non-
bleeding patient, transferrin becomes saturated, and iron accumulates in the reticuloendothelial
system, liver, heart, spleen, and endocrine organs, causing tissue damage and leading to heart
failure, liver failure, diabetes, and hypothyroidism.[3]
Adverse transfusion reactions during surgery under anaesthesia
As mentioned in this study, it can range from mild anaphylaxis to any of the severe life-threatening
disorders. Adverse responses in conscious people may be simple to detect with good heamovigilance
and monitoring. However, identifying unfavorable transfusion responses under anaesthesia and in
cases when patients are unable to describe symptoms (e.g., newborns, children, comatose) is
extremely challenging. The traditional appearance of unfavorable transfusion responses is frequently
disguised in these instances. However, it is possible to suspect it while under anaesthesia if the
patient develops various types of arrhythmias, tachycardia and hypotension, localised or systemic
cutaneous reactions, increased airway resistance due to laryngospasm or bronchospasm, and
uncontrolled bleeding immediately after blood transfusion. The presence of haemoglobinuria or
diffuse bleeding (DIC) may be the only symptoms of acute intravascular red cell haemolysis, with
additional causes must be checked out. It is recommended that the following information be
included on the patient's notes at all times: The type of transfusion response suspected, the length
of time the reaction occurred after the commencement of transfusion, the volume, type, and pack
numbers of the blood products transfused. Adverse transfusion responses can be identified during
anesthesia and surgery by using the International Society of Blood Transfusion guidelines.[41]
SUMMARY
The majority of significant adverse reactions or occurrences are caused by acute transfusion
responses. Knowledge of the numerous clinical signs of acute transfusion responses, as well as the
capacity to detect significant reactions in real time, can contribute to a better prognosis. Throughout
the transfusion session, observation and monitoring are essential, especially in the first 15 minutes. A
standard operating protocol should be in place that outlines the documenting, reporting,
assessment, and follow-up of all adverse responses. The use of an evidence-based "restrictive
strategy" or "conservative approach" to blood transfusion to limit the amount of unnecessary
transfusions has resulted in a significant shift in clinical practice.
