Blood transfusion and transfusion reactions

• Transfusion gives specific blood components (red cells, platelets, plasma, cryoprecipitate) to people who lack them or are bleeding; each has its own indication and threshold.
• A restrictive red cell threshold of 70 g per litre (7 g per dL) is used for most stable patients, rising to 80 g per litre after acute coronary syndrome. ^[3]
• Most transfusions are uneventful, but a new symptom during or shortly after infusion must be treated as a possible transfusion reaction until excluded.
• The first steps in every reaction are the same: stop the transfusion, keep the vein open with saline, check the patient, and check the identity of patient and unit.
• The life-threatening reactions to separate quickly are acute haemolytic (ABO mismatch), anaphylaxis, bacterial contamination, TRALI and transfusion-associated circulatory overload (TACO).
• Irradiated and leukoreduced products, careful patient identification and exact documentation prevent most serious reactions.

By the end of this page you should be able to:

1. State the indications, thresholds and typical doses for red cells, platelets, fresh frozen plasma and cryoprecipitate.
2. Recognise and classify an acute transfusion reaction by timing, mechanism, presentation and severity.
3. Carry out the immediate actions for any reaction and decide which samples to send.
4. Use the reactions table to move from a presentation to the correct management.
5. Recognise massive transfusion, its protocol ratios, and the associated risks of hyperkalaemia and hypocalcaemia. ^[4]
6. Explain the roles of irradiated and leukoreduced products and apply safe practice in resource-limited settings.

A blood transfusion is the infusion of donated blood or a purified component of it into a recipient's circulation. A transfusion reaction is any adverse event associated with that infusion. Haemovigilance is the systematic surveillance and reporting of these events so that patterns can be seen and prevented.

A practical classification is by time. An acute transfusion reaction (ATR) occurs within 24 hours of the start of a transfusion. A delayed transfusion reaction (DTR) occurs after that point. ATRs share early, overlapping features such as fever, chills and breathlessness, so the diagnosis is made by combining the clinical picture with severity, timing and the investigation results. ^[1][2]

Related terms are worth defining once:

• ABO incompatibility: transfusion of red cells whose ABO blood group does not match the recipient, usually from an identification or laboratory error.
• Direct antiglobulin test (DAT): a test that detects antibodies or complement bound to the surface of the recipient's red cells.
• Leakoreduction: removal of donor white cells from a component to reduce febrile reactions and alloimmunisation.
• Irradiation: gamma or X-ray treatment of a cellular component that stops donor lymphocytes from dividing, preventing graft-versus-host disease.

Serious transfusion reactions are uncommon but not rare. Data from the UK haemovigilance scheme reported an incidence of serious reactions of 14 per 100,000 components transfused, and one review has noted that reactions are under-recognised and under-reported. ^[1] The true load depends on monitoring: patients monitored by trained staff, with clear reporting, identify more reactions but treat them earlier.

Fever during transfusion occurs in many patients; it may be a mild febrile non-haemolytic reaction or may be the first sign of haemolysis or bacterial contamination. Allergic reactions are seen more often with platelets and plasma than with red cells. ^[1]

Most serious acute reactions arise from one of four causes:

1. An identification or sampling error, which is the dominant cause of acute haemolytic reactions due to ABO incompatibility. ^[1]
2. An immune mismatch or incompatibility between donor and recipient, including delayed haemolysis from an anamnestic antibody response.
3. Donor factors: high-titre antibodies in multiparous donors (TRALI), bacterial contamination (more common in room-temperature platelets), and sensitisation in repeated transfusion.
4. Recipient factors: IgA deficiency with anti-IgA antibodies, impaired cardiorespiratory function (TACO, hyperkalaemia, hypocalcaemia risk), and immunodeficiency (graft-versus-host disease).

A history of allergies raises the risk of an allergic transfusion reaction, although most mild urticarial reactions do not predict future events. A documented previous reaction changes what is ordered: washed or IgA-deficient components, leukoreduced or irradiated products, and premedication in selected cases.

Antibodies in the recipient plasma bind to antigens on the donor red cells. ABO incompatibility is the classic cause because ABO antibodies are naturally occurring, complement-activating and present in high titre. Complement activation lyses cells intravascularly, releasing free haemoglobin and activating coagulation and cytokine cascades. The result can be fever, rigors, pain, hypotension, haemoglobinuria, acute kidney injury and disseminated intravascular coagulation.

