BLOOD TRANSFUSION

Blood transfusion
Shubha Allard

infection. Donors can give around 450 ml of whole blood up to three times a year, which is separated into red cells, platelets and plasma. UK plasma is no longer used for fractionation for manufacture of blood products such as albumin, intravenous immunoglobulin, anti-D or factor concentrates (see below). Testing of donor blood Transfusion-transmitted infection: the epidemiology of infection in the population of a particular country can help guide the testing required to maximize safety of the blood supply. In the UK, all donations are tested for syphilis, hepatitis B, hepatitis C, human T-lymphotropic virus type 1 (HTLV1) and HTLV2 and human immunodeciency virus (HIV). Data available for 2008e2010, estimating the risk of a potentially infectious unit entering the blood supply in the UK, are shown in Table 1. Where indicated by their travel history, donors are also tested for malaria and Trypanosoma cruzi antibodies. Other discretionary tests include anti-HBc (e.g. after body piercing). Some donations are also tested for cytomegalovirus (CMV) antibody to help provide CMV-negative blood for particular patient groups. In the UK, the Advisory Committee on the Safety of Blood, Tissues and Organs in the UK (SaBTO) has reviewed evidence available and recommended that leucodepletion of all blood components (other than granulocytes) provides adequate CMV risk reduction for almost clinical situations, but CMV seronegative red cell and platelet components should be provided for intra-uterine transfusions and for neonates, and for pregnant women requiring repeat elective transfusions during the course of pregnancy. Variant Creutzfeldt-Jakob disease (vCJD): to date, there have been three cases in the UK where blood transfusion may have been implicated in transmission of vCJD and one case where an abnormal prion was demonstrated at autopsy, in a patient who did not have neurological symptoms but was known to have received blood from a donor who subsequently developed vCJD. A further transmission of vCJD prions was described in February 2009, in a patient with haemophilia who had received batches of factor VIII to which a donor who subsequently developed vCJD had contributed plasma. The patient died of other causes but was found to have evidence of prion accumulation in his spleen. There is no blood test currently available for detecting prions. The full risk of vCJD in the UK population remains uncertain and accordingly the UK blood services have taken a number of precautionary measures to reduce the potential risk of transmission of prions by blood, plasma and blood products, the latter requiring fractionation of very large volumes of plasma. These include:  universal leucodepletion (removal of white cells) of all blood donations since 1998  importation of plasma for countries other than the UK for fractionation to manufacture plasma products  importation of fresh frozen plasma for use in children born after January 1996  exclusion of blood donors who have received a transfusion in the UK since 1980. Processing of blood Donor blood is collected into plastic packs containing citric phosphate dextrose, an anticoagulant that helps to support red

Abstract
The term blood transfusion generally refers to the therapeutic use of whole blood or its components (red cells, platelets, fresh frozen plasma and cryoprecipitate). Careful donor selection and stringent testing by the blood service is required to ensure a safe blood supply. Blood transfusion may be essential for many clinical treatments where it can be life saving. However, donated blood is a limited resource and hospital blood transfusion practice must focus on ensuring safe and appropriate use. Clinical guidelines are essential in all specialities using blood and components, supported by education and training with regular audit of practice. Particular emphasis must be placed on accurate patient identication through the whole transfusion process from taking the initial blood sample, through laboratory testing and the transfer of blood to clinical areas to the nal bedside check before transfusion to minimize errors. The reporting and monitoring of all adverse events in relation to blood transfusion via national haemovigilance schemes has highlighted key areas for action resulting in improved transfusion safety. Transfusion medicine must be practised within a strict regulatory framework; the European Union (EU) blood directives, in particular, have had far-reaching implications for the UK blood services and for hospital transfusion laboratories.

