Blood Transfusion Reactions

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 335 per 5.5 million units of red cells transfused¹)
• Infections (bacterial, viral, possibly prion)
• Immunomodulation
• Litigation

The 2004 SHOT report includes analysis of 4 transfusion related deaths and 540 serious transfusion-related events and 1076 "near misses". 67% UK hospitals entered a report.²
In response to the growing awareness of avoidable risk, improved reporting systems have lead to better safety procedures as well as steps to minimise the use of transfusion.

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 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. In the UK, between 1994 and 2000, a rate of 2/million units transfused developed such a condition but this is likely to be an underestimate.¹ Platelets are more likely to be associated with bacterial contamination than red cells.

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 by a severe reaction with fever, non-productive cough and breathlessness. CXR shows multiple perihilar nodules with infiltration of the lower lung fields. Implicated donors are usually multiparous women and should be removed from the blood panel where possible.

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 must receive packed cells rather than whole blood and should receive their transfusions slowly 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 affect 1-2% patients due to patient antibodies to transfused white cells. Multiparous women and those who have received 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. 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.

Serious or life-threatening acute reactions are rare but new symptoms or signs arising during a transfusion can be the first sign of a life-threatening reaction so must be taken seriously. 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.
• 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 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.
• Initial management where a serious acute reaction is suspected is to:
  • Stop the transfusion.
  • Keep the iv line open with saline.
  • Call a doctor urgently to review the patient.
  • Check and record patient observations (temp, BP, pulse, respiratory rate, O₂ sats or blood gases) and respiratory signs (dyspnoea, tachypnoea, wheeze and cyanosis).
  • Recheck patient identity/blood unit and documentation.
  • Notify blood bank.
• Where a patient is hypotensive (systolic BP>20% below pretransfusion level),provided there are no signs of acute fluid overload, give saline (20-30 ml/kg) over 5 minutes and monitor observations including urine output. Where hypotension does not respond and becomes sustained:
  • Seek expert help.
  • Insert a central venous line.
  • Take blood cultures.
  • Infuse more iv fluids to maintain a CVP 5 to 10 cm.
  • Decide on need for iv hydrocortisone/broad spectrum antibiotics/adrenaline or other inotrope.
• Where bacterial contamination is suspected,seek expert advice and choose antibiotic cover appropriate for gram positives including Staph. Aureus) and gram-negatives.
• Where DIC is suspected, seek expert advice and transfuse platelets/FFP guided by coagulation screen and bleeding status.
• Where anaphylaxis or severe allergic reaction is suspected, give:
  • High concentration oxygen
  • Chlorpheniramine 10-20 mg by slow IV injection
  • Hydrocortisone 100-200 mg iv
  • Adrenaline 0.5-1 mg im and repeat every 10minutes until improvement occurs
  • Salbutamol 2.5-5mg by nebuliser
  • 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).
  • 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 frusemide 40mg 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. 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 will be dangerous if the patient later receives a red cell transfusion and can cause haemolytic disease of the newborn.

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. Usually 5-9 days post 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.In the UK, variant CJD has caused great concern as it is thought that the infection is transmissible by blood transfusion. In 2003, the UK announced its first case of probable blood-borne vCJD. 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.⁷

Immunomodulation^3,8

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. RCT evidence that certain patient subgroups (those receiving leucodepleted blood and those receiving less blood) have reduced overall mortality still requires fuller investigation.

• 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 may also be reported in hospital-wide "adverse incident reporting schemes" and fed into NPSA's central UK reporting scheme to generate national information and recommendations to improve patient safety.
• Transfusion reactions should be prominently recorded in the patient's clinical notes.
• All transfusion reactions should be reviewed by the hospital's transfusion committee.
• 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.
• Adverse reactions associated with licensed plasma derivatives or blood products should be reported via the Yellow Card system to the UK Medical and Healthcare Regulatory Authority (MHRA).

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.
• 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.
• 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 100 g/l was standard but evidence suggests that in the critically ill (who are stable haemodynamically and not actively bleeding) aiming to maintain haemoglobin concentration between 70-90 g/l was at least equivalent, if not better, than aiming for 100-120 g/l. The only exceptions are thought to be in the elderly and in those with cardiac disease, where a safer target is over 90 g/l.
• Accepting smaller transfusions to just bring haemoglobin concentration over trigger level.