27th May 2023

Transfusion

Red blood cell transfusion

Indications

Red cell transfusion is an essential tool in clinical medicine. In an actively bleeding patient, transfusion can prevent circulatory collapse and maintain tissue perfusion. In a patient with acute ischaemia, it can improve tissue oxygen delivery, relieve symptoms, and prevent complications. In a patient with chronic anaemia, it can relieve symptoms and improve quality of life. Blood product transfusion is, however, associated with significant potential risk and high cost. Judicious stewardship and selection of blood products is critical.

The decision to transfuse red cells is based on clinical assessment of the patient, as well as a full blood count (FBC) value. As a result, there is no universal trigger for transfusion and instead a patient-centred decision must be made. However general principles apply:

• In the haemodynamically stable, non-bleeding patient, transfusion should be considered if the haemoglobin (Hb) is 80g/L or less.
• If the Hb is below 70g/L, transfusion is usually indicated.
• Higher thresholds may be appropriate in individual cases, for example an anaemic patient with ischaemic heart disease and chest pain.
• In patients with gastrointestinal bleeding, once haemodynamically stable, over-transfusion may increase the risk of recurrent bleeding by increasing portal venous pressure.  Therefore, individual targets taking into account the case complexities should be used.
• Local protocols should be followed post-cardiac surgery and in cases of acute cerebral ischaemia/traumatic brain injury.

A red cell transfusion of 4ml/kg will produce an average rise in haemoglobin of ~10g/L, so a unit of packed red cells (250-300ml) should produce a 10g/L rise for a patient weighing 70-80kg. Patients who are not bleeding should be transfused a single unit and then reassessed before further blood is given. Haematology, oncology, gastrointestinal medicine (including liver disease) and renal medicine are the largest users of blood products.

Safe red cell transfusion

Provision of ABO compatible blood products is essential: transfusion of ABO incompatible red cells is almost universally fatal. The four ABO blood group types (A, B, AB and O) are identified based on the presence or absence of the A and B red cell antigens. Patients who lack an ABO antigen will produce the corresponding antibody. For example, patients who lack the A antigen (blood groups B and O) will produce an anti-A antibody.

Transfusion of products containing other red cell antigens (such as RhD or Kell) to patients with the corresponding antibody also presents a significant clinical risk. Unlike the A and B antigens, patients who lack RhD do not produce the antibody automatically, but can start to produce the antibody after exposure to foreign red cells.

To enable safe red cell selection for transfusion, a group and screen (G&S) should be performed. The G&S establishes the patient’s ABO and RhD blood group and identifies the presence of any atypical red cell antibodies in the patient’s plasma. If a historic G&S result is available, there are no issues with grouping the patient’s red cells and no atypical antibodies are identified, the patient may be appropriate for electronic issue of blood components. Otherwise, manual serological crossmatch is performed: donor red cells are combined with patient plasma using the indirect antiglobulin test (IAT) to check for evidence of a reaction.

For patients with haemoglobin disorders, the decision on whether to transfuse red cells is complex and requires input from a clinician with significant relevant expertise. The blood issued to sickle-cell patients should be negative for sickle haemoglobin and less than 14 days old; “fresher” blood may be associated with improved outcomes in this group of patients.  Up to 30% of patients on long-term transfusion support develop antibodies against red cell antigens, which reduces the probability of finding compatible red cells for future transfusions. In this group of patients, extended phenotyping should be carried out to allow the provision of more closely matched red cell transfusions (matched for ABO, full Rh and Kell antigens) which reduces the risk of forming red cell alloantibodies. Due to chronic haemolysis with increased red blood cell turnover in the morphologically abnormal sickle cells, it can be challenging to identify when a patient has developed a delayed haemolytic reaction during a sickle cell crisis. Making the diagnosis of a delayed haemolytic reaction is important as further transfusion can worsen the hyperhaemolysis.

Patients who require regular red cell transfusion support, for example those with myelodysplasia, are at risk of transfusional haemosiderosis and organ damage due to iron overload. In selected patients, iron chelation therapy with desferrioxamine is indicated. Iron chelation requires specialist monitoring.

