Transfusion Medicine and Transfusion Reactions

Products and their indications

• Packed red cells raise oxygen-carrying capacity; a restrictive threshold (around 7 g/dL, higher in acute coronary syndrome) is standard, since liberal transfusion does not improve outcomes.
• Platelets for thrombocytopenic bleeding or profound counts; contraindicated or hazardous in TTP and HIT, where they can fuel thrombosis.
• Fresh frozen plasma replaces coagulation factors; cryoprecipitate supplies fibrinogen, factor VIII, von Willebrand factor and factor XIII.

Reactions by timing

• Acute haemolytic — within minutes, from ABO incompatibility, almost always a clerical identification error. Fever, flank pain, hypotension, haemoglobinuria, DIC. Preformed IgM, complement-mediated intravascular haemolysis. Stop, support, aggressive fluids.
• Febrile non-haemolytic — the commonest reaction; fever and chills from cytokines accumulated in stored product; prevented by leukoreduction.
• Allergic / urticarial — mild, from plasma proteins; anaphylaxis in IgA-deficient recipients with anti-IgA antibodies, who need washed products.
• TRALI — within 6 hours: hypoxaemia and bilateral infiltrates with a normal filling pressure, from donor antileukocyte antibodies. Non-cardiogenic.
• TACO — circulatory overload: hypoxaemia with raised filling pressures, hypertension and a positive fluid balance. Distinguishing TRALI from TACO is the classic question.
• Delayed haemolytic — days later, anamnestic response to a minor antigen; falling haemoglobin and a positive direct antiglobulin test.
• Massive transfusion brings hypocalcaemia (citrate), hyperkalaemia, hypothermia and dilutional coagulopathy.

Immune mechanisms (recipient or donor antibody)

• Preformed recipient IgM anti-A/anti-B: acute haemolytic reaction after ABO-incompatible red cells; the root cause is nearly always a clerical/bedside identification error, not a laboratory failure.
• Anamnestic IgG against minor red cell antigens: delayed haemolysis, classically Kidd (anti-Jk^a), also Kell, Duffy, Rh (E, c). Sensitisation comes from prior pregnancy or transfusion, and titres fall below detection between exposures (evanescent antibodies).
• Recipient anti-IgA in IgA deficiency: anaphylaxis to plasma-containing products.
• Donor anti-HLA class I/II or anti-human neutrophil antigen antibodies: TRALI; such antibodies are enriched in multiparous female donors.
• Recipient anti-HPA-1a: post-transfusion purpura, typically a previously pregnant woman.
• Viable donor T lymphocytes: transfusion-associated graft-versus-host disease in severely immunocompromised or HLA-similar (directed family donor) recipients.

Non-immune mechanisms

• Storage lesion: leukocyte-derived cytokines accumulate and cause febrile non-haemolytic reactions; potassium leaks from stored red cells; citrate anticoagulant chelates calcium.
• Volume and rate: TACO is a pure hydrostatic problem of infused volume against limited cardiac or renal reserve.
• Bacterial contamination: highest with platelets (room-temperature storage); Yersinia enterocolitica is the classic cold-growing contaminant of refrigerated red cells.

Modifiable risk factors

• Failure of two-person or electronic patient identification at the bedside.
• Use of non-leukoreduced components, unwashed products in IgA deficiency, non-irradiated products in at-risk recipients.
• Rapid infusion rate and large cumulative volume; use of female-donor plasma (mitigated in the US by male-predominant plasma donor strategies mandated through AABB standards).

Non-modifiable risk factors

• Prior transfusions or pregnancies (alloimmunisation), sickle cell disease and thalassaemia requiring chronic transfusion.
• IgA deficiency, congenital or acquired T-cell immunodeficiency, purine-analogue therapy (fludarabine), stem cell transplant.
• Age extremes, heart failure, chronic kidney disease, low body weight — all TACO risks.
• Sepsis, shock, chronic alcohol use and mechanical ventilation — recipient priming factors for TRALI.

