Blood Transfusion Reactions; Complications of

transfusions
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Haematology
Blood Transfusion Reactions

Authored by Dr Colin Tidy, 07 Sep 2015

PATIENT PROFESSIONAL REFERENCE

Professional Reference articles are written by UK doctors and are based on research
evidence, UK and European Guidelines. They are designed for health professionals to use.
You may find the Blood article more useful, or one of our other health articles.

See also the separate Blood Products for Transfusion article.

Blood transfusion can be life-saving and provides great clinical benefit to many patients but
it is not without risks:[1]
Immunological complications.

Errors and 'wrong blood' episodes - UK data from Serious Hazards of Transfusion (SHOT)
suggests an error incidence of 283 per million components transfused in 2014.[2]
Infections (bacterial, viral, possibly prion).

Immunomodulation.

Litigation.

Growing awareness of avoidable risk, and improved reporting systems, have led to a
culture of better safety procedures as well as steps to minimise the use of transfusion.
However, transfusion errors continue to occur and some serious adverse reactions
continue to be unreported.[2]
Alternative approaches to patient management should be used to reduce or eliminate the
need for transfusion whenever possible.[3]
Causes of acute complications of transfusion[4]
Early complications of transfusion are rare, occurring in less than 1 in 1,000 transfusions;
however, they tend to be more severe.[5]
Acute haemolytic transfusion reaction

Incompatible transfused red cells react with the patient's own anti-A or anti-B antibodies or
other alloantibodies (eg, anti-rhesus (Rh) D, RhE, Rhc and Kell) to red cell antigens.
Complement can be activated and may lead to disseminated intravascular coagulation
(DIC).

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Infusion of ABO incompatible blood almost always arises from errors in labelling sample
tubes/request forms or from inadequate checks at the time of transfusion. Where red cells
are mistakenly administered, there is about a 1 in 3 risk of ABO incompatibility and 10%
mortality with the severest reaction seen in a group O individual receiving group A red cells.

Non-ABO red cell antibody haemolytic reactions tend to be less severe but the Kidd and
Duffy antigens also activate complement and can cause severe intravascular haemolysis.

Infective shock

Bacterial contamination of a blood component is a rare but severe and sometimes fatal
cause of transfusion reactions.

Acute onset of hypertension or hypotension, rigors and collapse rapidly follows the
transfusion.

Three UK cases of bacterial contamination of blood products during 2008-2009 were

confirmed by SHOT.

Platelets are more likely to be associated with bacterial contamination than red cells, as
they are stored at a higher temperature.

Transfusion-related acute lung injury (TRALI)

TRALI is a form of acute respiratory distress due to donor plasma containing antibodies
against the patient's leukocytes.

Transfusion is followed within six hours of transfusion by the development of prominent

nonproductive cough, breathlessness, hypoxia and frothy sputum.[6] Fever and rigors may
be present.
CXR shows multiple perihilar nodules with infiltration of the lower lung fields.

Implicated donors are usually multiparous women (who are more likely to have become
alloimmunised) and should be removed from the blood panel where possible. Gas
exchange was significantly worse after transfusion of female but not male donor blood
products in one study of high plasma volume transfusions in the critically ill.[7]
Fluid overload

Fluid overload occurs when too much fluid is transfused or too quickly, leading to
pulmonary oedema and acute respiratory failure.
Patients at particular risk are those with chronic anaemia who are normovolaemic or
hypervolaemic and those with symptoms of cardiac failure prior to transfusion.

These patients should receive packed cells rather than whole blood via slow transfusion,
with diuretics if required.

Non-haemolytic febrile reactions to transfusion of platelets and red cells

Fevers (>1°C above baseline) and rigors may develop during red cell or platelet transfusion
due to patient antibodies to transfused white cells.

This type of reaction affects 1-2% of patients.

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Multiparous women and those who have received multiple previous transfusions are most
at risk. Reactions are unpleasant but not life-threatening. Usually symptoms develop
towards the end of a transfusion or in the subsequent two hours. Most febrile reactions can
be managed by slowing or stopping the transfusion and giving paracetamol.

Severe allergic reaction or anaphylaxis

Allergic reactions occur when patients have antibodies that react with proteins in transfused
blood components.

Anaphylaxis occurs where an individual has previously been sensitised to an allergen

present in the blood and, on re-exposure, releases immunoglobulin E (IgE) or IgG
antibodies. Patients with anaphylaxis become acutely dyspnoeic due to bronchospasm
and laryngeal oedema and may complain of chest pain, abdominal pain and nausea.
Individuals with severe IgA deficiency may develop antibody to IgA and, with repeated
transfusion, are at high risk of allergic reaction.

