Transfusion Reactions

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Definition
A transfusion reaction is defined as any unfavorable event
that occurs during or after a transfusion of blood and its compo-
nents.
Classification of Transfusion Reactions
Transfusion reactions can be classified as follows:
1. Acute and delayed: These are again subdivided into immuno-
logical and non-immunological
2. Depending upon the severity as:
a. Mild reactions
b. Moderately severe reactions, and
c. Life-threatening reactions
ACUTE TRANSFUSION REACTIONS—IMMUNOLOGICAL
• Febrile non-haemolytic transfusion reaction (FNHTR)
• Allergic reactions
• Anaphylactic and anaphylactoid reactions
• Acute haemolytic transfusion reactions (AHTRs)
• Transfusion related acute lung injury (TRALI)
ACUTE TRANSFUSION REACTIONS—NON-IMMUNOLOGICAL
• Bacterial contamination
• Transfusion-associated circulatory overload (TACO)
• Physical and chemical haemolysis
• Metabolic derangements
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Delayed Transfusion Reactions—Immunological
• Delayed haemolytic transfusion reactions (DHTRs)
• Transfusion-associated graft-versus-host disease (TA-GvHD)
• Post-transfusion purpura
Delayed Transfusion Reactions—Non-immunological
• Iron overload
• Post-transfusion haemosiderosis
• Transfusion-transmitted diseases
Common Signs and Symptoms
Common signs
Symptoms
Nausea
Heat at infusion site
Chills
Itching
Coughing
Myalgia
Cyanosis
Hypotension
Dyspnea
Oliguria/anuria
Facial flushing
Pulmonary edema
Fever (>1oC )
Wheezing
Headache
Chest/back pain
Urticaria
Abnormal bleeding
Rash
Hemoglobinuria
Uneasy feeling
FEBRILE NON-HAEMOLYTIC TRANSFUSION REACTION (FNHTR)
This is a frequent kind of reaction, occurs in 1:200 cases.
Definition
There is increase of 1°C temperature or more associated with
transfusion of blood when there is no medical explanation for
fever other than blood transfusion.
Causes
Patient has immunologic sensitization to donor WBCs, platelets
or plasma proteins.

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Common Sources
Prior transfusions, previous pregnancies, previous transplants.
Pathophysiology
This is caused from HLA class I antigens or leucocyte antigens
on the WBCs of the donor that react with the recipient’s anti-
bodies (blood components with WBCs) and activate comple-
ment system which releases cytokines (IL-1, IL-6, and TNF).
These act on thermoregulatory center in hypothalamus and
responsible for increase in temperature.
Signs and Symptoms
• Fever with or without chills, with increase of 1 degree C to
2 degree C temperature.
• Most symptoms are mild.
• With severe reaction there can be hypotension, cyanosis,
tachycardia, tachypnea, dyspnea, cough, etc.
• There can be headache, flushing, anxiety, muscle pain.
Prevention
• Anti-pyretics are used to treat fever or are given prior to
blood transfusion as a preventive measure.
• Discontinue blood transfusion if the patient has severe reaction.
• Pre-storage leucocyte reduced units of red blood cell or
platelet packs may also be given. Leucocyte reduced units
should have the following:
a. As per the standards, minimum of 85 percent red cell
recovery should be ensured in 95 units tested.
b. The whole blood unit should have less than 5 × 106 white
blood cells. This is log 3 reduction.
c. This is best achieved by 3rd and 4th generation filters.
Note: Also refer to topic on “safe use of blood”.

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ALLERGIC REACTIONS
This is a frequent kind of reaction.
Causes
Exact mechanism for sensitization is not known.
Patient is sensitized (usually IgE antibody) to foreign plasma
antigens. Commonly caused by transfusion of plasma contain-
ing blood components, e.g. FFP, cryoprecipitate, platelet
concentrates.
Pathophysiology
Signs and Symptoms
• Flushing
• Headache
• Itching
• Urticaria
• Rarely, angioedema—epiglottal oedema; bronchial airway
constriction, hypotension, dyspnea and rales.
This is not life threatening.
Management
Pre-medicate patient with anti-histamines.
If signs/symptoms are mild and/or transient, restart trans-
fusion after treatment.
Do NOT restart transfusion if pulmonary symptoms/signs
and fever are present.