Alternatives to red blood cell transfusion

Key principles

In all stable, non-bleeding patients, where appropriate, transfusion should be avoided due to associated risks. Three principles can be adopted: to maximise red cell mass, minimise bleeding and optimise physiological reserve. Pre-operative optimisation of patients should address any identified anaemia.  Review and consider altering medications which may increase the risk of bleeding. Blood conservation techniques may include intraoperative or postoperative cell salvage and reinfusion, the use of tissue sealants (sprays which promote haemostasis) or anti-fibrinolytic drugs such as tranexamic acid. In extreme scenarios, minimising blood tests and therefore blood loss may need to be considered.

It is important to respect patient autonomy after an informed decision is made with capacity. If this is a faith-based decision, for example in Jehovah’s Witnesses, it is important to assess an individual’s preferences to whole blood, specific blood components and the derivatives of blood components (albumin, cryoprecipitate, clotting factor concentrate and immunoglobulins). Check for advanced decision documents, place a copy in the notes and document a conversation around transfusion alternatives. Involve the hospital’s liaison for Jehovah’s Witnesses. In the case of critically ill patients with temporary incapacity, if there is no clear evidence of an Advance Decision, then life-saving treatment must be given. Where legal guardians of children under 16 refuse blood transfusion and in the opinion of the treating clinician, that transfusion is essential, then a Specific Issue Order can be rapidly obtained from a court. Autologous donation is rarely done, as the shelf-life of red cells is only 35 days making it logistically challenging to deliver and it doesn’t protect against errors such as incorrect re-infusion.

Iron therapy

The speed of response to oral iron depends on the Hb deficit and the presence of continued blood loss, but at least 3 months of treatment after recovery of Hb is needed to restore body stores. Due to side effects like constipation, tolerance may be variable and lower doses may need to be considered for more protracted periods. IV iron may be used in patients intolerant of oral iron or in patients with anaemia of chronic disease where response to oral iron may be poorer. With newer preparations now available, IV iron prescription has become much safer, but is contraindicated in the first trimester of pregnancy, chronic liver disease or in acute or chronic infection.

Erythropoietin (EPO)

EPO is produced in the kidneys in response to reduced oxygen and increases red blood cell production in the bone marrow. Recombinant EPO is used in the treatment of anaemia from renal failure and in myelodysplastic syndrome (MDS). Baseline EPO levels should be taken:

• <100IU/L are likely to respond to EPO therapy
• >500IU/L are unlikely to respond
• If levels are 100-500IU/L, then a trial of treatment could be discussed with the patient

Recombinant EPO can cause hypertension and thromboembolic problems. Haematocrit should be carefully monitored. Recombinant EPO should not be started in the presence of iron deficiency, without concurrently managing the iron deficiency.

Transfusion of other blood products

Platelet transfusion

ABO compatible platelets should be used wherever possible. Platelet transfusion is indicated if:

• An invasive procedure/surgery must be carried out and the platelet count is <50×10⁹/L. If this is for neurosurgery or eye surgery, a platelet count of 100×109/L is used.
• In major haemorrhage, a platelet count of >75×10⁹/L should be maintained or >100×109/L if poly-trauma and concern over head/spinal/eye injuries.
• In DIC where there is bleeding, a platelet count of >50×10⁹/L should be maintained. In non-bleeding patients, transfusion is indicated if the platelet count is <10×10⁹/L. Some centres use a threshold of 20×10⁹/L.
• In reversible bone marrow failure, for example during high intensity chemotherapy, where the platelet count is <10×10⁹/L. In chronic bone marrow failure such as myelodysplastic syndrome (MDS), the use of platelets should be guided by symptoms.

Platelet transfusions should not be administered in cases of peripheral platelet destruction, as in immune thrombocytopenic purpura except in cases of life-threatening bleeds. Treatment should instead focus on immunosuppression to reduce platelet destruction or raising platelet production through thrombopoietin mimetics like Eltrombopag or Romiplostim.

Platelet transfusion is contraindicated in thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) because it will contribute to further microthrombi.