Urticaria and itching are common within minutes of starting a transfusion.

Symptoms are usually controlled by slowing the transfusion and giving antihistamine and
the transfusion may be continued if there is no progression at 30 minutes.

Pre-treatment with chlorphenamine should be given when a patient has experienced

repeated allergic reactions to transfusion.

Presentation[4]
Symptoms or signs may occur after only 5-10 ml of transfusion of incompatible blood so
patients should be observed closely at the start of each blood unit transfused.

Symptoms

Feeling of apprehension or 'something wrong'.

Flushing.

Chills.

Pain at the venepuncture site.

Myalgia.

Nausea.

Pain in the abdomen, flank or chest.

Shortness of breath.

Signs

Fever (rise of 1.5°C or more) and rigors.

Hypotension or hypertension.
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Tachycardia.

Respiratory distress.

Oozing from wounds or puncture sites.

Haemoglobinaemia.

Haemoglobinuria.

Investigation[4, 8]
Initial treatment of acute transfusion reactions (ATR) should be directed by symptoms and
signs. Treatment of severe reactions should not be delayed until the results of
investigations are available. In all moderate and severe transfusion reactions, standard
investigations, including FBC, renal and liver function tests and assessment of the urine for
haemoglobin should be performed.

If febrile symptoms of moderate severity are sustained, implicated units should be returned
to the laboratory for further investigation, the blood service contacted immediately so that
associated components from the implicated donation can be withdrawn and the patient
sampled for repeat compatibility and culture.

Patients who have experienced moderate or severe allergic reactions should have IgA
levels measured. Low levels found on screening, in the absence of generalised
hypogammaglobulinaemia, should be confirmed by a more sensitive method and IgA
antibodies should be checked. Patients with IgA deficiency diagnosed after an ATR should
be discussed with an allergist or immunologist regarding future management.

In the absence of platelet or granulocyte transfusion refractoriness, or acute post-

transfusion thrombocytopenia or leukopenia, investigation of the patient with ATR for
leukocyte, platelet or neutrophil-specific antibodies is not indicated.

Where a serious ATR is suspected, stop the transfusion and take down the donor blood and
send back to the blood bank with notification of event.

To detect a haemolytic reaction, send post-transfusion blood (for FBC and clotting, repeat
type and crossmatch, antibody screen and direct Coombs' test) and urine specimen (for
detection of urinary haemoglobinuria) from the transfusion recipient.

Where an anaphylactic reaction is suspected, seek advice. Usual investigations require

clotted blood samples and include serum Ig levels, HLA antibody investigations and mast
cell tryptase.

Where bacterial contamination is suspected, send blood cultures from patient and bag
remnants.

If the patient is dyspnoeic, obtain blood gases, CXR and central venous pressure (CVP)
reading. Where TRALI is suspected, send anti-leukocyte antibody investigations.

Type of reaction Investigation findings

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 Acute haemolytic Visual inspection of centrifuged plasma - pink-red discolouration
reactions (haemoglobinaemia) where significant intravascular haemolysis.

Visual inspection of centrifuged urine - red discolouration due to

haemoglobinuria.

Retype donor and recipient red blood cells (RBCs) - discrepancy suggests that
the transfusion has been mismatched and blood samples mixed up.

Direct antiglobulin (Coombs') test (DAT) - ABO-related ACR usually cause a

positive DAT test.

Evidence of increased RBC destruction - eg, fall in Hb, rise in lactate

dehydrogenase (LDH), rise in bilirubin.

May be evidence of DIC.

Negative blood cultures.

Febrile non- Visual inspection of recipient's plasma and urine is normal.

haemolytic reactions
Concordant retyping and negative DAT test.

Allergic and Do not usually cause an increased number of eosinophils in subsequent white
anaphylactic blood cell (WBC) differentials.
reactions
Need to demonstrate anti-IgA in a pre-transfusion sample of recipient's serum
or plasma to establish the diagnosis.

Mast cell tryptase can be useful to differentiate anaphylactoid from allergic

reactions.

TRALI Blood gases - hypoxaemia.

CXR - bilateral lung infiltrates.

FBC frequently shows leukopenia and eosinophilia.

Investigate donor HLA and HNA antibody status.

Graft-versus-host Pancytopenia.
disease (GvHD)
Abnormal LFTs.

Deranged U&Es where diarrhoea.

Transfusion- Blood cultures positive and congruent for both donor and recipient blood.
transmitted bacterial
infection

Management[4, 8]
All patients should be transfused in clinical areas where they can be directly observed and
where staff are trained in the administration of blood components and the management of
transfused patients, including the emergency treatment of anaphylaxis. Patients should be
asked to report symptoms which develop within 24 hours of completion of the transfusion.

