Blood transfusion

Acute transfusion reactions

Serious or life threatening acute reactions are very rare. However, new symptoms or signs that arise during a transfusion must be taken seriously as they may be the first warnings of a serious reaction.

Acute, life-threatening complications of transfusion include:

• acute haemolytic transfusion reaction

• infusion of a bacterially contaminated unit

• transfusion-associated lung injury

• fluid overload

• severe allergic reaction or anaphylaxis.

Acute haemolytic transfusion reaction

Incompatible transfused red cells react with the patient's own anti-A or anti-B antibodies (for more information please click here). This reaction can destroy red cells in the circulation, initiate acute renal failure and cause disseminated intravascular coagulation (DIC). Infusion of ABO-incompatible blood is most commonly due to errors in taking or labelling the sample, collecting the wrong blood from the refrigerator or inadequate checking when the transfusion of the pack is being started.
If red cells are mistakenly administered to the wrong patient, the chance of ABO incompatibility is about 1 in 3. The reaction is usually most severe if Group A red cells are infused to a Group O patient. In a conscious patient, even a few ml, of ABO incompatible blood may cause symptoms within a few minutes.

Bacterial contamination

Infusion of the contents of a blood pack contaminated by bacteria
This is likely to cause a very severe acute reaction with rapid onset of hypotension, rigors and collapse.

Transfusion-related acute lung injury (TRALI)

Transfusion is followed by rapid onset of breathlessness and non-productive cough. The chest X-ray characteristically shows bilateral infiltrates often described as 'white out'. Treatment is that for adult respiratory distress syndrome from any cause. In TRALI, it is usually found that plasma of one of the donors contains antibodies that react strongly with the patient's leucocytes. The implicated donors are almost always parous women. It is very important to report TRALI to the blood service so that an implicated donor can be contacted and taken off the donor panel.

Fluid overload

When too much fluid is transfused or the transfusion is too rapid, acute left ventricular failure (LVF) may occur with dyspnoea, tachypnoea, non-productive cough, raised jugular venous pressure (JVP), basal lung crackles, hypotension and tachycardia. The transfusion should be stopped and standard medical treatment including diuretic and oxygen given.
Patients with chronic anaemia are usually normovolaemic or hypervolaemic and may have signs of cardiac failure before any fluid is infused. If such a patient must be transfused, each unit should be given slowly with diuretic (e.g., frusemide, 20 mg), and the patient closely observed. Restricting transfusion to one unit of RCC in each 12-hour period should reduce the risk of LVF. Volume overload is a special risk with 20% albumin solutions.

Severe allergic reaction or anaphylaxis

This is a rare but life-threatening complication usually occurring in the early part of a transfusion. More of a risk with blood components that contain large volumes of plasma, eg FFP or platelets. Signs consist of hypotension, bronchospasm, peri-orbital and laryngeal oedema, vomiting, erythema, urticaria and conjunctivitis. Symptoms include dyspnoea, chest pain, abdominal pain and nausea.

Anaphylaxis occurs when a patient who is pre-sensitised to an allergen producing IgE antibodies is re-exposed to the particular antigen. IgG antibodies to infused allergens can also cause severe reactions.

A few patients with severe IgA deficiency develop antibodies to IgA. Some of these patients have severe anaphylaxis if exposed to IgA by transfusion. If the patient who has had a reaction has to have further transfusion, it is essential to use saline-washed red cells or, if available, blood components from IgA-deficient donors.

Management of acute transfusion reactions

Since it may be impossible to identify immediately the cause of a severe reaction, the initial supportive management should generally cover all the possible causes.

If the only feature is a rise in temperature of less than 1.5°C from baseline or an urticarial rash:

• recheck that the right blood is being transfused

• give paracetamol for fever

• give antihistamine for urticaria

• recommence the transfusion at a slower rate

• observe more frequently than routine practice.

If a severe acute reaction is suspected:

• stop the transfusion - keep the IV line open with saline

• check and record patient's temperature, BP, pulse, respiratory rate

• check for respiratory signs - dyspnoea, tachypnoea, wheeze, cyanosis

• recheck the identity of patient and blood unit and documentation

• notify blood bank

• check blood gases or O2 saturation

• provide further management according to the patient's developing clinical features.

Hypotension (systolic BP >20% below pretransfusion level)
In the absence of signs of acute fluid overload:

• resuscitate with saline 20-30 ml/kg over 5 mins
• monitor observations including urine output.

Sustained hypotension

• seek expert advice
• insert central venous line
• take blood cultures
• infuse more intravenous fluid to maintain CVP +5 cm to +10 cm
• decide on the need for:
  - IV hydrocortisone 100mg
  - broad spectrum antibiotics (see below)
  - adrenaline or other inotrope.