Platelet refractoriness is defined as a platelet increment <10×10⁹/L at 10-60 minutes occurring after more than 1 transfusion. Reduced increments may be due to consumption in bleeding, DIC or hypersplenism or due to immune destruction due to HLA or human platelet antigen (HPA) antibodies. If HLA or HPA antibodies are detected, matched platelets should be prescribed.

Fresh frozen plasma (FFP) transfusion

FFP is indicated for the treatment of bleeding in patients with deranged coagulation due to deficiency of multiple clotting factors, for example in DIC or during major haemorrhage. It is not indicated in non-bleeding patients with abnormal clotting tests. The minimum dose is 12–15 mL/kg (equivalent to four units in an average adult). In addition to replacing clotting factors, 4 units of FFP should raise the fibrinogen by ~1g/L in an adult. For patients with deficiency in a single clotting factor, such as factor VIII (haemophilia A), single factor replacement is needed.

Cryoprecipitate transfusion

The adult dose is two five-unit pools (approximately 3g fibrinogen) and should raise the fibrinogen by ~1g/L in an adult. In addition to fibrinogen, it contains Factor VIII, von Willebrand factor (VWF) and Factor XIII.

Indications include:

• Acute DIC with bleeding and fibrinogen <1.5 g/L
• Severe liver disease with bleeding
• Prophylaxis for surgery when fibrinogen <1.5 g/L
• Hypofibrinogenaemia associated with massive transfusion (where the aim is to maintain >1.5 g/L).

Major Haemorrhage

Management of major haemorrhage

Major haemorrhage is bleeding which is life-threatening. A number of definitions exist, based on quantifying the volume or blood lost, but in the clinical setting major haemorrhage is best recognised as bleeding with haemodynamic instability.

• Loss of more than one blood volume within 24 hours (around 70 mL/kg which is >5 litres in a 70 kg adult)
• 50% of total blood volume lost in less than 3 hours
• Bleeding in excess of 150 mL/minute
• Bleeding with haemodynamic instability (heart rate >110 or systolic blood pressure <90mmHg).

It is critical that the source of bleeding is addressed. Meanwhile, massive transfusion is required to maintain vital organ transfusion. Hospital Major Haemorrhage Protocols ensure timely and appropriate provision of blood product resuscitation. The transfusion of large volumes of red cells with no coagulation factor or platelet replacement causes dilutional coagulopathy. Therefore, in a major haemorrhage shock-pack, pre-defined ratios of blood components are provided by the laboratory, which includes packed red cells, FFP and platelets. Peripheral blood haematocrit and Hb concentration may be misleading in early major blood loss and the decision to transfuse should be based on clinical criteria and observations.

Immediate priorities:

1. Resuscitation and early communication with the laboratory through a 2222 major haemorrhage alert
2. Baseline FBC, clotting screen and crossmatch
3. Control bleeding (may need to involve surgeons and interventional radiology) and consider early administration of anti-fibrinolytics such as tranexamic acid
4. Maintain organ perfusion through transfusion of blood and other fluids
5. Initially use Group O red cells. If female and <50 years old, then they should receive RhD negative red cells to avoid sensitisation.
6. Once available use group-specific blood.
7. Typically for 6 units of packed red cells: 4 units of FFP, 2 pools of cryoprecipitate and 1 adult therapeutic dose of platelets should be administered.
8. Once laboratory results are available this can be better tailored. For example: if the Hb is falling, give red cells; if the prothrombin time ratio is >1.5, then give FFP; if fibrinogen <1.5g/L, then give cryoprecipitate 2 pools; if platelets <75 x10⁹/L, then give 1 adult therapeutic dose.
9. In certain cases vitamin K, desmopressin, PCC, activated PCC (FEIBA™), recombinant factor concentrates (such as NovoSeven™) or specific direct oral anticoagulant (DOAC) reversal therapy may be indicated and must always involve a discussion with a haematologist.
10. Sometimes a principle of ‘damage control resuscitation’ is used with permissive hypotension to minimise secondary blood loss

Tranexamic acid reduces blood transfusion in patients undergoing emergency or urgent surgery in a Cochrane review (2012) and the risk of death in bleeding trauma patients in CRASH-2 trial (2010) and bleeding post-partum haemorrhage patients in WOMAN trial (2017). However, in the HALT-IT trial (2020) analysing the use of tranexamic acid in gastrointestinal bleeding, it did not reduce death and thromboembolic events were found to be higher. This is possibly because it is challenging in gastrointestinal bleeding to determine the age of the bleeding and the benefit from tranexamic acid comes in early administration to reduce fibrinolysis.

