Transfusion reactions, TRALI vs TACO, acute haemolysis, haemovigilance

Definition / Overview

• An acute transfusion reaction (ATR) is any adverse event occurring during or within 24 hours of blood product administration.
• ATRs range from benign (mild febrile or urticarial reactions) to immediately life-threatening (acute haemolytic reaction, anaphylaxis, TRALI, septic shock from bacterial contamination).
• Every ED transfusing blood products must have a protocol-driven response that begins with stopping the transfusion and calling the blood bank, regardless of reaction severity.

The spectrum of acute reactions:

Pathophysiology

Febrile Non-Haemolytic Transfusion Reaction (FNHTR)

• Cytokines accumulate in stored blood products from donor white cells and platelet fragments.
• Recipient antibodies to donor leukocyte antigens trigger fever without haemolysis.
• Leukocyte reduction of products significantly reduces but does not eliminate FNHTR.

Acute Haemolytic Transfusion Reaction (AHTR)

• Nearly always caused by ABO incompatibility secondary to an administrative error (wrong patient, wrong unit, labelling failure) rather than a serological failure.
• Pre-formed anti-A and anti-B IgM antibodies activate complement, causing rapid intravascular haemolysis.
• Free haemoglobin precipitates in renal tubules, triggering acute tubular necrosis.
• Complement activation simultaneously activates the coagulation cascade, precipitating disseminated intravascular coagulation (DIC).

Anaphylaxis

• The most severe allergic reaction occurs in patients with selective IgA deficiency (prevalence approximately 1:300-500), who carry IgG anti-IgA antibodies.
• On exposure to IgA-containing plasma, massive mast cell degranulation causes distributive shock, angioedema, and bronchospasm.

TRALI

• Donor plasma containing anti-HLA class I/II or anti-human neutrophil antigen (anti-HNA) antibodies binds to recipient neutrophils in the pulmonary capillary bed, triggering neutrophil activation and capillary leak.
• Results in non-cardiogenic pulmonary oedema.
• All plasma-containing products are implicated; the highest risk is from multiparous female donors.
• Central venous pressure (CVP) is normal, distinguishing TRALI from TACO.

TACO

• High-volume or rapid infusion overwhelms left ventricular compliance, raising left atrial pressure and causing hydrostatic pulmonary oedema.
• Common in elderly patients and those with pre-existing cardiac or renal impairment.

Bacterial Contamination

• Platelet concentrates stored at room temperature (20-24°C) carry the highest risk; common organisms include Staphylococcus aureus and Staphylococcus epidermidis.
• Red cells stored at 4°C are more likely to harbour cold-tolerant Gram-negatives (e.g. Yersinia enterocolitica, Pseudomonas spp.).
• Endotoxin release causes fever, rigors, hypotension, and rapidly progressive septic shock.

Clinical Features and Diagnosis

FNHTR

• Temperature rise ≥1°C above baseline during or within 4 hours of transfusion
• Chills, rigors, mild dyspnoea
• No haemolysis, no hypotension
• Diagnosis of exclusion: AHTR and bacterial contamination must be excluded at presentation

Allergic / Urticarial Reaction

• Pruritus, urticaria, flushing, oedema
• No fever, no haemodynamic compromise, no respiratory compromise
• Confined to skin: this feature separates mild allergic reaction from anaphylaxis

Anaphylaxis

• Rapid onset: bronchospasm, laryngeal oedema, hypotension, urticaria
• Shorter interval from transfusion commencement to symptom onset correlates with severity
• Suspect IgA deficiency if severe anaphylaxis without prior sensitisation history

AHTR

• Typically within the first 30 minutes of transfusion
• Fever, rigors, loin/flank pain (tubular haem deposition), crushing chest pain, agitation, restlessness
• Hypotension, tachycardia, haemoglobinaemia (plasma turns pink)
• Haemoglobinuria (red-brown urine), falling haematocrit
• Progresses to DIC, acute renal failure, multi-organ failure
• In anaesthetised patients: unexplained hypotension, haemoglobinuria, or oozing from wound edges may be the only signs

TRALI vs TACO Differentiation

Bacterial Contamination

• High spiking fever (often >39°C), rigors within minutes of commencement
• Rapid haemodynamic deterioration out of proportion to volume administered
• Product may appear visually abnormal (clots, discolouration, turbidity)
• Must be differentiated from AHTR and anaphylaxis

Investigation and Monitoring

Immediately on stopping transfusion (all reactions):

1. Recheck patient identification against the blood unit label at the bedside: the most common cause of AHTR is an administrative mismatch
2. Send the implicated unit with the giving set (do not flush) back to the blood bank
3. Take a new blood sample from a different limb for:
   • Group and hold / direct antiglobulin test (DAT / direct Coombs)
   • Full blood count, coagulation screen (APTT, PT, fibrinogen), film
   • Renal function, electrolytes, LFTs, LDH, haptoglobin, unconjugated bilirubin
   • Blood cultures $\times$ 2 (peripheral) before any antibiotics
4. Urinalysis: free haemoglobin (haemoglobinuria) confirms intravascular haemolysis
5. For suspected TRALI or TACO: BNP or NT-proBNP, 12-lead ECG, portable CXR, bedside echocardiogram (LV function, IVC, B-lines on lung ultrasound)
6. Blood bank: perform repeat ABO/Rh typing on both donor and recipient; serological crossmatch of residual product