Non-ABO antibodies (for example Kidd, Duffy) can also produce acute haemolysis through an anamnestic response in patients who are alloimmunised by prior transfusion or pregnancy.

Donor leukocytes or inflammatory mediators (cytokines accumulated during storage) trigger fever and chills without red cell destruction. Pre-storage leukoreduction reduces the rate of these reactions.

Soluble donor proteins, or, in the unusual but important case of IgA deficiency, recipient anti-IgA antibodies reacting with donor IgA, produce urticaria, angioedema, bronchospasm or vascular collapse. Platelets and plasma cause these more often than red cells. IgA deficiency is defined as selective IgA deficiency below 0.05 mg per dL in patients older than 4 years, after other causes of hypogammaglobulinaemia are excluded. ^[1]

Donor antibodies to human leukocyte antigens (HLA) or human neutrophil antigens (HNA), or bioactive lipids and soluble CD40 ligand accumulated in stored components, activate primed recipient neutrophils that are adherent to the pulmonary endothelium. Capillary leakage produces non-cardiogenic pulmonary oedema without circulatory overload.

Volume load exceeds cardiac reserve: hydrostatic pulmonary oedema from left ventricular failure, most often with large-volume or rapid transfusion in older or volume-sensitive patients.

• Bacterial contamination: endotoxin and bacterial products from Gram-negative or Gram-positive organisms, most often in room-temperature platelets.
• Graft-versus-host disease (GVHD): donor lymphocytes in cellular components engraft and attack host tissues in an immunocompromised recipient.
• Hyperkalaemia and hypocalcaemia during massive transfusion: potassium leaks from stored red cells; citrate anticoagulant chelates ionised calcium.

Because the reactions share fever, breathlessness and hypotension, the diagnosis is clinical. Three patterns are useful:

• Fever with rigors and back or flank pain in the first few minutes suggests acute haemolysis.
• Urticaria and pruritus alone, without systemic symptoms or vital sign change, is usually a mild allergic reaction.
• Sudden breathlessness with hypoxia and bilateral infiltrates within 6 hours points to TRALI or TACO; the distinction rests on volume status and blood pressure.

Table: signs and symptoms of acute transfusion reactions

Acute reactions may begin during the infusion or in the hours after it ends, and patients discharged the same day should be told to report symptoms within the following 24 hours. ^[1]

Fever after transfusion can represent the patient's underlying disease (for example febrile neutropenia), a drug reaction, bacterial infection unrelated to the transfusion, or haemolysis from the blood component itself. Breathlessness can be TACO, TRALI, allergy, or the underlying cardiac or pulmonary disease. Isolated hypotension must be distinguished from bleeding: if the patient is bleeding, continuation of the transfusion can be life-saving, whereas if the component is the cause, the transfusion must be stopped.

For moderate or severe reactions:

• Track and save the unit: return the implicated component in a sealed plastic bag with the administration set and clamped tubing, together with the transfusion reaction form.
• Repeat compatibility testing: ABO and Rh grouping of the patient and the returned unit, antibody screen on the pre- and post-transfusion samples, cross-match of both samples against the returned unit, and a DAT on the post-transfusion sample.
• First voided post-transfusion urine sample for haemoglobinuria.
• Full blood count, coagulation profile, renal and liver function tests.
• Chest X-ray (and echocardiography where volume status is unclear) for respiratory symptoms.
• Blood cultures from the patient, and culture of the unit if bacterial contamination is suspected.
• IgA level measurement after anaphylaxis or recurrent moderate to severe allergic reactions.
• B-type natriuretic peptide as an adjunct marker for TACO.
• Arterial blood gas (partial pressure of oxygen / fraction of inspired oxygen) where TRALI is possible.

• Mild: oral temperature at least 38 degrees C with a 1 to 2 degree C rise, without other systemic features. ^[1]
• Moderate to severe: oral temperature at least 39 degrees C, or a rise of at least 2 degrees C, or any rise with systemic symptoms such as chills, rigors, myalgia, nausea or vomiting. ^[1]

Bacterial contamination should be suspected whenever fever is moderate or severe, persistent or unresponsive to symptomatic treatment, or accompanied by severe hypotension or shock. Symptoms may appear within four hours of starting the transfusion. ^[1]

All six criteria are needed; if criteria one to five are met but there is also another risk factor for acute lung injury, the case is called possible TRALI.