Keywords Better Blood Transfusion initiatives; blood components; EU

blood directive; haemovigilance; transfusion

Transfusion medicine has evolved over recent years with several scientic and clinical advances. The introduction of more advanced serological and molecular techniques for microbiological testing and stricter criteria for selection of donors have greatly reduced the risks of transfusion-transmitted infection (Table 1). Additional steps during processing of blood and components, including leucodepletion and, where feasible, viral inactivation, have further improved safety. The key priorities for clinical transfusion practice include avoidance of unnecessary transfusion and reducing avoidable transfusion errors wherever possible. A robust clinical governance infrastructure within a hospital, including an active hospital transfusion team and hospital transfusion committee, is essential for implementing key activities to ensure safe transfusion practice and appropriate use of blood.

Blood donation and processing

Blood donation All donors in the UK are unpaid volunteers. They are carefully selected using a donor health questionnaire to ensure that they can donate safely, and to exclude anyone at risk of transmitting

Shubha Allard MD FRCP FRCPath is Consultant Haematologist at Barts Health NHS Trust and NHS Blood and Transplant, London, UK. Competing interests: none declared.

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Transfusion-transmitted infection in the UK: estimated risk in 2008e2010

Test Testing introduced 1940s 1970 onwards 1985/2002 onwards 1991/1999 onwards Examples of testing methods used Antibody Surface antigen (HBsAg) Antibody/nucleic acid testing Antibody/nucleic acid testing Approximate risk of infection

into English Law as the UK Blood Safety and Quality Regulations and was implemented in 2005. Impact of blood safety and quality regulations in hospitals The chief executive of each hospital with a transfusion laboratory has to submit a formal annual statement of compliance to the Medicines and Healthcare products Regulatory Agency (MHRA). Hospital transfusion laboratories can be inspected by the MHRA and, in the event of signicant deciencies, can be given the order to cease and desist from activities. The key requirements for hospitals include:  a comprehensive quality management system based on the principles of good practice, including stringent requirements for storage and distribution of blood and components, with emphasis on cold chain management  traceability, requiring all hospitals to trace the fate of each unit of blood/blood component (including name and patient identication) with records being kept for 30 years  education and training of staff involved in blood transfusion, with maintenance of all training records  haemovigilance, with reporting of all adverse events (see below). Hospital transfusion laboratories undertaking any processing activities such as irradiation must have a licence from the MHRA indicating blood establishment status. Better Blood Transfusion (see Further Reading) Although not a regulation, Better Blood Transfusion health service circulars published in 1998, 2002 and 2007 provide strong recommendations for promoting safe transfusion practice within hospitals, with particular emphasis on the appropriate use of blood and components in all clinical areas. All hospitals must have transfusion committees (HTCs), with multidisciplinary representation. These committees are responsible for overseeing implementation of guidelines, clinical audit, and training of all staff involved in transfusion. The HTC has an essential role within the hospital clinical governance framework and must be accountable to the chief executive. The hospital transfusion team (HTT), which comprises the transfusion nurse specialist, transfusion laboratory manager and consultant haematologist in transfusion, undertakes various activities on a dayto-day basis to achieve the objectives of the HTC. Patient Blood Management Many of the above principles of the Better Blood Transfusion initiatives have now been encompassed in Patient Blood Management (PBM) an evidence-based, patient-focused initiative, involving an integrated multidisciplinary multimodal team approach, with the aims of optimizing the patients own blood volume (especially red cell mass), minimizing the patients blood loss, and optimizing the patients physiological tolerance of anaemia, thereby reducing unnecessary transfusion.

Syphilis Hepatitis B HIV HCV

1 in 1 million 1 in 6 million 1 in 72 million

HCV, hepatitis C virus; HIV, human immunodeciency virus.