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Prevention
• Use plasma deficient blood components.
• Prophylactically treat with antihistamines.
Note: Also refer to topic on “Safe use of blood”.
ANAPHYLACTIC AND ANAPHYLACTOID REACTIONS
Anaphylaxis can range from mild urticaria to severe shock and
death although rare. These occur at the rate of about 1 per
150,000 patients.
Pathophysiology
Pre-formed anti-IgA antibodies are present in the recipient’s
blood with IgA deficiency which reacts with IgA present in
the donor plasma.
Signs and Symptoms
Anaphylactic reactions: Coughing, dyspnea, nausea, emesis,
bronchospasm, flushing of skin, hypotension, abdominal
cramps, diarrhoea, cardiac arrest, shock, and death.
Anaphylactoid reactions (less severe): Urticaria, periorbital
swelling, dyspnea, or peri-laryngeal oedema.
Fig. 10.1: Anaphylaxis in IgA deficient recipient with pre-formed IgA
antibodies, when transfused with donor having IgA

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Therapy and Prevention
• Stop transfusion.
• Keep IV line open.
• Medication: Use epinephrine (vasoconstrictors and broncho-
dilators) and corticosteroids.
• Use washed RBCs and blood components.
• Transfuse IgA deficient blood.
ACUTE HAEMOLYTIC TRANSFUSION REACTIONS (AHTRs)
Most common cause for AHTR is ABO incompatibility often
due to clerical error.
Incidence: 1:25,000.
As little as 10–15 mL can trigger a reaction. Occurs within
24 hours.
Causes
• Transfusion of incompatible donor RBCs into patient.
• Usually an ABO incompatibility, most commonly antibodies
of A, B or AB.
• Red cell destruction due to complement activation by
IgM antibodies. Antibodies in patient plasma attach to
antigens on donor RBCs causing RBC destruction intra-
vascularly.
• Potent anaphylatoxins including C3a and C5a are released,
later form membrane attack factor.
• C3a and C5a cause hypotension.
• Mast cells release histamine and serotonin which constricts
small arteries and arterioles leading to renal ischemia.
• Release of bradykinin causes vasodilatation and increased
vascular permeability.
• Release of cytokines like TNF-, IL-1 and IL-8 induces
hypotension.
• Antigen and antibody interaction has effects on coagulation
cascade causing disseminated intravascular coagulation
(DIC).

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Signs and Symptoms of AHTR
Signs
Symptoms
Chills
Fever
Facial flushing
Dyspnea
Hypotension
Generalized bleeding
Renal failure
Haemoglobinemia
DIC
Haemoglobinuria
Shock
Nausea
Chest pain
Vomiting
Pain along infusion vein
Back pain
Differential Diagnosis for AHTR
• Microbial contamination
• Physical/chemical/drug related damage to stored RBCs
• Auto-immune haemolytic anaemia
Steps to be taken when a transfusion reaction occurs due to AHTR:
• Stop the transfusion immediately.
• An intravenous line with normal saline should be maintained.
• Obtain vital signs.
• Begin O2 if pulmonary symptoms are prominent.
• Obtain a new blood sample for repeat ABO compatibility
test and for evidence of haemolysis.
• Obtain a urine sample, if the patient can void.
• Obtain a chest X-ray if pulmonary symptoms are prominent.
• Physician is notified.
• Bedside clerical checks of all forms, labels and patient
identification for correctness of the unit and the intended
recipient are required.
• The unit and all tubing should be returned to the blood bank,
along with post-infusion blood and urine samples.
• Finally, the reaction should be documented in the patient’s
chart.
• Once these initial measures have been implemented, the
investigation of the reaction by the transfusion service can
proceed.

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This type of reaction is a most dangerous immunologic
complication of red cell unit transfusion.
• It carries high risk of morbidity or mortality.
• Morbidity is because of renal failure and DIC.
• Mortality: Occurs in 1 per 100,000 transfusions.
Management
• Treat hypotension, renal failure, DIC, etc.
• Submit blood samples for blood bank/laboratory tests.
• Avoid, if possible, further transfusions till work-up is
complete and/or patient recovers from reaction.
• To prevent renal failure, fluids (saline) are infused along with
diuretics to increase urine output.
Prevention
Preventing or detecting errors in every phase of the transfusion
process such as:
• Sample acquisition
• At all steps in laboratory testing
• At the time of issue
• At the time of transfusion
• Good manufacturing practices with written standard
operating procedures should be followed.
• Perform pre-transfusion compatibility testing.
• Ensure that all clinical staff to recognize signs and symptoms
of acute haemolytic transfusion reaction.
Laboratory Investigations in AHTRs
On pre-transfusion sample: Re-confirm ABO, Rh and antibody
screen tests.
On post-transfusion sample: Following are to be undertaken.
• ABO, Rh, antibody screen
• DCT
• Urine for haemoglobinuria
• Serum bilirubin
• Haemoglobinaemia (>50 mg/dL)