If a patient being transfused for haemorrhage develops hypotension, a careful clinical risk
assessment is required. If the hypotension is caused by haemorrhage, continuation of the
transfusion may be life-saving. However, if the blood component is considered the most
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likely cause of hypotension, the transfusion must be stopped or switched to an alternative
component and appropriate management and investigation commenced.

Where the only feature is a rise in temperature of <1.5°C from baseline or urticaria, recheck
that the correct blood is being transfused, give paracetamol and antihistamine, reset the
transfusion at a slower rate and observe more frequently.

Whilst fever or rigors are not uncommon in response to a transfusion and may represent a
non-haemolytic febrile reaction, they may also be the first sign of a severe adverse
reaction.

Where the reaction is more severe:

Stop the transfusion and call a doctor urgently to review the patient.

Vital signs (temperature, BP, pulse, respiratory rate, O2 saturation levels or blood gases)
and respiratory status (dyspnoea, tachypnoea, wheeze and cyanosis) should be checked
and recorded.

Check the patient's identity and recheck against details on blood unit and compatability
label or tag.

Initial management where ABO incompatibility is suspected is to:

Keep the intravenous (IV) line open with saline.

Give oxygen and fluid support.

Monitor urine output, usually following catheterisation. Maintain urine output at more than
100 ml/hour, giving furosemide if this falls.

Consider inotrope support if hypotension is prolonged.

Treat DIC appropriately - seek expert advice early and transfuse platelets/fresh frozen
plasma (FFP) guided by the coagulation screen and bleeding status.

Inform the hospital transfusion department immediately.

Where another haemolytic reaction or bacterial infection of blood unit is suspected:

Send haematological and microbiological investigations as outlined above.

General supportive management is as for ABO incompatibility.

Start broad-spectrum antibiotics if bacterial infection is considered likely. If expert

microbiological advice is not immediately available, current guidance is to follow local
neutropenic sepsis protocols.

Involve haematology and intensive care at an early stage.

Where anaphylaxis or severe allergic reaction is suspected:

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Adrenaline (epinephrine) 0.5-1 mg intramuscularly (IM) and repeat every 10 minutes until
improvement occurs.

High-flow oxygen.

IV fluids.

Nebulised salbutamol by face mask if required.

Steroids are second-line and antihistamines are third-line treatments. IV antihistamines

should be used very cautiously as they may further lower blood pressure.

NB: call the anaesthetist if there is difficulty maintaining the airway.

Where TRALI is suspected:

Seek expert help.

Give high-concentration oxygen, IV fluids and inotropes (as for acute respiratory distress
syndrome).

Monitor blood gases, serial CXR and CVP/pulmonary capillary pressure.

Ventilation may be urgently required - discuss with ICU.

TRALI improves over 2-4 days in over 80% cases with adequate ITU management and
respiratory support.

Where fluid overload is suspected:

Give furosemide IV and high-concentration oxygen.

Delayed complications of transfusion[4]

Delayed haemolysis of transfused red cells

In those who have previously been immunised to a red cell antigen during pregnancy or by
transfusion, the level of antibody to the blood group antigen may be so low as to be
undetectable in the pre-transfusion sample.

However, after transfusion of red cells bearing that antigen, a rapid, secondary immune
response raises the antibody level drastically, leading to the rapid destruction of transfused
cells.

5-10 days post-transfusion, patients present with fever, falling Hb (or unexpectedly poor rise
in Hb), jaundice and haemoglobinuria.

A rise in bilirubin and positive DAT will also be present.

Development of antibodies to red cells in patient's plasma (alloimmunisation)

Transfusion of red cells of a different phenotype to the patient's will cause alloimmunisation
- for example, development of anti-RhD in RhD-negative patients who have received RhD-
positive cells.

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This is dangerous if the patient later receives a red cell transfusion, and can cause
haemolytic disease of the newborn (HDN).

Development of antibodies that react with antigens of white cells or platelets

Transfusing red cells of a different phenotype to the patient's can also cause the
development of leukocyte and/or platelet antibodies. This can cause non-haemolytic febrile
transfusion reactions in the future.

The use of leukocyte-depleted red cells and platelets reduces the risk.

Post-transfusion purpura

This is a rare but serious complication caused by platelet-specific alloantibodies, more often
seen in female transfusion recipients.

It usually occurs 5-9 days following transfusion.

Bleeding associated with a very low platelet count develops.

High-dose IV Ig is the current treatment of choice.

Graft-vs-host disease (GvHD)

GvHD is a rare complication of transfusion, caused by T-lymphocytes.