1. Acute respiratory distress during or within 6 hours of completing the transfusion.
2. Hypoxaemia: partial pressure of oxygen in arterial blood divided by fraction of inspired oxygen 300 mmHg or below, oxygen saturation below 90 percent on room air, or other clinical evidence of hypoxia. ^[1]
3. Bilateral pulmonary infiltrates on a frontal chest X-ray.
4. No evidence of circulatory overload, with pulmonary arterial wedge pressure 18 mmHg or below or central venous pressure 15 mmHg or below. ^[1]
5. No pre-existing acute lung injury.
6. No alternative risk factor for acute lung injury (aspiration, severe sepsis, pneumonia, multiple fractures, pancreatitis, shock, cardiopulmonary bypass, burns, toxic inhalation, lung contusion, drug overdose or near drowning).

TRALI usually develops within the first 2 hours and recovers over 24 to 72 hours with respiratory support; 5 to 25 percent of cases are fatal. ^[1]

Onset during transfusion or within 6 hours, with acute respiratory distress, dyspnoea, cyanosis, orthopnoea, hypoxia, an increase in systolic blood pressure of more than 20 mmHg above baseline, and signs of cardiac overload (raised jugular venous pressure, bilateral crepitations). Chest X-ray shows pulmonary oedema with cardiomegaly. Risk factors include extremes of age (patients over 60 or under 3 years), cardiac or renal dysfunction, transfusion after acute myocardial infarction, plasma transfusions, a positive fluid balance in the 24 hours before transfusion and large-volume transfusions. Both TRALI and TACO improve or worsen with fluid in opposite directions: TRALI improves with fluid challenge and worsens with diuretics, while TACO improves with diuretics and worsens with fluid. ^[1]

A falling haemoglobin with a positive DAT, a rise in serum lactate dehydrogenase and haemoglobinuria, together with pain at the infusion site, flank pain and a feeling of impending doom; progression can be to acute kidney injury, disseminated intravascular coagulation and death.

A delayed reaction presents days to weeks after transfusion, most often with fever, jaundice, a falling haemoglobin and a positive DAT, and is usually caused by an anamnestic response to a non-ABO red cell antibody. Management is supportive; further transfusion should avoid the offending antigen, and an acute haemolytic reaction should be excluded if the patient is deteriorating.

Restrictive thresholds apply to most stable patients without major haemorrhage, acute coronary syndrome, or chronic transfusion-dependent anaemia. Use a haemoglobin threshold of 70 g per litre with a target of 70 to 90 g per litre after transfusion. A threshold of 80 g per litre with a target of 80 to 100 g per litre is used after acute coronary syndrome. ^[3] In non-bleeding adults, single-unit transfusion (or equivalent weight-based volumes in children or low-weight adults) is preferred, reassessing and rechecking haemoglobin after each unit. Transfusion volumes in children are usually prescribed in millilitres rather than units.

Offer platelets for thrombocytopenia with clinically significant bleeding and a count below 30 times 10 to the 9 per litre. Use higher thresholds up to 100 times 10 to the 9 per litre for severe bleeding (WHO grades 3 and 4) or bleeding in critical sites such as the central nervous system including the eyes. Offer prophylactic platelets below 10 times 10 to the 9 per litre in people who are not bleeding and not undergoing a procedure, unless they have chronic bone marrow failure, autoimmune thrombocytopenia, heparin-induced thrombocytopenia or thrombotic thrombocytopenic purpura. Consider raising the count above 50 times 10 to the 9 per litre for invasive procedures or surgery, and above 100 times 10 to the 9 per litre for surgery in critical sites. Do not routinely give prophylactic platelets for low-bleeding-risk procedures such as adult central venous cannulation or bone marrow aspiration. A typical adult dose is one unit, repeated only if needed after reassessment. ^[3]

Consider plasma only for clinically significant bleeding (without major haemorrhage) when coagulation tests are abnormal, for example when the prothrombin time ratio or activated partial thromboplastin time ratio is above 1.5. Do not use plasma to correct clotting in people who are not bleeding unless they are having an invasive procedure or surgery with a risk of clinically significant bleeding, and do not use it to reverse vitamin K antagonists. Consider prophylactic plasma before procedures in people with abnormal coagulation who are at bleeding risk. An adult starting dose is a weight-based volume (often 20 mL per kg in major haemorrhage protocols), reassessed with repeat coagulation tests. ^{[5] [3]}

