Acute Haemolytic Transfusion Reaction, ABO incompatibility, pathophysiology and management

Overview

• Transfusion reactions encompass a broad spectrum of adverse events occurring during or after administration of any blood component, ranging from mild urticaria to life-threatening anaphylaxis, acute haemolytic reactions, and TRALI.
• Accurate recognition, systematic investigation, and timely management are essential competencies for the haematology fellow.
• Adverse transfusion events are classified temporally as acute (within 24 hours) or delayed (days to weeks later), and by mechanism as immunological or non-immunological.
• All serious adverse reactions must be reported to the Hospital Transfusion Team and to the relevant national haemovigilance scheme, in the UK, the Serious Hazards of Transfusion (SHOT) scheme; in Australia and New Zealand, the ANHVS.

Classification of Transfusion Reactions

General Principles: Recognition and Initial Response

• All patients receiving blood components must be observed in a clinical area allowing direct monitoring.
• Baseline observations (temperature, pulse, blood pressure, respiratory rate, oxygen saturation) are recorded before starting and repeated regularly throughout transfusion.

Initial Steps for a Suspected Severe Reaction

1. Stop the transfusion: disconnect the blood pack and giving set immediately (do not discard either).
2. Maintain venous access with physiological saline; commence resuscitation if required.
3. Collect samples: full blood count, renal and liver function, coagulation screen, blood cultures (patient), DAT, LDH, plasma and urine haemoglobin, repeat compatibility testing.
4. Check patient identification: confirm the identity band matches the compatibility label and the unit being transfused. Clerical error (wrong blood in tube, WBIT) remains the predominant cause of ABO-incompatible transfusion.
5. Clinical assessment to guide differential:
   • Fever + shock without anaphylaxis → ABO-incompatible transfusion or bacterial sepsis
   • Dyspnoea → TRALI or TACO; check SpO₂/arterial blood gases and chest X-ray
   • Laryngeal oedema with dyspnoea/stridor → anaphylaxis or severe allergic reaction
6. Notify the transfusion laboratory immediately; return the implicated unit.
7. Escalate to the critical care team early in severe or life-threatening reactions.

Acute Haemolytic Transfusion Reaction (AHTR)

Pathophysiology

• AHTRs most commonly result from ABO-incompatible transfusion caused by clerical or patient identification error.
• Pre-formed recipient IgM antibodies activate complement through to the membrane attack complex, causing intravascular haemolysis with haemoglobinaemia, haemoglobinuria, DIC, renal cortical ischaemia, and potentially fatal cardiovascular collapse.
• Rarely, other antibodies capable of activating complement to completion (e.g. anti-Vel, anti-PP1P$^\text{k}$) produce intravascular AHTR.
• IgG-mediated non-ABO incompatibility typically causes extravascular haemolysis via splenic and hepatic macrophages.

Laboratory Investigation

Management

• Aggressive IV fluid resuscitation (normal saline) targeting urine output $\geq 1~\text{mL/kg/hour}$; furosemide if oliguria persists after adequate volume loading
• Early renal team involvement; haemofiltration if renal failure established
• Treat DIC with platelets, cryoprecipitate, and/or fresh frozen plasma as indicated
• Return the implicated unit to the blood bank for investigation
• Haemovigilance reporting

Febrile Non-Haemolytic Transfusion Reaction (FNHTR)

• FNHTR is defined as a rise in temperature $\geq 1{^\circ}\text{C}$ above baseline during or within 4 hours of transfusion, without haemolysis.
• Mechanisms include recipient antibodies against donor HLA or human neutrophil antigens (HNA), and accumulation of cytokines in stored components.
• Universal pre-storage leucodepletion has substantially reduced incidence.
• Management: Slow or temporarily stop the transfusion; administer an antipyretic (paracetamol).
• Critically, exclude AHTR and bacterial contamination before attributing the reaction to FNHTR, fever may be the first sign of a more sinister reaction and ongoing monitoring is mandatory.

Allergic and Anaphylactic Reactions

• Allergic reactions are common, particularly with platelet transfusions and plasma-containing components.
• Sensitisation to allergens in donor plasma is the usual mechanism. IgA deficiency is a critical special case: recipients with IgA deficiency may develop anti-IgA antibodies, and exposure to IgA in plasma-containing components can trigger severe anaphylaxis.
• These patients require washed red cells and platelets, or components from IgA-deficient donors.

• Premedication: Antihistamines mitigate symptoms but do not prevent allergic reactions and are not recommended routinely, reserve for patients with a documented history of allergic transfusion reactions.
• Washed cellular components reduce the incidence of allergic reactions.
• Leucodepletion and microaggregate filters do not reduce allergic reactions.
• Corticosteroids given prior to transfusion may benefit patients with serious recurrent reactions.
• Studies support synergistic H1 + H2 blockade (e.g. diphenhydramine + ranitidine) for histamine-mediated reactions.