Table 1

cell metabolism. All units are then transported without delay to the blood centre for processing, with initial leucodepletion to remove white cells. Further processing is then undertaken to produce red cells, platelets and plasma under stringent standards of quality control. The standard unit of red cells available in the UK has most of the plasma removed and replaced by a saline solution containing saline, adenine, glucose and mannitol (SAGM), also known as optimal additive solution. Red cells are stored at 4 C with a shelf life of 35 days. An adult therapeutic dose (ATD) or one unit of platelets can be produced either by single donor apheresis or by centrifugation of whole blood followed by separation and pooling of the platelet-rich layer from four donations suspended in plasma. Platelets can be stored for 5 days at 20e24 C with constant agitation to maintain optimal platelet function. Bacterial screening of platelets before release can reduce the risk of bacteriological contamination, with an extension of the shelf life of platelet units to 7 days. Platelet components must not be placed in a refrigerator. Fresh frozen plasma (FFP) is produced by separation and freezing of plasma at 30 C. In the UK, single donation units, sourced from the USA and treated with methylene blue to reduce microbial activity, are indicated for all children born after 1996. Solvent-detergent plasma is prepared commercially from pools of 300e5000 plasma donations that have been sourced from nonUK donors and treated with solvent and detergent to reduce the risk of viral transmission. Cryoprecipitate is prepared by undertaking controlled thawing of frozen plasma to precipitate high-molecular-weight proteins including factor VIII, von Willebrand factor and brinogen. Cryoprecipitate consists of the cryoglobulin fraction of plasma containing the major portion of factor VIII and brinogen. It is obtained by thawing a single donation of FFP at 4 C 2 C. The cryoprecipitate is then rapidly frozen to e30 C. It is available as pools of ve units.

Laboratory transfusion
Blood group serology e ABO groups There are four different ABO blood groups, which are determined by whether or not an individuals red cells have the A antigen (Group A), the B Antigen (Group B), both A and B antigens (Group AB) or neither (Group O).

Blood transfusion regulation and the EU blood directives

The EU blood directive on blood safety set standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and components. This was written

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Depending on the ABO group, individuals produce anti-A or antiB antibodies in early life that are mainly immunoglobulin M (IgM) and can rapidly attack and destroy incompatible cells with activation of the full complement pathway, resulting in intravascular haemolysis (acute haemolytic reaction). It is therefore essential that only red cells of a compatible ABO group are transfused. RhD group and antibodies Individuals who lack the RhD antigen are called RhD-negative and account for about 15% of the population, with the majority who do have the RhD antigen called RhD-positive. RhD-negative individuals can become sensitized and develop anti-D after being exposed to RhD-positive cells during transfusion or pregnancy. The clinical complications include haemolytic disease of the newborn (HDN), the risk of which can be minimized by use of anti-D immunoglobulin prophylaxis in RhD-negative mothers. Transfusion of RhD-positive red cells to an RhD-negative individual who is already sensitized can result in a delayed transfusion reaction, in which the red cells become coated with IgG and are removed by the reticulo-endothelial system by extra vascular haemolysis. This can result in a failure of the haemoglobin to rise together with jaundice. There are around 300 human blood groups that belong to 30 separate red cell antigen systems as recognized by the International Society of Blood Transfusion. The ABO and RhD antigens are particularly important but there are many other antigens on red cells that may result in formation of antibodies following pregnancy or transfusion, such as Kell, other Rh antigens (c, C, E and e), Duffy antigens (fya, fyb), Kidd antigens (jka, jkb), and these antibodies can also cause delayed transfusion reactions or HDN. Blood group and compatibility testing The patients red cells are grouped for ABO and RhD type and the plasma is tested for anti-A and anti-B antibodies. The majority of laboratories in the UK now use automated blood grouping and antibody testing with advanced information technology systems for documentation and reporting of results. Since errors related to having the wrong blood in tube are relatively common with potential risk of ABO mismatched transfusions, the current British Committee for Standards in Haematology (BCSH) guideline (2012) recommends that a second sample should be requested for conrmation of the ABO group of any new patient, provided this does not impede the delivery of urgent red cells or components. The hospital transfusion laboratory can readily provide red cells that are ABO and RhD compatible using electronic issue (or computer cross-match), with no further testing needed, provided the patient does not have any antibodies and that there are robust automated systems in place for antibody testing and identication of the patient. If a patient has red cell antibodies, electronic issue should not be used and a full cross-match must be carried out. Special requirements The hospital transfusion laboratory also needs to ensure that appropriate blood and components are provided for patients with special requirements such as CMV-negative blood (see above) or irradiated blood. The latter is needed for immunocompromised

patients to minimize risk of transfusion-associated graft-versushost disease. In addition to providing RhD-compatible blood, it is important to avoid transfusing Kell-positive red cells to Kellnegative girls and women with child-bearing potential, to prevent formation of anti-K antibodies that can cause severe HDN. Certain patient groups, such as those with sickle cell disease, are at very high risk of forming red cell alloantibodies, which increases the risk of delayed haemolytic transfusion reactions. Patients with haemoglobinopathy should therefore receive blood that is matched for the patients full extended Rh type (c, C, D, Ee) and K type, to prevent their forming antibodies to these highly immunogenic antigens.