ED Management

Universal First Steps (All Reactions)

1. Stop the transfusion immediately. Do not flush the giving set.
2. Maintain IV access; obtain new IV access in a separate limb if required.
3. Notify the blood bank immediately.
4. ABCDE assessment with continuous monitoring: $SpO_2$, ECG, BP, RR, temperature.
5. Administer $O_2$ if $SpO_2 < 94\%$.

FNHTR

• Administer paracetamol 1 g PO or IV (or if febrile reaction accompanies rigors, consider pethidine 25 mg IV for rigor control).
• Exclude AHTR and bacterial contamination clinically and with initial investigations.
• If temperature settles, patient remains haemodynamically stable, and no features of haemolysis or sepsis: restart transfusion at a slower rate with close monitoring after blood bank consultation.
• For patients with recurrent FNHTRs: liaise with blood bank for leukocyte-reduced products; consider pre-medication with paracetamol 1 g PO 30-60 minutes prior (only in patients with prior reactions, not routine prophylaxis).

Allergic / Urticarial Reaction

• Stop transfusion.
• Administer cetirizine 10 mg PO for mild urticaria; injectable promethazine must not be used (ASCIA: it can worsen hypotension and cause muscle necrosis).
• If symptoms confined to skin and resolve within 15 minutes: restart transfusion slowly with blood bank approval.
• Escalate to anaphylaxis management if any systemic features develop.

Anaphylaxis

Following ANZCOR anaphylaxis guidelines:

1. Adrenaline 0.5 mg IM (1:1000) into the anterolateral thigh immediately; repeat every 5 minutes if no response.
2. Position: supine with legs elevated (unless respiratory compromise mandates sitting).
3. High-flow $O_2$ via non-rebreather mask.
4. IV fluid resuscitation: sodium chloride 0.9% 500-1000 mL IV bolus and repeat as required for haemodynamic response.
5. Second-line agents (after adrenaline):
   • Salbutamol for bronchospasm: 8 puffs via MDI or 5 mg nebulised
   • Hydrocortisone 200 mg IV (delayed onset, prevents biphasic reaction)
   • A non-sedating oral antihistamine (e.g. cetirizine 10 mg) for persistent urticaria once anaphylaxis is treated. Injectable promethazine must not be used (ASCIA: it can worsen hypotension and cause muscle necrosis)
6. If refractory shock requiring intubation: RSI with ketamine 1.5 mg/kg IV and rocuronium 1.2 mg/kg IV with early adrenaline infusion (0.1-0.5 mcg/kg/min).
7. For known IgA deficiency in future transfusions: use IgA-depleted products and washed red cells; coordinate with blood bank and haematology.
8. Disposition: resus area; minimum 4-hour observation post-adrenaline; admit if second dose of adrenaline required or biphasic reaction risk.

Acute Haemolytic Transfusion Reaction (AHTR)

1. Stop transfusion immediately; do not flush the line.
2. IV fluid resuscitation: induce diuresis with IV fluids and diuretics (Lifeblood) to maintain renal output and preserve renal perfusion.
3. Insert urinary catheter: hourly urine output monitoring is mandatory.
4. Do not use diuretics in the absence of fluid overload; forced diuresis is not supported by evidence.
5. Treat DIC: fresh frozen plasma (FFP) 15 mL/kg, cryoprecipitate for fibrinogen <1.5 g/L, platelet transfusion if $< 50 \times 10^9/\text{L}$ and actively bleeding.
6. Vasopressors (noradrenaline 0.1-0.3 mcg/kg/min) for persistent hypotension after fluid resuscitation; titrate to MAP ≥65 mmHg.
7. Early nephrology and haematology consultation.
8. Disposition: ICU admission for renal replacement therapy anticipation, DIC management, and multi-organ monitoring.

TRALI

1. Stop transfusion.
2. High-flow $O_2$; prepare for early escalation to non-invasive ventilation (NIV: BiPAP/CPAP) or intubation.
3. If intubation required: RSI with ketamine 1.5 mg/kg IV and rocuronium 1.2 mg/kg IV; lung-protective ventilation (tidal volume 6 mL/kg ideal body weight, PEEP 5-8 cmH₂O, $FiO_2$ titrated to $SpO_2 \geq 92\%$).
4. Diuretics are contraindicated: the mechanism is capillary leak, not volume overload; diuretics worsen hypotension.
5. Corticosteroids have no proven benefit in TRALI.
6. Vasopressors (noradrenaline) if distributive hypotension persists.
7. Mandatory blood bank notification: donor and product information collected for haemovigilance; the implicated unit tested for donor HLA/HNA antibodies.
8. Disposition: ICU; mortality up to 10%, although most survive with supportive care.