Acute haemolytic reaction

• Recipient IgM anti-A/anti-B binds donor red cells, fixes complement through C1 to the C5b-9 membrane attack complex, and lyses cells inside the vessel. Free haemoglobin saturates haptoglobin, then filters into urine — hence haemoglobinuria with a normal-looking urinary sediment.
• Free haemoglobin scavenges nitric oxide, producing vasoconstriction and flank/back pain; the anaphylatoxins C3a and C5a plus TNF-α and IL-1 drive fever and vasodilatory hypotension. Red cell stroma exposes tissue factor, triggering DIC; pigment casts plus renal vasoconstriction and hypotension cause acute tubular injury.

Delayed haemolytic reaction

• Memory B cells re-encounter a minor antigen; IgG coats red cells without efficiently fixing complement, so splenic macrophages remove them extravascularly. Haemolysis is gradual — unconjugated hyperbilirubinaemia and a falling haemoglobin days later, not haemoglobinuria.

Febrile non-haemolytic reaction

• Cytokines released by leukocytes during storage (IL-1β, IL-6, TNF-α) act on hypothalamic prostaglandin E2 to reset the thermal set point; recipient antibodies against donor leukocytes can do the same. No red cell destruction occurs.

Allergic and anaphylactic reactions

• Recipient IgE against soluble donor plasma proteins cross-links mast cell receptors → histamine → urticaria. In IgA deficiency, anti-IgA antibodies bind infused IgA and cause massive mediator release with bronchospasm and distributive shock.

TRALI versus TACO

• TRALI is a two-hit process: recipient neutrophils are primed and sequestered in the pulmonary microvasculature by sepsis, surgery or inflammation (first hit), then activated by donor anti-HLA/anti-HNA antibodies or bioactive lipids (second hit). Degranulation and oxidant injury break the alveolar–capillary barrier, producing protein-rich, non-cardiogenic pulmonary oedema with normal filling pressures.
• TACO is hydrostatic: infused volume raises left atrial pressure, forcing a protein-poor transudate into alveoli, with hypertension and a rising natriuretic peptide.

Massive transfusion

• Citrate chelates ionised calcium (perioral tingling, prolonged QT); leaked extracellular potassium and cold product add hyperkalaemia and hypothermia, which together with dilution of factors and platelets impair clot formation.

Within minutes of starting the unit

• Acute haemolytic: fever, rigors, flank or back pain, a sense of impending doom, hypotension, and red-brown urine. The stem names an anaesthetised or obtunded patient in whom hypotension, diffuse oozing from the surgical field and haemoglobinuria are the only clues, because pain and chills cannot be reported.
• Anaphylactic: urticaria, wheeze, angio-oedema and shock without fever, beginning after only a few millilitres. The exposure the stem names is a young patient with recurrent "allergic reactions" to blood or a history of IgA deficiency (often with recurrent sinopulmonary and giardial infection).
• Bacterial contamination: high fever, rigors and shock within minutes to hours, most often after a platelet unit.

Within 1–6 hours

• Febrile non-haemolytic: temperature rise ≥1°C with chills, but haemodynamically stable and no haemolysis; the classic stem is a multiply transfused or multiparous patient receiving non-leukoreduced product.
• TRALI: acute dyspnoea, hypoxaemia, fever and hypotension with bilateral infiltrates and clear lungs on auscultation relative to the imaging, no JVD, no S3.
• TACO: dyspnoea, orthopnoea, hypertension, JVD, S3 gallop, bibasilar crackles and peripheral oedema; the stem plants an elderly patient with heart failure or CKD who received several units quickly.