Clinical transfusion practice

All hospitals must have a transfusion policy with clear guidance on correct patient identication and the safe administration of blood and components, including the detection and management of adverse reactions. The National Patient Safety Agency has issued a safe practice notice entitled Right Patient, Right Blood, which states that all hospital staff involved in the transfusion process, including phlebotomists, porters, medical and nursing staff, must undergo training and competency testing. The decision to transfuse must be based on a thorough clinical assessment of the patient and their individual needs, and the indication for transfusion should be documented in the patients clinical records. Errors in the requesting, collection and administration of blood components (red cells, platelets and plasma components) can lead to signicant risks for patients. The Serious Hazards of Transfusion (SHOT) scheme, launched in 1995, has shown repeatedly that wrong blood into patient episodes are an important reported transfusion hazard; these are due mainly to human error that can lead to life-threatening haemolytic transfusion reactions and other signicant morbidity. All patients receiving a blood transfusion must wear an identication band (or risk-assessed equivalent), with the minimum patient identiers including last name, rst name, date of birth and unique patient number. Positive patient identication is essential at all stages of the blood transfusion process including blood sampling, collection of blood from storage and delivery to the clinical area and administration to the patient. The detection and clinical management of acute transfusion reactions is covered in Haematological Emergencies in MEDICINE 2013; 41(5) (Figure 1). Any adverse events or reactions related to the transfusion should be appropriately investigated and reported to local risk management, SHOT and the MHRA via the Serious Adverse Blood Reactions and Events (SABRE) system. Use of red cells: red cells are indicated to increase the haemoglobin and hence the oxygen-carrying capacity of blood following acute haemorrhage, or in chronic anaemia, with examples as shown in Table 2. There has been a trend in favour of lowering the haemoglobin (Hb) threshold used as a trigger for red cell transfusion (e.g. Hb trigger of 7 or 8 g/litre for most patients with a trigger of 8 or 9 g/litre if there is a history of cardiac disease), but

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Patient exhibiting possible features of an acute transfusion reaction, which may include: fever, chills, rigors, tachycardia, hyper- or hypotension, collapse, flushing, urticaria, pain (bone, muscle, chest, abdominal), respiratory distress, nausea, general malaise STOP THE TRANSFUSION Undertake rapid clinical assessment, check patient identification/blood compatibility label, visually assess unit Evidence of: Iife-threatening Airway and/or Breathing and/or Circulatory problems and/or wrong blood given and/or evidence of contaminated unit

Yes

No

SEVERE/LIFE-THREATENING Call for urgent medical help Initiate resuscitation ABC Is haemorrhage likely to be causing hypotension? If not, discontinue transfusion (do not discard implicated unit/s) Maintain venous access Monitor patient: e.g. TPR, BP, urinary output, oxygen saturations

Inform medical staff

MODERATE Temperature 39C or rise 2C and/or Other symptoms/signs apart from pruritus/rash only

MILD Isolated temperature 38C or rise 12C and/or Pruritus/rash only

If likely anaphylaxis/severe allergy, follow anaphylaxis pathway If bacterial contamination likely, start antibiotic treatment Use BP, pulse, urine output (catheterise if necessary) to guide intravenous physiological saline administration Inform hospital transfusion department Return unit (with administration set) to transfusion laboratory If bacterial contamination suspected, contact blood service to discuss recall associated components Perform appropriate investigations

Consider bacterial contamination if the temperature rises as above and review patients underlying condition and transfusions history Monitor patient more frequently e.g. TPR, BP, oxygen saturations, urinary output