Transfusion-Related Acute Lung Injury (TRALI)

Definition and Pathophysiology

TRALI is defined as new acute lung injury within 6 hours of transfusion (usually within 2 hours), characterised by:

• Acute onset hypoxaemia: $\text{SpO}_2 < 90\%$ on room air, or $\dfrac{\text{PaO}_2}{\text{FiO}_2} \leq 300~\text{mmHg}$
• Bilateral infiltrates on frontal chest radiograph
• No evidence of circulatory overload
• No pre-existing ALI before transfusion
• The two-hit model predominates: the first hit is an underlying patient condition (sepsis, haematological malignancy, post-surgical state) that sequesters and primes neutrophils in pulmonary vasculature; the second hit is transfusion of plasma containing anti-HLA or anti-HNA antibodies that activate primed neutrophils (immune TRALI), causing capillary endothelial injury.
• Alternatively, bioactive lipids, cytokines, and leukoagglutinins in stored components may mediate non-immune TRALI without alloantibody involvement.
• TRALI is one of the leading causes of transfusion-related death reported to haemovigilance systems (alongside TACO, AHTR, and septic reactions).

TRALI vs TACO: Key Distinguishing Features

Management and Prevention

• Stop the transfusion; management is primarily supportive
• Supplemental oxygen; mechanical ventilation if required (manage as ARDS)
• Diuretics are not indicated and may worsen TRALI
• Implicated donors must be evaluated for HLA and HNA antibodies; plasma-containing products from donors with confirmed anti-HLA or anti-granulocyte antibodies should not be used
• Prevention strategies: use of male-only plasma donors for FFP and buffy-coat platelet pools; screening of female apheresis plasma donors for HLA/HNA antibodies, these measures have substantially reduced TRALI incidence
• Post-mitigation TRALI risk estimates: approximately 0.4 per 100,000 units for plasma; 1 per 100,000 units for platelets; 0.5 per 100,000 units for red cells

Transfusion-Associated Circulatory Overload (TACO)

• TACO is the leading cause of transfusion-related mortality and major morbidity in contemporary haemovigilance reports (including SHOT).
• Risk factors include advanced age (>70 years), pre-existing cardiac or renal disease, hypoalbuminaemia, and rapid transfusion rates.
• Management: Stop or slow the transfusion; sit the patient upright; supplemental oxygen; IV furosemide.
• High-dependency monitoring may be required. Prevention: appropriate transfusion triggers, single-unit strategies with clinical reassessment between units, and slower infusion rates in at-risk patients.

Septic Transfusion Reactions

• Bacterial contamination is particularly associated with platelet components (stored at 22°C).
• Gram-negative organisms generate endotoxin during storage, causing rapid and severe reactions; gram-positive organisms may produce more delayed reactions.
• Septic reactions are reportedly underrecognised, true patient risk may be 10- to 40-fold higher than passive haemovigilance data suggest.

Clinical features: fever $\geq 38{^\circ}\text{C}$ with a rise $\geq 1{^\circ}\text{C}$, rigors, tachycardia, hypotension, dyspnoea, nausea/vomiting, and shock, typically during or within 4 hours of transfusion completion; delayed presentations occur with some organisms.

• Investigation: Gram stain and culture from the returned unit (at 20°C and 37°C); blood cultures from the patient before starting antibiotics.
• Definitive diagnosis requires isolation of the same organism from both; presumed in a culture-negative patient with clinical sepsis if bacteria are identified from the unit.

Management: Stop transfusion; draw blood cultures then commence broad-spectrum IV antibiotics immediately; haemodynamic resuscitation; ICU support as required.

Delayed Haemolytic Transfusion Reaction (DHTR)

• DHTRs occur when a recipient previously sensitised to a red cell antigen (by prior transfusion or pregnancy) has an antibody level that is undetectable at pretransfusion testing.
• Transfusion of the corresponding antigen triggers a secondary anamnestic IgG response; IgG- and/or complement-coated red cells are destroyed extravascularly in the spleen and/or liver, typically 3-14 days post-transfusion.

DHTRs are always caused by IgG antibodies and haemolysis is therefore always extravascular.

Commonly implicated antibodies: Kidd (anti-Jk$^\text{a}$, anti-Jk$^\text{b}$, notorious for rapid decline to undetectable levels, dosage effect, and frequent co-occurrence with other antibodies), Duffy, Kell, Rh (non-D).

Laboratory Features Suggesting DHTR

• Haemoglobin falls more rapidly than expected, or transfusion increment is less than anticipated
• Spherocytosis on blood film
• Positive DAT
• Elevated unconjugated bilirubin and LDH; reduced haptoglobin
• Serological investigation: Repeat antibody screen and crossmatch on pre- and post-transfusion samples; antibody elution from post-transfusion red cells to confirm specificities.
• Full serological investigation is warranted only when there is clinical or laboratory evidence of haemolysis; ideally the pre-transfusion sample is tested in parallel.