Days to weeks later

• Delayed haemolytic: 3–14 days out, an unexplained fall in haemoglobin despite transfusion, low-grade fever, jaundice and dark urine from urobilinogen; frequently in a patient with sickle cell disease.
• Post-transfusion purpura: abrupt severe thrombocytopenia with mucocutaneous bleeding about a week after transfusion, typically in a previously pregnant woman.
• Transfusion-associated GVHD: 1–6 weeks later with fever, maculopapular rash, diarrhoea, hepatitis and pancytopenia — marrow aplasia is the distinguishing feature from marrow-sparing solid-organ GVHD.

Step one for every reaction

• Stop the transfusion, keep the line open with normal saline, and recheck the identification band against the unit label. Return the unit and tubing to the blood bank with a fresh post-transfusion sample.

Confirming haemolysis

• Direct antiglobulin (Coombs) test: the key confirmatory test — positive, often mixed-field, in acute and delayed haemolytic reactions. Negative in febrile non-haemolytic and allergic reactions.
• Visual plasma inspection and plasma free haemoglobin: pink-red supernatant in the post-transfusion sample is the earliest and cheapest evidence of intravascular haemolysis.
• Supporting labs: undetectable haptoglobin, elevated LDH, indirect hyperbilirubinaemia, and urine dipstick positive for blood with no red cells on microscopy (haemoglobinuria).
• Repeat ABO typing and crossmatch on pre- and post-transfusion samples plus a clerical audit identifies the misidentification.
• Antibody screen and elution identify the offending minor antigen in delayed reactions (Kidd, Kell, Duffy, Rh).
• DIC panel: falling platelets and fibrinogen, prolonged PT/aPTT, elevated D-dimer.

Separating TRALI from TACO — the classic exam decision

• Chest radiograph: bilateral infiltrates in both; cardiomegaly and vascular redistribution favour TACO.
• BNP/NT-proBNP: elevated in TACO, typically not markedly raised in TRALI. Echocardiography showing normal filling pressures and normal LV function supports TRALI; the 2019 consensus TRALI definition requires acute hypoxaemia within 6 hours with bilateral infiltrates and no evidence of hydrostatic overload as the sole cause.
• Response to diuresis favours TACO; TRALI does not improve with furosemide.
• Oedema fluid with a high protein-to-plasma ratio (exudate) indicates TRALI, though this is rarely obtained clinically.

Other targeted studies

• Gram stain and culture of the unit and the patient when fever with rigors and shock suggests bacterial contamination.
• Quantitative serum IgA and anti-IgA antibody testing after anaphylaxis.
• Anti-HPA-1a antibodies for post-transfusion purpura; HLA chimerism or skin biopsy for transfusion-associated GVHD.
• Ionised calcium, potassium, core temperature and fibrinogen during massive transfusion.

Immediate, before any diagnosis

• Stop the transfusion and disconnect the tubing; maintain venous access with normal saline through new tubing. Verify identifiers and notify the blood bank. This is the single best next step in essentially every transfusion-reaction stem.

Acute haemolytic reaction

• Aggressive isotonic crystalloid to support blood pressure and maintain brisk urine output, preserving renal perfusion and clearing pigment; vasopressors if shock persists. AABB and hospital transfusion-service protocols direct return of the unit and clerical investigation.
• Loop diuretics (furosemide) only after volume repletion if oliguria persists; treat DIC with component support guided by fibrinogen and platelet count.
• Do not restart the implicated unit under any circumstance.

Anaphylactic reaction

• Epinephrine 0.3 mg IM (0.5 mg in adults per current anaphylaxis practice) is first line, with airway support and fluids; antihistamines and corticosteroids are adjuncts only, consistent with AAAAI/Joint Task Force anaphylaxis parameters.
• Future transfusions require washed red cells and platelets or IgA-deficient donor plasma.