Not consistent with condition or history Discontinue (do not discard implicated unit/s) Perform appropriate investigations

If consistent with underlying condition or transfusion history, consider continuation of transfusion at slower rate and appropriate symptomatic treatment

Continue transfusion Consider symptomatic treatment (see text) Monitor patient more frequently as for moderate reactions If symptoms/signs worsen, manage as moderate/severe reaction (see left)

Continue transfusion

Transfusion-related event Review at HTC Report to SHOT/MHRA as appropriate

Transfusion unrelated

Document in notes that no HTT/HTC review/SHOT report necessary

Figure 1 Reproduced with kind permission of the British Committee for Standards in Haematology.

individual patient factors must be taken into account. The initial assessment should include an evaluation of the patients age, body weight and any co-morbidity that can predispose to transfusion-associated circulatory overload (TACO), such as cardiac failure, renal impairment or hypoalbuminaemia, and uid overload should be considered when prescribing the volume and rate of transfusion, and in deciding whether diuretics should be co-prescribed. As a general guide, transfusing one unit of red cells gives an Hb increment of 1 g/litre but only if applied as an approximation for a 70e80-kg patient. The use of single unit transfusions in small, frail adults (or prescription in ml, as for paediatric practice) is recommended.

Blood for planned procedures Patients undergoing surgery in which transfusion may be required should have a group and screen sample taken in the pre-operative assessment clinic. Providing the antibody screen is negative, the transfusion laboratory can provide blood components quickly as needed, without the need for reserving cross-matched units. A maximum surgical blood-ordering schedule (MSBOS) should be agreed. This species how many blood units will be reserved (in the blood bank or satellite refrigerator) for standard procedures, based on audits of local practice. Guidelines should also include strategies for blood conservation, including preoperative assessment (to detect and correct

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Use of red blood cells7

Acute haemorrhage, especially where >30% blood loss, following:
C C C C

surgery trauma childbirth gastrointestinal bleed

Bone marrow disorders causing anaemia, such as: myelodysplasia C haematological malignancies (e.g. acute leukaemia, myeloma) C bone marrow brosis C bone marrow inltration with secondary cancer C aplastic anaemia C chemotherapy/radiotherapy or bone marrow transplantation
C

Platelet refractoriness e a failure to obtain a satisfactory increment to platelet transfusions may be due to immune or non-immune causes. The main immune cause is human leukocyte antigen (HLA) alloimmunization, which occurs following previous pregnancy or transfusion. Non-immune clinical factors include infection (and its treatment with antibiotics and antifungal drugs), disseminated intravascular coagulation (DIC) and splenomegaly. HLA-matched platelet transfusions are indicated if no obvious non-immune cause is present and if HLA antibodies are detected. Use of fresh frozen plasma and cryoprecipitate: there is a lack of good evidence for the clinical use of FFP. In adults, the therapeutic dose of FFP is 12e15 ml/kg body weight. FFP is indicated in patients with acute DIC in the presence of bleeding and abnormal coagulation results (see Acquired Disorders of Coagulation on pages 228e230 of this issue). Solvent-detergent treated plasma is indicated for patients undergoing plasma exchange for thrombotic thrombocytopenic purpura. In the UK, all children born after 1996 should receive non-UK sourced plasma as a CJD risk reduction measure, methylene blue treated. FFP sourced from outside the UK is available for paediatric use. FFP should not be used for reversal of oral anticoagulation (warfarin), where the use of prothrombin complex (prothrombin complex concentrate) is indicated (BCSH anticoagulation guidelines) (see Acquired Disorders of Coagulation on pages 228e230 of this issue). The coagulopathy of liver disease is also complex, with many studies showing the lack of evidence of clinical benet of prophylactic FFP transfusion in this setting. The main indication for use of cryoprecipitate is in massive haemorrhage for replacement of brinogen, where the concentration is below 1.5 g/litre. The adult dose is two pools of cryoprecipitate with ve units in each pool. Cryoprecipitate must not be used for replacement of coagulation factors in inherited conditions such as haemophilia or von Willebrands disease, since specic factor concentrates are available for the treatment of these conditions.