Transfusion reactions

Early recognition of a transfusion reaction is important. Vital signs are monitored closely during blood product transfusion. There is a wide differential diagnosis for severe acute reactions. Regardless of the cause, if a patient becomes unwell during a transfusion:

1. Stop the transfusion
2. Perform an ABCDE assessment and resuscitate the patient
3. Recheck the ID details of the patient, ID wristband and compatibility label of the blood component
4. Inspect the product for clumps or discolouration

For significant acute transfusion reactions (a temperature rise of >2°C or to >39°C or any additional symptoms apart from isolated rash)

5. Contact the hospital transfusion laboratory
6. Return the transfusion pack to the transfusion laboratory for further investigation
7. Investigations should include FBC, renal and liver function and a coagulation screen
8. If any concern about haemolysis, send a direct antiglobulin test (DAT), lactate dehydrogenase (LDH), haptoglobin, blood film and urinary haemosiderin.
9. If the patient is febrile, send blood cultures
10. If there is concern over anaphylaxis then administer IM adrenaline and send IgA level and serial mast cell tryptase levels at 0, 3 and 24 hours.

Serious adverse reactions and events will be reported to the Serious Hazards of Transfusion (SHOT) scheme and the Serious Adverse Blood Reactions and Events (SABRE) reporting system.

Haemolytic reactions

Acute haemolytic reaction

In ABO-incompatible red cell transfusion, a patient’s anti-A or anti-B antibodies cause rapid haemolysis of the transfused red cells and inflammatory cytokine release. Shock, acute renal failure and disseminated intravascular coagulation (DIC) may occur. ABO-incompatible red cell transfusion is almost universally fatal. Stringent safety checks when taking G&S samples, transporting blood products and carrying out blood product administration aim to avoid this ‘never event’. Patients become very unwell within minutes of transfusion with flushing, abdominal pain, a sense of impending doom, tachycardia, hypotension and may have signs of bleeding from needle wounds.

Delayed haemolytic transfusion reaction

Delayed haemolytic transfusion reactions (DHTR) can occur 1-14 days after transfusion in a patient who has been previously alloimmunised to a red cell antigen by blood transfusion or pregnancy.  This alloantibody may have fallen to an undetectable level and therefore may not be identified on the G&S antibody screen. DHTR should be suspected if the following occur:

• A falling haemoglobin/failure to increment
• Jaundice
• Fever
• Haemoglobinuria

A haemolysis screen should be performed. Treatment is supportive, but the antibody history must be recorded by the laboratory.

Post-transfusion purpura

A significant fall in platelet count can occur 5-12 days after blood product transfusion. This reaction is caused by previous alloimmunisation to a platelet antigen by transfusion or pregnancy. Treatment is supportive, but if the patient has life-threatening bleeding, then IVIG should be administered.

Non-haemolytic immune reactions

Febrile non-haemolytic transfusion reaction

This is a common occurrence, particularly in the cohort of hospital inpatients. There is an isolated fever >38°C, but less than <2°C from baseline. This can occur up to 2 hours after transfusion completion. Management is temporarily stopping or slowing of the transfusion, giving paracetamol and monitoring closely for a more severe transfusion reaction.

Anaphylaxis

Anaphylaxis is more common when transfusing plasma-rich blood components, such as platelets or FFP. Patients present with shock, bronchospasm, stridor, urticaria or angioedema. The UK Resuscitation Council guidelines recommend:

1. Urgent administration of IM adrenaline. The adult dose is 0.5ml of 1:1000 (500mg).
2. Initial resuscitation and involvement of critical care teams.

In the event of recurrent severe allergic reactions, patients may benefit from receiving washed blood components or components in different additive solutions. Patients with IgA deficiency may be at increased risk of severe allergic reactions due to circulating anti-IgA antibodies.