Immunodeficient patients, especially allogenic bone marrow recipients and fetuses
receiving intrauterine transfusions, are at greatest risk.

Transfusion-associated GvHD is almost always fatal (mortality rate 75-90%) and there is no
effective treatment.

Acute GvHD begins between day 4 and day 30 following transfusion, with high fever and
diffuse erythematous skin rash progressing to erythroderma, diarrhoea and abnormal liver
function. Patients deteriorate with bone marrow failure and death occurs through
overwhelming infection.

Transfusion-associated GvHD is preventable with the irradiation of cellular blood products.

Patients requiring irradiated blood include:

Allograft bone marrow and stem cell recipients (for at least six months and some centres
recommend indefinitely).

Patients who have in the past received purine analogue treatment.

Patients with Hodgkin's disease.

Patients with congenital cellular immunity deficiency.

They should be given an information leaflet and card informing them of their need for
irradiated blood and must inform any clinical staff dealing with them in the future.

Iron overload

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Each unit of blood contains 250 mg of iron and those receiving red cells over a long period
may develop iron accumulation in cardiac and liver tissues.

Chelation therapy (with desferrioxamine) is used to minimise iron accumulation in those

most at risk.

Infection

The risk of HIV, hepatitis B or hepatitis C from transfusion is now extremely small (1 in 4
million for HIV, 1 in 100,000 for hepatitis B and less than 1 in 400,000 for hepatitis C).
However, prior to effective tests and screening of blood donors and products, significant
numbers were infected and this should make us wary.

Since there is always the potential for unrecognised or unknown infection to be spread via
transfusion, all non-essential transfusions should be avoided.

Locally non-endemic infection such as human T-cell leukaemia virus type 1 (HTLV-1) and
type 2 (HTLV-2), West Nile virus, malaria and Trypanosoma cruzi (causing Chagas'
disease) may be transmitted by transfusion but donor selection procedures have limited the
risk.

In the UK, variant Creutzfeldt-Jakob disease (vCJD) has caused great concern as it is
thought that the infection is transmissible by blood transfusion. To date, three possible
cases of transfusion-borne vCJD have been reported in the UK. Patients thought to have
received vCJD-implicated plasma products have been contacted and should inform anyone
giving them medical, surgical or dental treatment and should not donate blood, tissue or
organs.[9]
Immunomodulation[10]
Concerns have been raised that tumour recurrence rates and postoperative infection rates
are raised post-transfusion. However, clinical trials comparing recipients of autologous or
leukocyte-depleted red cells and those receiving allogenic or non-leukocyte-depleted red
cells found no difference in these outcomes.

Surveillance and reporting[1]

All suspected transfusion reactions should be reported immediately to the local hospital
transfusion department in case blood packs have been accidentally transposed and
another patient is at immediate risk.

Transfusion reactions should be prominently recorded in the patient's clinical notes.

All transfusion reactions should be reviewed by the hospital's transfusion committee.

UK and European law requires that adverse reactions associated with licensed plasma
derivatives or blood products be centrally reported. This currently occurs via an online
system, Serious and Adverse Blood Reactions and Events (SABRE), linked to the UK
Medical and Healthcare products Regulatory Agency (MHRA).[11]
Nationally, SHOT is the UK's confidential, voluntary reporting system for serious events
following transfusion of blood components and autologous transfusion. The body produces
annual reports highlighting systemic problems and making recommendations to improve
patient safety.[2]
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Improving safety[1, 4]
Reducing transfusion errors

Introduction of robust hospital transfusion protocols.

Training for all staff involved in blood administration/taking samples for cross-matching,
including locum and agency staff.

An understanding of transfusion medicine should be a core curricular component for all

doctors in training.

Improved information technology - use of a unique barcode on the patient's wristband/blood

sample and prepared blood.

Appointing specialist transfusion practitioners - roles include development and evaluation of

transfusion protocols and guidelines; facilitation of audit and improving blood ordering and
administration systems; education of staff and patients about benefits and risks of blood
transfusion, and sometimes direct involvement in near patient testing and cell salvage
techniques.

Reducing unnecessary transfusion

Transfusion risks related to the use of allogenic blood can be eliminated by the use of
autologous blood (where patients collect and store their own blood for use in planned
surgery). This is not risk-free however.

Similarly, 'directed donation' (from family or friends) is discouraged as there is no evidence

that this is safer and there are higher incidences of complications such as transfusion-
associated GvHD in related individuals.

Ensuring that blood products are only used when the patient is judged more likely to benefit
than be harmed by a transfusion.