Consider cryoprecipitate for clinically significant bleeding without major haemorrhage when the fibrinogen level is below 1.5 g per litre. Consider prophylactic cryoprecipitate before procedures or surgery with a risk of clinically significant bleeding when fibrinogen is below 1.0 g per litre. The adult dose is 2 pools (or 5 to 10 mL per kg up to 2 pools in children), with reassessment of level and clinical status. ^[3]

1. Stop the transfusion at once. Maintain venous access with 0.9 percent saline; do not flush the existing line with the blood component.
2. Check the airway, breathing and circulation; give high-flow oxygen for dyspnoea and take standard observations.
3. Position a hypotensive patient flat with legs elevated.
4. Repeat all identity checks at the bedside: patient, wristband and compatibility label on the component.
5. Visually inspect the pack for clots, haemolysis, unusual discolouration or cloudiness.
6. Identify the likely severity and reaction type from the features, and treat; never delay treatment of a serious reaction to wait for results.
7. Report every reaction to the hospital blood bank, regardless of severity, using the local reaction form.
8. Send the appropriate samples. For moderate and severe reactions this means an EDTA post-transfusion sample, a first-voided post-transfusion urine sample when feasible, and the implicated unit in a sealed bag with the set and clamped tubing. Add blood cultures if bacterial contamination is suspected. Send all products transfused within the previous 24 hours if possible.

The table below is the core working summary. Units and cut-offs are given in international units.

Prevention of recurrence:

• Mild febrile reactions: premedication with paracetamol (acetaminophen) one hour before transfusion can be considered in recurrent cases, although firm evidence is lacking; wash or leukoreduce future units if feasible. ^[1]
• Allergic reactions: no routine prophylaxis before mild reactions; consider antihistamine prophylaxis before moderate to severe reactions; wash red cells for severe or recurrent cases; for IgA-deficient patients with antibodies use IgA-deficient donors or thoroughly washed components, and do not delay life-saving transfusion to obtain them. ^[1]
• TACO: pre- or mid-transfusion diuretics, slow transfusion, one unit at a time with reassessment, postponing non-urgent transfusion until cardiac failure is controlled, and use of split units in heart failure. ^[1]
• TRALI: no precautions are needed for the recipient; national policies often use male donors for plasma and platelets to reduce HLA antibody exposure. ^[1]

Massive transfusion is defined as the administration of more than 10 units of red cells within 24 hours. ^[4] A massive transfusion protocol (MTP) arranges rapid, balanced delivery of red cells, plasma and platelets, usually in predefined packs. There was no difference between early administration of plasma, platelets and red cells in a 1 to 1 to 1 ratio and in a 1 to 1 to 2 ratio, and a ratio of at least 1 unit of fresh frozen plasma to 2 units of red cells is recommended in early resuscitation of major haemorrhage (in major trauma clinicians may consider aiming for a 1 to 1 ratio). ^[5] A 1 to 1 to 1 ratio of platelets, plasma and red cells approximates whole blood.

Clinical triggers are based on active haemorrhage and haemodynamic status, with permissive hypotension (systolic blood pressure around 90 mmHg) in bleeding trauma until control; calcium is monitored and replaced early, because hypocalcaemia from citrate compounds the lethal triad of coagulopathy, acidosis and hypothermia into the so-called diamond of death. Tranexamic acid is used in major trauma, and uterine or pelvic haemorrhage follows the same balanced principles. ^[4]

Aim for end-points of haemoglobin around 80 g per litre, fibrinogen above 1.5 g per litre, platelets above 75 times 10 to the 9 per litre and a prothrombin time ratio below 1.5 once bleeding is controlled, using viscoelastic testing (thromboelastography or rotational thromboelastometry) or laboratory tests to guide further targeted therapy rather than continuing fixed ratios indefinitely. ^[5]

Complications of transfusion include the reactions above plus hyperkalaemia, hypocalcaemia, hypothermia and coagulopathy of dilution during massive transfusion, volume overload, alloimmunisation and infection. Prognosis is good for mild febrile and allergic reactions, which are transient. Acute haemolytic reactions, bacterial contamination, severe anaphylaxis and TRALI carry real mortality; TRALI recovers over 24 to 72 hours but is fatal in 5 to 25 percent of cases, while acute kidney injury and disseminated intravascular coagulation drive the risk in haemolysis. ^[1]