Management: Usually supportive; document the antibody and ensure all future transfusions use antigen-negative units; update the patient's transfusion record.

Post-Transfusion Purpura (PTP)

• PTP is a rare but severe immune thrombocytopenia occurring 5-12 days post-transfusion, with profound thrombocytopenia (platelet count often $<10 \times 10^9/\text{L}$) and bleeding.
• Alloantibodies, most commonly anti-HPA-1a, destroy both donor platelets and, by an incompletely understood bystander mechanism, the patient's own HPA-1a-negative platelets.
• Gum bleeding and purpura are characteristic presenting features.

Management:

Transfusion-Associated Graft-Versus-Host Disease (TA-GvHD)

• TA-GvHD results from proliferation of viable donor T lymphocytes in a recipient unable to eliminate them.
• It presents with fever, erythematous rash, diarrhoea, and hepatitis 2 days to 6 weeks post-transfusion and is almost universally fatal.
• Diagnosis is confirmed by typical acute GvHD features on biopsy of affected organs, with detection of donor-derived cells or DNA in patient blood or tissues.

At-risk recipients requiring irradiated components:

• Fetuses receiving intrauterine transfusion; neonates post-IUT
• Congenital T-cell immunodeficiency disorders
• Allogeneic haematopoietic stem cell transplant recipients
• Recipients of purine analogue-based chemotherapy (e.g. fludarabine, cladribine)
• Recipients of donations from HLA-matched or first-degree relative donors (even if immunocompetent)

Patients receiving conventional combination chemotherapy for cancer are not at increased risk.

• Prevention: Gamma-irradiation (minimum 25 Gy to the component, minimum 15 Gy to any point) of all cellular blood components for at-risk patients.
• Leucodepletion alone does not prevent TA-GvHD.

Alloimmunisation

• Repeated transfusion and pregnancy lead to alloantibody formation against red cell, platelet, or HLA antigens.
• Red cell alloimmunisation is particularly problematic in chronically transfused patients (thalassaemia major, sickle cell disease).
• Extended phenotype matching, at minimum Rh (C/c/E/e), K, and in high-risk patients additionally Fy, Jk, S/s, is recommended to minimise alloimmunisation in chronically transfused patients.
• Molecular typing is increasingly used to predict RBC phenotype and facilitate compatible component selection.
• A double ABO determination performed separately on two samples is recommended, especially when a historical result is unavailable.

Haemovigilance and Reporting

All serious adverse transfusion reactions must be:

1. Reported immediately to the Hospital Transfusion Team
2. Reported confidentially to the national haemovigilance scheme (e.g. SHOT in the UK)

Reactions are classified by severity (mild, moderate, severe, fatal) and imputability (definite, probable, possible, unlikely, unclassifiable) per International Society for Blood Transfusion / International Haemovigilance Network definitions.

• Near-miss events, particularly WBIT errors, must also be reported.
• SHOT estimates approximately 1 incorrect blood component is transfused for every 100 near-miss events; WBIT errors numbered 643 in 2013 alone, the majority being near-misses.
• Traceability of every unit from donor to recipient must be maintained.
• Electronic transfusion management systems with barcode scanning linked to laboratory information systems significantly reduce bedside identification errors.

Special Situations and Additional Complications

Hypotensive Transfusion Reactions

• Transient isolated fall in systolic blood pressure $\geq 30~\text{mmHg}$ during transfusion without other features, typically resolving with cessation.
• Associated with ACE inhibitor use and bedside leucodepletion filters (bradykinin generation).
• Pre-storage leucodepletion has reduced incidence.

Transfusion-Associated Dyspnoea

• Acute respiratory distress within 24 hours of transfusion cessation when TRALI, TACO, and allergic reactions have been excluded, a diagnosis of exclusion.
• Incidence approximately 1 in 28,000 transfusions.

Hyperhemolytic Crisis in Sickle Cell Disease

• An accelerated haemolysis syndrome post-transfusion in sickle cell patients, haemoglobin falls below pretransfusion levels with a positive DAT.
• May overlap with DHTR.
• Management emphasises avoidance of further transfusion where possible; IVIg and corticosteroids may be used.

Iron Overload

• Each unit of red cells contains approximately 200-250 mg of iron; there is no physiological mechanism for iron excretion.
• Progressive iron accumulation in chronically transfused patients (cardiac, hepatic, and/or renal insufficiency) requires iron chelation therapy (desferrioxamine, deferasirox, or deferiprone), generally initiated when serum ferritin exceeds approximately 1000 µg/L.

Transfusion-Transmitted Infection (TTI)

• Current donor screening has reduced TTI to very low levels.
• Investigation is triggered either by a symptomatic recipient (bottom-up) or by a donor subsequently found to be infected (top-down).
• Emerging pathogens (e.g. Babesia spp. dengue virus) represent ongoing haemovigilance challenges.
• Transfusion-transmitted Babesia carries a particularly high fatality rate (~17% in historical series).