Blood transfusion reactions

What is a blood transfusion?

Blood transfusion can be life-saving and provides great clinical benefit to many patients but it is not without risks¹ :

• Immunological complications.

• Errors and 'wrong blood' episodes - the Serious Hazards of Transfusion (SHOT) report for the UK documented that an error incidence of 2,623 of just over 2 million components transfused in 2020² .

• 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. The reporting rate of transfusion errors is improving although un-reporting of some serious adverse reactions still occasionally occurs² .

Alternative approaches to patient management should be used to reduce or eliminate the need for transfusion whenever possible³ .

Causes of acute complications of transfusion⁴

Early complications of transfusion are rare, occurring in fewer than 1 in 1,000 transfusions; however, they tend to be more severe⁵ .

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).

• 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.

• No UK cases of bacterial contamination of blood products were confirmed by SHOT in 2020² .

• 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 sputum⁶ . 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 ill⁷ .

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.

• 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.

Blood transfusion reaction symptoms⁴

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.

• Tachycardia.

• Respiratory distress.

• Oozing from wounds or puncture sites.

• Haemoglobinaemia.

• Haemoglobinuria.

Investigation^{4 8}

Initial treatment of acute transfusion reactions (ATRs) 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 antibody 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.

Blood transfusion reaction treatment and 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 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:
  

  • 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 transfusion⁴

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.

• 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

• 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 case of transfusion-transmitted hepatitis B occurred in 2020² . There were no cases of confirmed transfusion-transmitted hepatitis C or HIV. 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.

• To date, there has not been any evidence of transmission of SARS-CoV-2 via transfusion of blood components, and this risk is therefore currently theoretical and considered highly unlikely⁸ .

• 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) caused great concern as the infection was transmissible by blood transfusion. To reduce the risk, plasma was imported from countries which had a lower incidence of vCJD. In 2019 it was considered that the risk was much lower than was initially thought, and the requirement to import plasma was withdrawn. It was recommended that other measures such as leukocyte depletion should continue⁹ .

Immunomodulation¹⁰

Concerns have been raised that tumour recurrence rates and postoperative infection rates are raised after transfusion of allogeneic red blood cells, platelet concentrates, or plasma units in cancer patients. There is increasing clinical evidence that this may actually lead to negative clinical outcomes by affecting patients' immune defence, stimulating tumour growth, tethering, and dissemination. There is no question that critically ill patients with life-threatening low blood cell counts or bleeding need transfusion. However, until clinical trials provide further evidence, the routine use of transfusion in critically ill cancer patients should be considered on an individual basis, and the risks and benefits evaluated as with any other treatment.

Surveillance and reporting¹

• 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 safety¹² .

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 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 information⁴