Blood Transfusion Reactions

See also - Blood Transfusion and Blood Products.

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 11.4/100,000 components transfused)²
• Infections (bacterial, viral, possibly prion)
• Immunomodulation
• Litigation

Growing awareness of avoidable risk, improved reporting systems have lead to a culture of better safety procedures as well as steps to minimise the use of transfusion. However, the 2007 SHOT report includes analysis of 4 transfusion related deaths (1 death considered directly attributable to transfusion and 3 deaths where transfusion was considered contributory) and whilst transfusion related mortality has continued to fall, avoidable, serious morbidity due to transfusion, such as that incurred by 12 cases of ABO incompatibility, remains persistent.²

Early complications of transfusion are rare, occurring in less than 1 in 1000 transfusions but tend to be more severe.⁴

Acute haemolytic transfusion reaction

• Incompatible transfused red cells react with the patient's own anti-A or anti-B antibodies or other alloantibodies (e.g. anti-Rh D, Rh E, Rh c 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 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 hyper- or hypotension, rigors and collapse rapidly follows the transfusion.
• 3 UK cases of bacterial contamination of blood products during 2006-7 were confirmed by SHOT.²
• 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 leucocytes.
• Transfusion is followed within 6 hours of transfusion by the development of prominent non-productive cough, breathlessness, hypoxia and frothy sputum.⁵ 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.⁶

Fluid overload

• This 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 normo 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^oC 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% 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 2 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 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 anti-histamine and the transfusion may be continued if there is no progression at 30 minutes.
• Pre-treatment with chlorpheniramine should be given when a patient has experienced repeated allergic reactions to transfusion.

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.

• Where a serious acute transfusion reaction 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 immunoglobulin levels, HLA antibody investigations and mast cell tryptase.
• Where bacterial contamination is suspected, send blood cultures from patient and bag remnants.
• If patient is dyspnoeic, obtain blood gases, CXR and CVP reading. Where TRALI is suspected, send anti-leucocyte antibody investigations.

• Where the only feature is a rise in temperature of <1.5^oC from baseline or urticaria, recheck that the correct blood is being transfused, give paracetamol and anti-histamine, 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 (temp, BP, pulse, respiratory rate, O₂ sats or blood gases) and respiratory status (dyspnoea, tachypnoea, wheeze and cyanosis) should be checked and recorded.
  • Check patient identity and recheck against details on blood unit and compatability label or tag.
• Initial management where ABO incompatibility is suspected is to:
  • Keep the 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 prolonged.
  • Treat DIC appropriately - seek expert advice early and transfuse platelets/FFP guided by the coagulation screen and bleeding status.
  • Inform 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:
  • High flow oxygen and nebulised salbutamol by facemask.
  • Give chlorpheniramine 10-20 mg by slow IV injection.
  • Where severe hypotension, give adrenaline 0.5-1 mg IM and repeat every 10 minutes until improvement occurs.
  • Call the anaesthetist if 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 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 pretransfusion 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 haemoglobin (or unexpectedly poor rise in Hb), jaundice and haemoglobinuria.
• A rise in bilirubin and positive direct antiglobulin test (DAT) will also be present.

Development of antibodies to red cells in patient's plasma (allo-immunisation)

• Transfusion of red cells of a different phenotype to the patient's will cause allo-immunisation - 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 leucocyte and/or platelet antibodies. This can cause non-haemolytic febrile transfusion reactions in the future.
• The use of leucocyte depleted red cells and platelets reduce 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 immunoglobulin is the current treatment of choice.

Graft vs. host disease (GvHD)

• This 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 for 6 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 C from transfusion is now extremely small (1 in 4 million for HIV, 1/100,000 for Hep B and less than 1/400,000 for Hep 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 HTLV1 and 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 CJD 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.¹⁰

Immunomodulation¹¹

Concerns have been raised that tumour recurrence rates and post-operative infection rates are raised post-transfusion. However, clinical trials comparing recipients of autologous or leucocyte depleted red cells and those receiving allogenic or non-leucocyte depleted red cells found no difference in these outcomes.

• 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 Regulatory Authority (MHRA).¹²
• Nationally, SHOT (Serious Hazards of Transfusion) 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.

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 component of all doctors in training's curriculum.
• Improved information technology - use of unique barcode on patient 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 these are safer either from an infection risk 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 reusing the patient's lost blood (cell salvage).
• Changing procedures such as checking for and correcting anaemia prior to planned surgery, stopping anti-coagulants and antiplatelet drugs before surgery, minimising the amount of blood taken for laboratory samples and using a simple protocol to guide when haemoglobin should be checked and when red cells should be transfused.
• Accepting a lower haemoglobin concentration as 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 haemoglobin concentration between 7-9 g/dl was at least equivalent, 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 haemoglobin concentration over trigger level.