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• Blood urea, creatinine
• Urine output
• Coagulation screen
• Identify discrepancies
Note: Also refer to topic on “Safe use of blood”.
TRANSFUSION RELATED ACUTE LUNG INJURY (TRALI)
This occurs in 1 in 5,000 transfusions.
Symptoms occur within 2 hours and may end in 2–4 days if
treated.
Patient displays acute respiratory insufficiency with X-ray
showing bilateral symmetric pulmonary oedema.
Pathophysiology
Fig. 10.2: Pathophysiology of TRALI with damage to endothelial cells in
lung.

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Donor antibodies activate recipient’s WBCs or vice versa
which cause damage to blood vessels in lung tissue.
Then fluids and proteins leak into alveolar space/interstitium.
Mechanism is similar to ARDS.
Non-cardiogenic bilateral pulmonary oedema develops.
Signs and Symptoms
• Severe dyspnea, cyanosis, tachycardia, and hypoxemia
• Hypotension
• Fever
• Chills
Prevention
• Avoid donations from multiparous women and those who
have received multiple transfusions.
• Transfuse washed RBCs from which plasma is removed.
• Platelet units can also be washed, but platelet function is
significantly reduced.
Management
• Steroids: Treat with IV steroids, although they may not work
well.
• Aggressive ventilatory support.
• Haemodynamic support.
Note: Also refer to topic on “safe use of blood”.
BACTERIAL CONTAMINATION
• Does not involve antigen–antibody interactions.
• Results from bacterial contamination of blood and blood
products.
Red cells can be contaminated by:
1. Gram-negative rods (those produce endotoxins and grow
in cold temperature), following are most common.
• Yersinia enterocolitica
• Serratia liquefaciens, E. coli
• Serratia
• Pseudomonas

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2. Gram-positive cocci (less common)
• Staphylococcus epidermidis
• Staphylococcus aureus
Platelets can be contaminated by
Majority are Gram-negative cocci,
• Gram-negative rods can also contaminate.
• Organisms listed above are also included.
Plasma products
• Uncommonly contaminated
• Rarely pseudomonas may contaminate
Pathophysiology
Bacteria growing in cold and room temperature produce toxins.
Symptoms and Signs
• Acute onset within 30 minutes after transfusion.
• Dryness and flushing of skin.
• Fever, hypotension, shaking chills, muscle pain, vomiting,
abdominal cramps, bloody diarrhoea, haemoglobinuria,
shock, renal failure, and DIC.
Management
• Stop transfusion immediately and treat with antibiotics.
• Hypotension can be treated with vasopressors and treat
accordingly depending on severity.
Therapy
• Stop transfusion
• Broad spectrum antibiotics
• Treat hypotension
• Symptomatic treatment
• Prevention: Care during phlebotomy and blood components
preparation and processing, thawing by sterile technique
should be undertaken.
Note: Also refer to topic on “Safe use of blood”.

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TRANSFUSION ASSOCIATED CIRCULATORY OVERLOAD (TACO)
Patients at significant risk are:
• Children
• Elderly patients
• Chronic anaemia
• Cardiac disease
• Thalassemia major, sickle cell disease or congenital haemo-
lytic anaemias
Pathophysiology
Symptoms and Signs
Symptoms
Signs
Dyspnea
Chest discomfort
Coughing
Headache
Cyanosis
Restlessness
Orthopnea
Tachycardia
Systolic hypertension
Therapy
• Rapid reduction of hypervolemia
• Respiratory and cardiac support
• Oxygen therapy
• Diuretics
• Therapeutic phlebotomy
Prevention
• Use appropriate transfusion rate. Run slowly, small aliquots
in 4 hr and subsequently within 24 hr.
• Use appropriate blood components.
Note: Also refer to topic on “Safe use of blood”.