TACO

1. Stop or significantly slow the transfusion.
2. Frusemide 40-80 mg IV (reduces preload; titrate to clinical response).
3. Upright positioning, supplemental $O_2$.
4. NIV (BiPAP) if $SpO_2$ does not correct with $O_2$ alone.
5. BNP / NT-proBNP and echo to confirm cardiogenic mechanism.
6. Consider GTN infusion for acute pulmonary oedema with hypertension (50 mg in 50 mL at 1-10 mL/hr, titrate to response).
7. Disposition: monitored bed or HDU; senior cardiology review if new cardiomyopathy identified.

Bacterial Contamination

1. Stop transfusion immediately; retain unit for culture.
2. Collect blood cultures $\times$ 2 peripheral, then commence ceftriaxone 2 g IV plus metronidazole 500 mg IV (or per local Gram-negative sepsis protocol pending cultures).
3. Manage as per sepsis bundle: MAP target ≥65 mmHg, fluid resuscitation 30 mL/kg crystalloid, vasopressors if required.
4. Send unit to blood bank and microbiology for direct Gram stain and culture.
5. Disposition: ICU if septic shock; resus area initially in all cases.

Haemovigilance Reporting

• Every suspected ATR must be reported to the blood bank at the time of the event: this is both a clinical safety imperative and a regulatory obligation.
• In Australia, serious adverse events are reportable to the Australian Red Cross Lifeblood haemovigilance program (Hemovigilance Australia).
• The blood bank physician must be contacted directly for all reactions beyond mild FNHTR; they coordinate serological re-investigation, quarantine of associated units, and retrospective donor lookback for TRALI.
• Documentation in the medical record must include: exact time transfusion commenced, time of reaction, volume transfused, product type, and unit identification number.
• Hospitals are required to maintain a blood management governance framework; ED incidents should trigger a clinical incident report through the institutional quality system.
• Common error: abandoning all future transfusion after an ATR. Most reactions are unit-specific or patient-specific and appropriately matched future products can be given safely. Coordinate with blood bank for crossmatching new units as soon as the reaction is investigated.

Complications and Special Considerations

Delayed Haemolytic Transfusion Reaction (DHTR)

• Occurs 2-10 days post-transfusion due to an anamnestic response from prior sensitisation (previous transfusion or pregnancy)
• Features: unexplained falling haematocrit, low-grade fever, mild jaundice, spherocytes on film, positive DAT
• Extravascular haemolysis: less severe than AHTR but can cause anaemia requiring treatment
• Management: avoid future transfusion with the implicated red-cell antigen; haematology follow-up

Patients with Sickle Cell Disease

• Exchange transfusion indications: acute chest syndrome, acute stroke, priapism unresponsive to conservative measures
• These patients are at high risk of alloimmunisation and delayed haemolytic reactions: extended antigen matching is mandatory

Massive Transfusion Protocol (MTP)

• MTP activates a 1:1:1 ratio of packed red cells:FFP:platelets
• Tranexamic acid (TXA) 1 g IV over 10 minutes, then 1 g over 8 hours, must be given within 3 hours of injury (earlier is better)
• Fibrinogen target ≥1.5 g/L: supplement with cryoprecipitate or fibrinogen concentrate
• Monitor with thromboelastography (TEG/ROTEM) where available to guide product selection

Emergency Uncrossmatched Blood

• Group O Rh-negative, Kell-negative for females of childbearing potential (prevents alloimmunisation and haemolytic disease of the newborn)
• Group O Rh-positive acceptable for males and post-menopausal females
• Group-specific (ABO/Rh only) available within approximately 35 minutes; incidence of adverse reaction comparable to O-negative

Pre-medication

• Routine prophylactic pre-medication with paracetamol or antihistamines before transfusion is not recommended in patients without prior reactions
• Pre-medication is appropriate for patients with documented prior febrile or allergic reactions

OSCE and SAQ Exam Priorities

• Name the reaction correctly and state the mechanism before launching into management: examiners reward diagnostic precision.
• TRALI vs TACO is a high-yield discriminator: bilateral infiltrates on CXR are common to both; CVP, BNP, echo, and blood pressure pattern differentiate them; treatment is opposite (diuretics harm TRALI, help TACO).
• Never omit: stop the transfusion, retain the unit, call the blood bank, send blood cultures before antibiotics in bacterial contamination.
• Anaphylaxis dose: adrenaline 0.5 mg IM (1:1000) anterolateral thigh; repeat every 5 minutes; this must be the first pharmacological intervention.
• AHTR: the diagnosis is primarily clinical in the first minutes; renal protection through urine output >1 mL/kg/hr is the cornerstone of management.
• Haemovigilance reporting is a mandatory component of every transfusion reaction answer in the written paper.