Bacterial contamination and antibiotics

• Seek expert advice if bacterial contamination is suspected
• Antibiotics should be chosen to cover gram-positives, including Staphylococcus aureus, and gram-negatives, e.g:
  - a third generation cephalosporin, quinolones or aminoglycosides
  - plus azlocillin, ticarcillin, pipericillin.

DIC

• Seek expert advice.
• Transfuse platelets and/or FFP, guided by coagulation screen and presence or absence of bleeding.

If anaphylaxis or a severe allergic reaction is suspected, give:

• high concentration oxygen

• chlorpheniramine 10-20 mg by slow IV injection over 1-2 minutes

• hydrocortisone 100-200 mg IV

• adrenaline 0.5-1 mg (0.5-1 ml of 1 in 1000) by IM injection; repeat every 10 minutes until improvement occurs

• salbutamol 2.5 to 5 mg by nebuliser.

If TRALI is suspected

• seek expert advice

• high concentration oxygen

• IV fluids and inotropes, as for acute respiratory distress syndrome

• mechanical ventilatory support may be urgently needed.

If fluid overload is suspected

• frusemide 40 mg IV

• high concentration oxygen.

• Note: It may be difficult to distinguish TRALI from fluid overload when respiratory distress develops during or shortly after transfusion. Raised CVP suggests fluid overload, while raised pulmonary wedge pressure suggests TRALI. Unlike other causes of ARDS, TRALI improves over 2-4 days in over 80% of cases provided there is adequate ITU management with respiratory support. The mortality was 20% in TRALI cases in the UK reported to SHOT.

Reactions due to red cell antibodies other than anti-A and anti-B

Intravascular haemolysis is normally associated with ABO incompatibility and only rarely with antibodies to other red cell antigens. Extravascular haemolysis occurs when red cells, coated with antibody and complement are destroyed by macrophages in the liver and spleen. This mechanism can remove as much as 400 ml of red cells from the circulation per day. The symptoms typically are fever and chills with elevated bilirubin and falling Hb. Antibodies with these properties occur against the ABO, S, Kell, Duffy and Kidd antigen systems. Antibodies against the Rh system antigens do not activate complement but antibody-coated red cells are nevertheless bound to, and destroyed by, macrophages.

Delayed haemolytic reaction

This rare type of reaction usually occurs in patients who have developed red cell antibodies in the past, from transfusion or pregnancy. These may be undetectable when the patient is tested months or years later. However, a subsequent red cell transfusion can quickly boost the antibody. Antibodies of the Kidd (Jk) system are often the cause of such delayed haemolytic reactions.

A combination of the following features, occurring some days after red cell transfusion, suggests that the transfused red cells are being destroyed abnormally quickly:

• Hb falls more rapidly than expected after a red cell transfusion

• rise in Hb is less than expected

• rise in bilirubin

• positive direct antiglobulin test.

Febrile non haemolytic transfusion reactions (FNHTR)
Fever or rigors during red cell or platelet transfusion affect 1-2% of recipients, mainly multi-transfused or previously pregnant patients, although these reactions are probably less frequent with leucodepleted components. Features are fever (>1°C above baseline) usually with shivering and general discomfort occurring towards the end of the transfusion or up to 2 hours after it has been completed. Most febrile reactions can be managed by slowing or stopping the transfusion and giving an antipyretic e.g., paracetamol (not aspirin). These reactions are unpleasant but not life-threatening.
It is important to remember that fever or rigors could be the first warning of a severe acute reaction.

Allergic reactions

Urticaria and/or itching within minutes of starting a transfusion are quite common, particularly with components including large volumes of plasma e.g., platelet concentrates and FFP. Symptoms usually subside if the transfusion is slowed and antihistamine is given (e.g., chlorpheniramine 10 mg, by slow intravenous injection or intramuscular injection in patients who are not thrombocytopenic). The transfusion may be continued if there is no progression of symptoms after 30 minutes. Chlorpheniramine should be given before transfusion if the patient has previously experienced repeated allergic reactions. If signs and symptoms fail to respond to this, saline-washed blood components should be considered.

Delayed complications of transfusion.

Graft-versus-host disease (GvHD)

Transfusion-associated graft-versus-host disease (TA-GvHD)

• Leucocyte filtration does not offer protection.
• The mortality is 75-90%.
• Blood components from a parent or other close relative must be irradiated before transfusion to the recipient.
• There is no effective treatment.
• The condition is almost always fatal.

Iron overload

Transfusion-dependent patients receiving red cells over a long period become overloaded with iron. Each unit of red cells contains 250 mg of iron and tissue accumulation can cause liver and cardiac damage. Chelation therapy with desferrioxamine is used to minimise accumulation of iron in patients likely to receive long-term transfusions.