Base prescribing decisions on the best available clinical guidelines modified according to
individual circumstance. Always record the indication for giving blood in the patient's notes.

The need for transfusion can be reduced by stimulating red cell production with
erythropoietin, reducing surgical bleeding with drugs such as aprotinin or surgical
techniques such as hypotensive surgery, use of fibrin guns and sealants, allowing more
time in theatre to achieve secure haemostasis and sometimes re-using the patient's lost
blood (cell salvage).

Changing procedures such as checking for and correcting anaemia prior to planned
surgery, stopping anticoagulants and antiplatelet drugs before surgery, minimising the
amount of blood taken for laboratory samples and using a simple protocol to guide when
Hb should be checked and when red cells should be transfused.

Accepting a lower Hb concentration as a trigger for transfusion. In the past, a trigger of 10

g/dL was standard but evidence suggests that in the critically ill (who are stable
haemodynamically and not actively bleeding) aiming to maintain Hb concentration between

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7-9 g/dL was at least equivalent to, if not better than, aiming for 10-12 g/dL. The only
exceptions are thought to be in the elderly and in those with cardiac disease, where a safer
target is over 9 g/dL.

Accepting smaller transfusions to just bring Hb concentration over the trigger level.

Patient information[4]
Currently there is no legal requirement in the UK to obtain formal consent from
patients (with use of consent forms, etc) prior to transfusion of blood products. However it
is good practice to discuss:

The need for a blood transfusion and probable benefits.

Where blood loss is acute and severe - eg, following an operation or accident - with the
body unable to compensate quickly, blood transfusion offers rapid relief of symptoms and
can be life-saving.

Where there is severe, symptomatic anaemia that is resistant to other treatments.

To enable other medical or surgical procedures to be done safely.

Risks associated with blood transfusion:

Risks are small - the largest is of being given the wrong blood; however, multiple checks
are taken to avoid this from happening.

The risk of infection from a blood infection is very small but not possible to eliminate.

Alternatives - patients may wish to discuss other options such as oral iron therapy or
autologous transfusion.

Reducing the need for blood transfusion - with elective procedures:

Eat a well-balanced diet prior to the operation.

Check whether iron supplements are advisable.

Check whether/when aspirin, warfarin or other anticoagulants should be stopped.

Any patient judged competent who chooses not to accept a transfusion needs to be treated
with respect and sensitivity, acknowledging their values, beliefs and cultural background.
Jehovah's Witnesses are encouraged to carry documentation detailing their wishes about
any future medical intervention and medical staff must take full account of this. Where
refusing blood or blood components, they should sign the appropriate form, indicating an
informed refusal.

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FURTHER READING AND REFERENCES

British Committee for Standards in Haematology (BCSH) Guidelines

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 Give blood; UK National Blood Service

1. Regan F, Taylor C; Blood transfusion medicine. BMJ. 2002 Jul 20325(7356):143-7.

2. SHOT Annual Reports and Summaries; Serious Hazards of Transfusion
3. Murphy MF, Waters JH, Wood EM, et al; Transfusing blood safely and appropriately.
BMJ. 2013 Jul 16347:f4303. doi: 10.1136/bmj.f4303.
4. Handbook of Transfusion Medicine 5th Edition; UK Blood Transfusion and Tissue
Transplantation Services, January 2014
5. Eder AF, Chambers LA; Noninfectious complications of blood transfusion. Arch
Pathol Lab Med. 2007 May131(5):708-18.
6. Holness L, Knippen MA, Simmons L, et al; Fatalities caused by TRALI. Transfus Med
Rev. 2004 Jul18(3):184-8.
7. Gajic O, Yilmaz M, Iscimen R, et al; Transfusion from male-only versus female
donors in critically ill recipients of high plasma volume components. Crit Care Med.
2007 Jul35(7):1645-8.
8. Guideline on the investigation and management of acute transfusion reactions;
British Committee for Standards in Haematology (Jul 2012)
9. Bird SM; Attributable testing for abnormal prion protein, database linkage, and blood-
borne vCJD risks. Lancet. 2004 Oct 9-15364(9442):1362-4.
10. Raghavan M, Marik PE; Anemia, allogenic blood transfusion, and immunomodulation
in the critically ill. Chest. 2005 Jan127(1):295-307.
11. Report a serious adverse event or reaction related to blood; Medicines and
Healthcare products Regulatory Agency (MHRA), December 2014

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ARTICLE INFORMATION

Last Checked 07 September 2015

12/13
 Next Review 05 September 2020

Document ID 292 (v5)

Author Dr Colin Tidy

Peer reviewer Dr Adrian Bonsall

Disclaimer: This article is for information only and should not be used for the diagnosis or
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