For mild allergic reactions characterised by rash or itch only, an antihistamine can be administered, and the transfusion restarted at a slower rate.

Transfusion Related Acute Lung Injury (TRALI)

TRALI is caused by passenger donor anti-HLA antibodies.  These react with the recipient’s HLA antigens, in particular in the lungs, causing pulmonary inflammation, leakage of plasma into the alveolar spaces and non-cardiogenic pulmonary oedema. It presents within 2-6 hours of transfusion and is more common with plasma-rich products. It is a diagnosis of exclusion. Symptoms include:

• Severe breathlessness
• Frothy pink sputum
• Hypotension
• Fevers
• Transient neutropenia or monocytopenia.

A chest x-ray may show bilateral perihilar and nodular shadowing.

Chest X-ray of a patient with TRALI.

Image Source: Wikimedia Commons (2008). Transfusion-related acute lung injury chest X-ray, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Transfusion-related_acute_lung_injury_chest_X-ray.gif (Accessed on: 10 January 2023).

Treatment is supportive, with high concentration oxygen therapy ± ventilatory support. Steroid therapy is not effective. It can be retrospectively confirmed through special investigation to demonstrative antibodies in the donor’s plasma that react with the recipient’s HLA or human neutrophil antigens (HNA). It is important to differentiate from TACO (see non-immune transfusion reactions), as diuretic therapy is not indicated. The incidence of TRALI has reduced since FFP donations have been sourced from male-only donors, as women of child-bearing age may have formed antibodies against non-self red cell antigens during pregnancies.

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

This rare and fatal complication occurs when viable lymphocytes in a blood donation engraft in the recipient and mount an immune response against the recipient’s cells. At risk patients have impaired cell-mediated immunity and are unable to reject the foreign lymphocytes. These include patients with inherited immunodeficiencies, Hodgkin’s lymphoma, stem cell transplant recipients or those treated with fludarabine, other purine analogues or alemtuzumab. Symptoms occur 7-14 days after transfusion and include fever, rash, diarrhoea, deranged liver function and cytopenias. A biopsy of affected organs will demonstrate GvHD. Patients at risk of developing TA-GvHD must receive irradiated blood components, which damages DNA and inactivates any residual lymphocytes in the blood product following standard leucodepletion.

Non-immune transfusion reactions

Transfusion Associated Circulatory Overload (TACO)

TACO is defined as acute or worsening pulmonary oedema within 6 hours of transfusion and presents with respiratory distress, tachycardia, and clinical evidence of a positive fluid balance. Patients with heart failure, renal impairment, low albumin and fluid overload should have appropriate volume and flow rate prescribed to reduce the risk of TACO. Treatment includes stopping the transfusion, oxygen and diuretic therapy. TACO remains the leading cause of transfusion-related combined mortality and major morbidity. In stable-non-bleeding anaemic patients, medical management of anaemia must be first considered.

Transfusion transmitted infection

Bacterial contamination of blood products is extremely rare. It is more likely to occur with platelet components, stored at 22-24°C degrees, compared to red cells, which are kept refrigerated at 2-6°C and for this reason all platelet donations undergo bacterial culture prior to use. Typical signs include rigors, fever, hypotension and rapid onset shock. The blood component pack may appear normal but should be visibly inspected for clumps and discolouration. Blood cultures should be taken, and intravenous broad-spectrum antibiotics delivered to cover both gram-negative and gram-positive bacteria. The blood component should be sealed and returned to the transfusion laboratory for further investigation so that any associated component can be withdrawn.

Rigorous pre-donation assessment and testing of donated products minimises the risk of transmission of viral infections. All blood donations are screened for hepatitis B, hepatitis C, hepatitis E, HIV and HTLV I and II.

Some blood products are tested for cytomegalovirus (CMV) as CMV-negative blood components are indicated in pregnant women and neonates. In immunocompromised individuals, standard components can be administered as leucodepletion alone is sufficient to reduce the risk of CMV infection. All blood components, apart from granulocytes, are leuco-depleted.