Immune modulation by transfusion

Allogeneic blood transfusion alters the recipient's immune system in several ways. There has been concern that tumour recurrence rates and/or the incidence of postoperative infection could be increased in transfusion recipients. However, well designed clinical trials have not shown a difference in either of these outcomes in recipients of autologous or leucodepleted red cells when compared to recipients of allogeneic or non-leucodepleted red cells. Recent randomised controlled trials (RCTs) have compared all-cause mortality in recipients of leucodepleted versus non-leucodepleted red cells or in patients managed to a high versus a lower Hb transfusion trigger level. These studies show some evidence of reduced mortality in certain subgroups of patients receiving either leucodepeleted blood or less blood overall. These observations are under investigation.

Post-transfusion purpura (PTP)

This is a rare but potentially lethal complication of transfusion of red cells or platelets. It is more often seen in female patients. It is caused by platelet-specific alloantibodies. Typically, 5-9 days after transfusion the patient develops an extremely low platelet count with bleeding.
Management:

High-dose intravenous immunoglobulin (IVIgG) (2g/kg given over 2 or 5 days) is the current treatment of choice with responses in about 85% of cases; there is often a rapid and prompt increase in the platelet count. Steroids and plasma exchange were the preferred treatments before the availability of IVIgG, and plasma exchange, in particular, appeared to be effective in some, but not all, cases.

Platelet transfusions are usually ineffective in raising the platelet count, but may be needed in large doses to control severe bleeding in the acute phase, particularly in patients who have recently undergone surgery, before there has been a response to high-dose IVIgG. There is no evidence that platelet concentrates from HPA-1a negative platelets are more effective than those from random donors in the acute thrombocytopenic phase, and the dose of platelets may be more important than the platelet type of the donor platelets. There is no evidence to suggest that further transfusions in the acute phase prolong the duration or severity of thrombocytopoenia

Infections transmissible by transfusion

Over the past 30 years, the viruses that cause hepatitis B, AIDS and hepatitis C have been identified. In each case, effective tests were developed and rapidly introduced to detect and exclude blood donations that could transmit these infections to a recipient. The risk of being infected with any of these viruses as a result of a transfusion in the UK is now very low.

Estimates of the risks of virus transmission by blood products in the UK:

Plasma derivatives (virus inactivated)
There is minimal or zero risk of transmitting HIV, human T-cell leukaemia virus (HTLV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Certain very small viruses that lack an outer lipid envelope are relatively resistant to inactivation procedures. If present in donor plasma they may not be fully inactivated in all current products.

Blood components
Plasma and cryoprecipitate may be subject to pathogen inactivation. Cellular products are not currently subject to pathogen inactivation but processes for platelets are under trial.

HIV, hepatitis B and hepatitis C

The risk of HIV hepatitis B, and hepatitis C from transfusion has become extremely small. The current risk of a blood component transmitting HIV is less than 1 in 4 million, for hepatitis B is around 1/100,000 and for hepatitis C is less than 1/400,000 (for anti-HCV tested components and less than 1 in 1 million for components that have been tested for both anti-HCV and HCV RNA). Therefore, in the UK (where approximately 3.4 million components are issued each year) we expect to issue one component in every 1 to 2 years that could transmit HIV, around 34 components per year that could transmit hepatitis B, and - with increasing use of HCV RNA testing - substantially less than 8 per year for hepatitis C. A UK government expert committee has estimated for HTLV I/II that at most 3 recipients per year are placed at risk of developing some manifestation of HTLV disease during their lifetime.

The fact that a potentially infective component is released does not mean that a patient necessarily is infected. The actual number of infected recipients predicted is much less and very similar to the numbers that have been reported in the UK.
 

CJD
In the UK, a great concern at the moment is vCJD, a human disease linked to BSE (so-called mad cow disease). There have been no reports of vCJD infection due to blood transfusion. Nevertheless, precautions have been introduced to try to reduce any possible risk.

Several recently described viruses such as GBV-C (so-called "hepatitis G"), TT virus and SEN-V have been shown to be transmissible by transfusion. None of these have been shown to be pathogenic. Human herpes virus 8 (HHV8), the causative agent of Kaposi''s sarcoma, has so far not been shown to be transmitted by cellular blood components.

Hepatitis C
Serological tests to detect hepatitis C virus infection were introduced in 1991 and have been progressively improved since then: less than 1 in 400,000 blood components tested for HCV antibody could result in hepatitis C infection. The introduction of direct testing for hepatitis C RNA reduces the risk to less than 1 in a million. The infection is usually asymptomatic and revealed only by disturbed liver enzyme tests. About half the affected patients have chronic infection that can lead, after some years, to severe liver damage.