Inherited anaemias: thalassaemia C sickle cell anaemia (e.g. following stroke)

C

Haemolytic disease of the newborn Autoimmune haemolytic anaemia Table 2

iron deciency anaemia or bleeding disorders) and cell salvage. Routine preoperative autologous donation and storage of blood prior to surgery is no longer recommended in the UK. The use of erythropoietin is now well established in chronic renal anaemia but the National Institute for Health and Clinical Excellence does not support its routine use in patients with anaemia secondary to cancer. Use of platelets: platelets are indicated for the treatment or prevention (prophylaxis) of bleeding in patients with thrombocytopenia (low platelet counts) or with platelet dysfunction in a number of situations (Table 3).

Indications for use of platelets

Situation Bone marrow failure Before invasive procedures To prevent spontaneous bleeding when platelet count <10 109/litre or <20 109/litre if there is an additional risk (e.g. sepsis) C Minor surgery or procedures e raise platelet count to >50 109/litre C Major surgery >80 109/litre C Eye surgery or neurosurgery >100 x 109/litre Aim to maintain platelet count >75 109/litre
C

Massive blood transfusion (platelet count <50 x 109/litre anticipated after 1.5e2 blood volume replacement) Disseminated intravascular coagulation (DIC) Platelet dysfunction Autoimmune thrombocytopenia

Platelet transfusion indicated in acute DIC if low platelets and bleeding but not in chronic DIC without bleeding C Inherited e Glanzmanns thrombasthenia C Acquired e antiplatelet drugs (e.g. aspirin and clopidigrel) Platelet transfusions should be used only if major haemorrhage present
C

Platelet transfusions are contraindicated in thrombotic thrombocytopenic purpura (TTP).

Table 3

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Patient information and consent The last Better Blood Transfusion 1998, 2002 and 2007 health service circular recommends that timely information should be made available to patients, informing them of the indication for transfusion, the risks and benets of blood transfusion, and any alternatives available. There is also a need to increase patient awareness regarding the importance of correct identication. In October 2011, the Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO) in the UK re-enforced the recommendation that valid consent for blood transfusion should be obtained and documented in the patients clinical record by the healthcare professional. A standardized information resource for clinicians, indicating the key issues to be discussed by the healthcare professional when obtaining valid consent from a patient for a blood transfusion, is now available at: http:// www.transfusionguidelines.org.uk/index.asp?PublicationBBT &Section22&pageid7691 A

FURTHER READING BCSH. Guidelines for the use of fresh frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126: 11e28. BCSH. Guidelines for the use of platelet transfusions. Br J Haematol2003; 122: 10e23.

Better Blood Transfusion e safe and appropriate use of blood. HSC2007/001. In: McLelland DBL, ed. Handbook of transfusion medicine. 4th edn. London: HMSO, 2007. British Committee for Standards in Haematology (BCSH). Guideline on the Administration of Blood Components, http://www.bcshguidelines.com; 2009. British Committee for Standards in Haematology (BCSH). Guideline on the investigation and management of acute transfusion reactions. Br J Haematol 2012; 159: 143e53. British Committee for Standards in Haematology (BCSH). Guidelines for pre-transfusion compatibility procedures in blood transfusion laboratories, http://www.bcshguidelines.com; 2012. British Committee for Standards in Haematology (BCSH) Guidelines. The clinical use of red cell transfusion. Also available at: http://www. bcshguidelines.com. Health Protection Agency. NHSBT/HPA Infection Surveillance Reports. Also available at: www.hpa.org.uk. National Patient Safety Agency. London: HMSO. Also available at: http:// www.npsa.nhs.uk; 2007. Serious Hazards of Transfusion: http://www.shotuk.org. The Medicines and Healthcare products Regulatory Agency. Also available at: http://www.mhra.gov.uk. UK Blood Transfusion and Tissue Transplantation Services. Guidelines for the blood transfusion services in the UK (RedBook). 7th edn. London: HMSO. Also available at: www.transfusionguidelines.org; 2005.

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