Transfusion Reactions

Context

Blood transfusion is a common intervention in hospitalised patients; nearly 2 million blood components are issued and transfused in England per year, at an estimated cost of over £300 million.1

Transfusion is not without risk. According to the Serious Hazards of Transfusion (SHOT) 2022 report, the risk of death related to transfusion in the UK is 1.57 per 100,000 components issued and the risk of serious harm is 6.47 per 100,000 components issued.2 Figure 1 highlights the risk of the different types of transfusion reactions based on data collected by the SHOT reporting group in the UK.2 Pulmonary complications were the highest cause of morbidity and mortality, accounting for 65% of transfusion-related deaths.3

Fig. 1: Risk of transfusion reaction according to SHOT data2

Definition and Classification

Transfusion reactions are defined as adverse events associated with the transfusion of whole blood or one of its components and can be classified according to their onset and mechanism. Acute transfusion reactions are defined as those occurring within 24 hours of the administration of blood or blood components, whereas delayed transfusion reactions occur more than 24 hours after transfusion.4 Transfusion reactions can be classified further as shown in Figure 2.

Fig. 2 Classification of Transfusion Reactions

Learning bite

Be aware that transfusion reactions can have a delayed onset, occurring over 24 hours after the transfusion is completed.

Identifying a Transfusion Reaction

Patients must be monitored during a transfusion of blood products to identify and manage adverse reactions early. According to the British Society for Haematology (BSH) guidelines, minimum monitoring standards should include5:

• Pre-transfusion observations (pulse, blood pressure, temperature and respiratory rate) recorded no more than 60 minutes before the start of transfusion.
• Observations recorded 15 minutes after the start of each unit.
• Post-transfusion observations recorded no more than 60 minutes after the end of the transfusion.
• Regular visual monitoring of the patient throughout the transfusion episode.

Any deterioration in the patient’s condition or development of symptoms may represent a transfusion reaction and should prompt further review.

Immune-mediated Acute Transfusion Reactions

Febrile reactions3,6

Febrile reactions are thought to be immune- mediated, caused by reactions to donor white blood cells present in the blood component being transfused.

Symptoms generally develop towards the end of the transfusion or in the subsequent two hours.

Febrile reactions are classified as:

• Mild – temperature ≥38°C or 1-2°C above pre-transfusion baseline
• Moderate – temperature ≥39°C or ≥2°C above pre-transfusion baseline

BSH guidelines recommend that patients with mild febrile reactions only are treated with oral paracetamol and the transfusion continued with close observation.

If a patient becomes febrile with systemic symptoms such as chills, rigours, myalgia, nausea or vomiting, then bacterial contamination or a haemolytic reaction should be considered.

If bacterial contamination is suspected:

• Discontinue the transfusion immediately
• Take blood cultures
• Fluid resuscitate with intravenous (IV) 0.9% sodium chloride
• Start broad-spectrum IV antibiotics
• Return the implicated unit to the Transfusion Lab for culture
• Report to your local Haematology Services and the National Blood Transfusion Service (NHSBT) to recall any other components manufactured from the implicated donation.

Haemolytic reactions are discussed later.

Allergic reactions3,6

Allergic reactions are hypersensitivity reactions to allergens in the transfused component.

Symptoms include pruritus, flushing, urticaria and angioedema, and usually appear within a few minutes of commencing the transfusion. Associated stridor, wheeze, dyspnoea or shock are suggestive of anaphylaxis and should be managed according to national guidelines with intramuscular (IM) adrenaline.

Mild to moderate allergic reactions without life threatening features or signs of anaphylaxis can be managed with antihistamines (e.g. chlorphenamine) and by slowing down the rate of the transfusion. There is no evidence for the use of corticosteroids.

If a patient reports a previous mild allergic reaction with blood transfusion, there is no evidence to support routine prophylaxis with antihistamines or corticosteroids, but antihistamines can be given if the patient develops an allergic reaction with the current transfusion. For recurrent moderate to severe allergic reactions, BSH guidelines state that antihistamine prophylaxis and transfusion of washed products can be considered.