Other hepatitis viruses
There have been four reports of hepatitis A transmission by blood components in the UK over the past 25 years. Further viral processes are being introduced to inactivate protein-enveloped viruses such as hepatitis A in plasma fractions.

HTLV(I and II)
HTLV can cause tropical spastic paresis and a rare form of adult T-cell leukaemia. There is a latent period usually of many years between infection and development of illness. Only a small proportion of those infected become ill. HTLV I is transmissible by the cellular blood components, not plasma. The prevalence of infection is high in some parts of the world, notably Japan and the Caribbean. The link between HTLV II infection and disease is less clear, but infection is found in some intravenous drug users. Surveys in the UK indicate that the risk of HTLV-related disease following transfusion of blood is exceedingly low. Blood donors in the UK are not currently screened for HTLV I/II infection. However, leucodepletion may well be shown to reduce the risk.

Cytomegalovirus (CMV)
Approximately 50% of UK blood donors have antibody to CMV, but only a small proportion of antibody-positive donations transmit the virus through transfusion. Transfusion-transmitted CMV is of proven clinical importance in premature infants weighing less than 1200-1500 g who are born to CMV antibody-negative mothers and in CMV antibody-negative bone marrow allograft recipients who receive CMV seronegative grafts. Although the risk of clinical CMV infection is much smaller in recipient of autografts, some centres recommend that CMV-seronegative patients undergoing autografts also should receive CMV- negative products, For these patients CMV-safe blood components should be given. This is normally done by using donations that do not contain detectable antibody to CMV. CMV is only transmitted by leucocytes. There is evidence that the use of leucocyte-depleted blood components is effective in preventing transmission of CMV by transfusion. However, the use of CMV antibody-negative components, in addition to leucocyte-depletion, currently remains the treatment of choice in clinical situations where there is high risk of CMV transmission (for more information please click here). Fresh frozen plasma and cryoprecipitate do not transmit CMV.

Human parvovirus B19
This protein-enveloped virus may not be inactivated in all current plasma fractions. Processes are being introduced to do this. There is evidence that HPV B19 infection is associated with bone marrow suppression affecting red cell production in occasional patients.

Treponemal infections
All donations are screened for serological evidence of Treponema pallidum infection. A further safeguard is that infectivity of T. pallidum declines as blood is stored at 2-6°C. Transfusion transmission is estimated to occur with a frequency of about 1/40,000 in the USA. There have been no reports of transfusion transmission in the UK in recent years.

Other bacterial infections
Bacterial contamination of a blood component is a rare cause of very severe and often lethal transfusion reactions. In the UK, 16 incidents (4 fatalities) were identified during the 6 years to 2000, giving a rate of about 2/million units transfused. This is likely to be an underestimate. Bacteria associated with severe septic reactions to red cell transfusion are usually cold-growing strains. Pseudomonas fluorescens, the type most often isolated is an environmental contaminant. Yersinia enterocolitica is an example of an organism that may enter a blood donor pack that is collected from a donor during an episode of asymptomatic bacteraemia. Skin contaminants such as staphylococci may proliferate in platelet concentrates stored at 20-22°C and this is a factor limiting the safe storage life of platelet concentrates. Platelets are more likely to be associated with bacterial complications than are red cells. New methods for reducing this risk are in development.

Malaria
Donor selection procedures are designed to exclude potentially infectious individuals from donating red cells for transfusion. Transfusion-transmitted malaria occurs with a frequency of about 0.25/million units collected in the USA. Comparable data for the UK are not available. Only four cases of transfusion malaria (all due to Plasmodium falciparum) have been reported in the UK in the past 25 years. A screening test for donors has been evaluated that detects malarial antibody in potential blood donors who have a history of potential exposure to malarial infection. This test may enable some people who are currently excluded to be accepted as donors.

Chagas disease
This is caused by Trypanosoma cruzi and is transmissible by transfusion. Four cases have been reported in the US, but none in the UK. It is an important problem in parts of South America where the infection is endemic. A new test for antibody can now allow the acceptance of donors at risk of infection who would previously have been excluded.

Joint National Institute of Biological Standards and Control and United Kingdom Blood
Transfusion Services guidelines www.transfusionguidelines.org.uk

Scottish Intercollegiate Guidelines Network. Perioperative Blood Transfusion for Elective
Surgery – A national clinical guideline. Number 54. October 2001. http://www.sign.ac.uk/

British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines
for the administration of blood and blood components and the management of
transfused patients. Transfusion Medicine 1999; 9 :227-238. http://www.bcshguidelines.com

Last updated 11/09/2015