• Two-person bedside verification of patient identity and the component label before every transfusion.
• Leukoreduced (leukodepleted) cellular components, which reduce febrile reactions, HLA alloimmunisation, platelet refractoriness and possibly TRALI; universal pre-storage leukoreduction is not available everywhere. ^[1][5]
• Irradiation of cellular components for patients at risk of graft-versus-host disease: haematopoietic stem cell transplant recipients and donors around harvest (7 days before and during harvest; 3 months after autologous transplant, or 6 months after total body irradiation), Hodgkin lymphoma (indefinitely), patients treated with purine analogues (fludarabine, cladribine, bendamustine, pentostatin) indefinitely, and certain antibody or serotherapy groups (anti-thymocyte globulin, alemtuzumab). Irradiation is not indicated for solid organ transplant recipients on that basis alone, and not routine in aplastic anaemia except in defined situations (HLA-selected platelets, granulocytes, relative donations). ^[5]
• Careful donor selection and bacterial risk: visual inspection of every unit at the bedside, and vigilance because a normal appearance does not exclude bacterial contamination; platelets are the most commonly implicated component. ^[1]
• Washed red cells for severe allergic reactions and for exchange transfusion in neonates (irradiated, fresh, low-potassium units), and IgA-deficient or thoroughly washed components for patients with anti-IgA antibodies. ^[1][5]
• Tranexamic acid, warming, calcium replacement and balanced replacement during severe haemorrhage. ^[4]

Many of the steps above require infrastructure that is unevenly available. Practical adaptations that follow the same principles include:

• Where universal leukoreduction is not in place, bedside leukofiltration and careful reporting still reduce risk, and missing leukoreduction increases the risk of febrile, alloimmunisation and platelet-refractory reactions. ^[1]
• Washed components or IgA-deficient donors may not exist locally; life-saving transfusion should not be withheld, but the unit should be given where staff and resuscitation facilities can manage a severe reaction. ^[1]
• In neonates and small patients, doses are given per kilogram, and exchange or top-up transfusions require fresh, irradiated, high-haematocrit cells; careful warming avoids both hypothermia and haemolysis. ^[5]
• Reporting to a haemovigilance system and regular review of transfusion practice allow safe care even where complex testing is limited. ^[1]

• Pregnancy and the peripartum period follow the same balanced MTP principles; sample sizes and dose limits apply.
• Children and neonates need component volumes prescribed in millilitres (not units) with lower red cell thresholds in different age and respiratory support categories, and exchange transfusion needs irradiated units with a short shelf life after irradiation. ^[5]
• Immunocompromised or multiply transfused patients need irradiated, phenotyped or matched components to avoid GVHD and alloimmunisation. ^[5]

• Transfuse red cells at a haemoglobin of 70 g per litre (target 70 to 90 g per litre) for most stable patients, and at 80 g per litre (target 80 to 100 g per litre) after acute coronary syndrome. ^[3]
• Platelets are offered for bleeding with a count below 30 times 10 to the 9 per litre, prophylactically below 10 times 10 to the 9 per litre, and raised above 50 times 10 to the 9 per litre for procedures. ^[3]
• Plasma is used for clinically significant bleeding with a coagulation ratio above 1.5; cryoprecipitate for bleeding with fibrinogen below 1.5 g per litre. ^[3]
• Every reaction begins with the same immediate actions: stop, keep the vein open, assess, identify, inspect the unit, report. ^[1][2]
• Distinguish TRALI (non-cardiogenic, hypotensive, normal heart size, worse with diuretics) from TACO (cardiogenic, hypertensive, enlarged heart, better with diuretics). ^[1]
• Acute haemolytic reaction is dominated by ABO incompatibility through clerical error; report and recall immediately. ^[1]
• Anaphylaxis is treated with intramuscular adrenaline at 0.5 mL of 1:1000 (500 micrograms) for adults and children over 12 years. ^[2]
• Massive transfusion is more than 10 units of red cells in 24 hours; use a fixed ratio of at least 1 plasma to 2 red cells, aiming for 1 to 1, and check calcium early. ^[4]
• Irradiated and leukoreduced components are the principal preventive tools for GVHD and febrile reactions. ^[5]
• Patients monitored by trained staff, with clear protocols, treat serious reactions earlier. ^[1]

• Anaemia and its differential diagnosis
• Thrombocytopenia
• Coagulopathy and disseminated intravascular coagulation
• IgA deficiency
• Massive haemorrhage and damage-control resuscitation
• Sickle cell disease and major haemoglobinopathies