Learning bite

Sustained febrile symptoms can be a sign of a haemolytic reaction or bacterial contamination. The transfusion should be discontinued and the patient assessed.

Acute Haemolytic Transfusion Reactions9

Acute haemolytic transfusion reactions typically result from ABO incompatibility leading to intravascular haemolysis. The most frequent preventable cause is misidentification of the patient or mislabelling of blood samples.

Symptoms present during or immediately following transfusion and include pyrexia, rigours, pain at the infusion site, flank or back pain, and anxiety or an ’impending sense of doom’. Severe haemolytic reactions can progress to renal failure, hypotension and DIC.

If an acute haemolytic transfusion reaction is suspected:

• Discontinue the transfusion immediately
• Return the remaining unit to the lab for repeat testing for compatibility
• Supportive management includes hydration aiming to maintain urine output above 0.5-1 mL/kg/hr to minimise renal injury, with forced diuresis using furosemide if appropriate
• Vasopressor support may be needed for resistant hypotension
• Renal dialysis may also be required in severe cases
• Monitor for the development of DIC

Initial investigations should include:

• Direct Antiglobulin Test (DAT)
• Repeat ABO compatibility testing
• Urine dipstick for haemoglobin

Learning Bite

In patients with suspected acute haemolytic reactions, the transfusion should be stopped immediately and the remaining unit returned to the lab for further compatibility testing.

Delayed Haemolytic Transfusion Reactions9,10

Delayed haemolytic reactions are caused by secondary immune responses in patients who have developed antibodies from previous transfusions or pregnancy.

Symptoms include a low grade fever, anaemia and jaundice occurring 2-30 days after transfusion. In the majority of cases symptoms are mild and no specific treatment is required. These cases should also be reported to the local Transfusion Service.

Transfusion – Related Acute Lung Injury (TRALI)9

TRALI is defined as non-cardiogenic pulmonary oedema and acute hypoxia occurring within six hours of a transfusion in the absence of other causes of acute lung injury or circulatory overload.

It is thought to result from granulocyte activation in the pulmonary vasculature by antibodies in donor plasma or other bioactive substances in transfused components. The inflammatory response leads to injury to the alveolar capillary membrane and increased permeability, causing pulmonary oedema.

Symptoms include dyspnoea, hypoxia, fever, hypotension and tachycardia. All suspected cases of TRALI should be discussed with Haematology and reported to the NHSBT.

If TRALI is suspected, treatment is largely supportive:

• Give supplemental oxygen
• Judicious use of IV fluids
• Escalation to ITU for invasive mechanical ventilation if required

Symptoms usually improve within 7 days after transfusion.

Non-immune-mediated Acute Transfusion Reactions

Transfusion- Associated Circulatory Overload (TACO)8,9

TACO is characterised by hydrostatic pulmonary oedema due to volume overload.

It presents with dyspnoea, jugular venous distension and elevated blood pressure, and usually occurs during or up to 12 hours after transfusion.

Patient groups at risk of TACO include those with heart failure, renal failure, chronic severe anaemia, the elderly and those receiving large volumes of blood products at rapid rates. SHOT recommends use of a formal pre-transfusion TACO risk assessment checklist, an example of which is shown in Figure 3 below.

B-type natriuretic peptide (BNP) may be raised in TACO due to increased myocardial stretching.

If TACO is suspected

• Stop the transfusion
• Give supplemental oxygen
• Give diuretics

Figure 3: TACO risk assessment checklist2

Although TACO and TRALI present similarly, distinguishing between them is important as the management of each differs. The main characteristics are summarised in Figure 4 below.

Figure 4: Differences between TACO and TRALI4

Delayed Transfusion Reactions

Transfusion-Associated Graft-Versus-Host Disease (TA-GvHD)4

TA-GvHD is a rare and almost always fatal delayed transfusion reaction. It is primarily observed in immunodeficient patients, where lymphocytes in a blood donation mount an immune response against the recipient’s cells.