Emergencies

• Acute haemolytic reaction with DIC and acute kidney injury — red cell stroma triggers tissue factor; the signals are diffuse oozing, falling fibrinogen, rising D-dimer, and oliguria with haemoglobinuric casts. Immediately life-threatening.
• Anaphylaxis — airway obstruction and distributive shock in the IgA-deficient recipient; hypotension without fever is the tell.
• Transfusion-transmitted bacterial sepsis — rigors and shock within an hour of a platelet unit; mortality is high without prompt antibiotics.
• TRALI — the leading cause of transfusion-related death historically reported to the FDA; may require mechanical ventilation, though most cases resolve within days.
• TACO — flash pulmonary oedema, particularly in elderly or renally impaired patients.
• Hyperkalaemia and citrate-induced hypocalcaemia during massive transfusion — peaked T waves or a prolonged QT with tetany; both can precipitate arrest.

Delayed or chronic complications

• Delayed haemolytic transfusion reaction — extravascular IgG-mediated clearance; unexplained haemoglobin fall with a positive DAT days later.
• Hyperhaemolysis syndrome — in sickle cell disease, post-transfusion haemoglobin falls below the pre-transfusion level with destruction of autologous cells; further transfusion worsens it.
• Red cell alloimmunisation — makes future crossmatching difficult and complicates pregnancy (haemolytic disease of the fetus and newborn from anti-D, anti-Kell).
• Transfusion-associated GVHD — donor T cells attack recipient marrow; rash, diarrhoea, hepatitis and pancytopenia, near-uniformly fatal, prevented only by irradiation (leukoreduction is insufficient).
• Post-transfusion purpura — profound thrombocytopenia about a week later; IVIG is the treatment.
• Iron overload — after chronic transfusion in thalassaemia or sickle cell disease; ferritin rises, then cardiomyopathy, cirrhosis and endocrinopathy. Managed with chelation (deferasirox, deferoxamine).
• Infection transmission — HIV, HBV, HCV risk is now extremely low with nucleic acid testing; residual concerns include hepatitis E, Babesia, Trypanosoma cruzi and CMV in seronegative immunocompromised recipients.
• Hypothermia and dilutional coagulopathy from rapid, unwarmed, unbalanced resuscitation.

• The universal first step is to stop the transfusion and keep the line open with normal saline. Every other answer choice — labs, antipyretics, diuretics — comes after. The one exception: isolated urticaria may be treated with an antihistamine and the unit resumed.
• Fever + flank pain + haemoglobinuria within minutes = ABO incompatibility from a clerical error. In the anaesthetised patient the presentation is hypotension plus diffuse surgical-field oozing. Confirm with a positive direct antiglobulin test and pink plasma.
• TRALI versus TACO is the classic discriminator: hypotension, fever and normal filling pressures with a normal BNP point to TRALI; hypertension, JVD, S3 and an elevated BNP with improvement after furosemide point to TACO. Diuretics help TACO and do not help TRALI.
• Anaphylaxis in a young patient with recurrent transfusion reactions = selective IgA deficiency. Next step is washed cellular products (or IgA-deficient plasma); check serum IgA. Epinephrine, not antihistamines, treats the acute event.
• Leukoreduction prevents febrile non-haemolytic reactions, HLA alloimmunisation and CMV transmission. Irradiation prevents transfusion-associated GVHD. Examiners test the swap: leukoreduction does not prevent GVHD, because viable T cells persist.
• **Unexplained haemoglobin drop and jaundice about a week after transfusion, with a newly positive DAT, is a delayed haemolytic reaction — think anti-Jk^a (Kidd), the classic evanescent antibody** that disappears from the screen between exposures.
• Platelets carry the highest bacterial sepsis risk because they are stored at room temperature; refrigerated red cells raise Yersinia enterocolitica.
• In massive transfusion, the citrate anticoagulant chelates calcium — perioral tingling, tetany, prolonged QT. Give IV calcium and transfuse in a balanced 1:1:1 ratio. Do not attribute the coagulopathy to hypocalcaemia alone; dilution and hypothermia contribute.
• Common distractor: giving platelets for thrombocytopenia in TTP or HIT. Both are consumptive-thrombotic states where platelet transfusion can fuel thrombosis.