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PHYSICAL AND CHEMICAL HAEMOLYSIS
Following are the causes:
Improper storage: Overheating or freezing.
Improper preparation: Freezing without cryoprotective agent.
Mechanical stress: Cardio-pulmonary bypass pump.
Simultaneous mixing of blood with drugs/hypotonic (5%
dextrose)/hypertonic solutions (50% dextrose).
METABOLIC DERANGEMENTS
• Citrate toxicity
• Hyperkalemia
• Hypothermia
• Coagulopathy in massive transfusion
• Air embolism
Note:
• These have synergistic effects.
• Blood warmer can prevent hypothermia.
• Slow infusion rate is required.
DELAYED HAEMOLYTIC TRANSFUSION REACTIONS (DHTRs)
• DHTRs may not be recognised for weeks or months after
transfusion. This is due to anamnestic reaction mediated by
IgG antibodies on the following occasions.
– Patient previously exposed to RBC antigen and has low
antibody titer until exposed again.
– Antibodies to Rh, Kidd, Duffy, and Kell blood groups.
• DAT is negative at first, but becomes positive later.
• Tests are performed to identify antibody.
• Patient may be asymptomatic.
• Fever and anaemia 2–14 days after transfusion are due to
DHTRs.
Symptoms
• Fever
• Mild jaundice

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Investigations
• Reduced haemoglobin more rapid than usual
• Falling Hct/PCV
• Reticulocytosis
• Haemoglobinuria
• High bilirubin
• Positive DAT in 50% of the cases
These patients must be given antigen negative blood.
Differential Diagnosis
• TA-GvHD
• Transfusion-induced malaria
Prevention
• Check the previous records for alloimmunization.
• Antigen negative blood to be transfused.
TRANSFUSION-ASSOCIATED GRAFT-VERSUS-HOST DISEASE 
(TA-GvHD)
Patients at risk are:
• Immuno-compromised patients
• Newborn and geriatric patients
• Patients with bone marrow transplantation
• Patients on chemotherapy
• Patients with radiation treatment
• Patients who receive relatives’ blood
Pathophysiology

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Signs and Symptoms
• Onset—3 to 30 days after transfusion.
• Clinically significant pancytopenia.
• Other effects include fever, rise in liver enzyme, copious
watery diarrhoea, erythematous skin, erythroderma and
desquamation.
Therapy
Drugs: Corticosteroids, methotrexate, azathioprine, antithymo-
cyte globulin.
Prevention
• No adequate therapy available.
• Irradiation of blood components is safer.
• Avoid potential fatalities.
• Avoid relatives’ blood
• Rare but fatal condition that has 90% mortality rate.
• Symptoms appear usually after about 12 days.
• Caused by donor lymphocytes, which are transfused into
an immune-compromised recipient.
• Pancytopenia occurs as a result of the immunologic
response.
• Any components that contain T-lymphocytes should be
irradiated to prevent GVHD.
POST-TRANSFUSION PURPURA
• Rare complication
• Rapid onset of thrombocytopenia as a result of anamnestic
production of platelet alloantibody.
• Usually occurs in multiparous women who do not have the
antigen.
Pathophysiology
Platelet antibody (anti-PLA1), attaches on platelet surface
and causes destruction of platelets by reticuloendothelial
system.

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Signs and Symptoms
• Purpura and thrombocytopenia occur.
• Occur 1–2 weeks after transfusion.
• The platelet count drops to <10,000 cells/cmm
Therapy and Prevention
• Corticosteroids
• Exchange transfusion
• Plasmapheresis
• Cerebral haemorrhage is a major concern
IRON OVERLOAD AND HAEMOSIDEROSIS
• 1 unit of packed red cells has 250 mg of iron.
• Iron that can be removed by the body—1 mg/day.
• Thus, with multiple transfusions iron accumulates in tissues
and causes haemosiderosis.
• Post-transfusion haemosiderosis—affected organs: Heart,
liver, endocrine glands.
Signs and Symptoms
Muscle weakness, fatigue, weight loss, mild jaundice, anaemia,
mild diabetes, and cardiac arrhythmia
• Occurs in individuals who receive multiple transfusions.
• Excess iron accumulates in macrophages in various tissues
(liver, heart, endocrine glands).
• It appears as dark brown granules in the cells.
• May lead to organ failure.
• Therapy: Iron-chelating agents.
• Prevention: Transfuse with young RBCs.
TRANSFUSION TRANSMITTED DISEASES (TTDs)
Blood transfusion can transmit diseases and the list of possible
transmitted diseases is given below:
Viral Infections
Hepatitis viruses: HBV, HCV
Retroviruses: HIV

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Herpes viruses: CMV, EBV
Parvovirus: Human B19 parvovirus
Prion: Infectious particle of CJD
Other viruses: West Nile disease
Bacterial Infection
Gram-negative and Gram-positive bacteria.
Syphilis
• Lyme disease (Borrelliosis)
• Parasitic infections
– Malaria
– Chagas’ disease
– Toxoplasmosis
– Leishmaniasis
Note: For details refer to chapter on transfusion transmitted
diseases (TTDs).