At risk patients have impaired immunity and are unable to reject the foreign cells. These include foetuses receiving intrauterine transfusion, patients with congenital immune deficiency disorders and Hodgkin’s lymphoma and allogenic stem cell transplant recipients.

Symptoms usually occur between 4-30 days after transfusion, and include fever, diffuse erythematous skin rash, diarrhoea, deranged liver function tests and bone marrow aplasia.

There is no definitive treatment and management is primarily by prevention through use of irradiated blood products in at risk groups.

Post-Transfusion Purpura

Post-transfusion purpura is a delayed transfusion reaction which occurs due to activation of platelet-specific antibodies in a recipient with prior sensitisation to foreign platelet antigens, usually during pregnancy or a previous transfusion. Both the donor platelets and recipient’s native platelets are destroyed, resulting in thrombocytopenia.4,6

It typically presents 5-12 days after transfusion with bleeding and disseminated purpura. Treatment is with high dose intravenous immunoglobulin (IVIg).4,6

Initial treatment should be based on clinical assessment and should not be delayed pending investigation results.

Standard investigations for all moderate to severe transfusion reactions include4:

• Full blood count (FBC)
• Renal function tests (U&Es)
• Liver functions tests (LFTs)
• Urinalysis for haemoglobin

Other investigations may be required according to the specific presentation4:

• Fever (≥39°C or ≥2°C rise from baseline) with systemic symptoms
  
  • Repeat ABO compatibility testing
  • DAT
  • LDH
  • Haptoglobin
  • Blood cultures
  • Coagulation screen
• Mucosal swelling
  
  • IgA levels
• Dyspnoea, wheeze or features of anaphylaxis
  
  • Arterial blood gas (ABG)
  • Chest x -ray
  • If an anaphylactic reaction is suspected, measure serial mast cell tryptase (immediately and at 3 and 24 hours).

The BSH guidelines outline the management of acute transfusion reactions. Figure 6 shows an algorithm adapted from these guidelines.

Any change in observations or development of adverse clinical features should trigger a clinician to stop the transfusion and undertake a further clinical assessment.

Figure 6: Algorithm for management of acute transfusion reactions10

Haemovigilance and Reporting Requirements:

Haemovigilance is the surveillance covering the entire blood transfusion chain, from the donation and processing of blood and its components, through to their provision and transfusion to patients and their follow-up. It is essential to ensure transfusion safety.2

The Medicines and Healthcare products Regulatory Agency (MHRA) is the designated body in the UK to whom all serious adverse events and serious adverse reactions pertaining to transfusion of blood components should be reported – this is a legal requirement.

Serious Hazards of Transfusion (SHOT) is the UK’s independent haemovigilance scheme. They collect and analyse data regarding transfusion related adverse events and make recommendations to improve patient safety.

All transfusion reactions except mild febrile and allergic reactions must be reported to appropriate regulatory and haemovigilance organisations and reviewed within the hospital.3 This is usually done via the blood bank, who use the designated online reporting system Serious Adverse Blood Reactions and Events (SABRE) to submit haemovigilance reports to the MHRA and SHOT.

Reporting to the blood transfusion service (NHSBT) is also required in cases of suspected TRALI or bacterial contamination as associated components from the implicated donation will need to be tracked and removed from supply.

Learning Bite

Reporting serious adverse transfusion events and reactions to the MHRA is a statutory requirement. Consult your local transfusion laboratory and haematology team for further guidance on local reporting procedures and policies.

• Prescribing and transfusing blood products when they are not clinically indicated. If the risks of transfusion can be avoided, they should be.
• Failure to recognise symptoms of acute transfusion reactions and respond in a timely manner, particularly delay in suspending transfusion.
• Misidentification of the type of reaction, resulting in inappropriate management.
• Failure to adequately assess and identify pre-existing risk factors for TACO and consider alternatives to transfusion in these circumstances.
• Underreporting, insufficient documentation and failure to adhere to local reporting protocols for any adverse transfusion reactions or near miss events.