HaematologyTier 1Disease (DEADMAN)

Delayed haemolytic transfusion reaction

Description

Haemolysis 2-10 days (up to 28 days) after transfusion, from an anamnestic antibody response to a minor red cell antigen
The mechanism in one line:
- Prior transfusion or pregnancy -> alloantibody formed -> titre falls below the detection limit of the antibody screen -> compatible crossmatch -> re-exposure -> memory B cell response over days -> IgG-coated cells cleared extravascularly
*The pre-transfusion crossmatch was genuinely compatible. This is not an error.*

Two forms

	Delayed haemolytic transfusion reaction (DHTR)	Delayed serological transfusion reaction (DSTR)
New alloantibody	Yes	Yes
Evidence of haemolysis	Yes	No
Action	Investigate, support, antigen-negative units in future	Record the antibody; antigen-negative units in future

Typical presentation: unexplained failure of the haemoglobin to rise, or an unexpected fall, with mild jaundice, a week after transfusion
- Fever and malaise are common; frank haemoglobinuria is not

~1 in 2,500-11,000 units transfused (serological reactions more common still)
Under-recognised - the patient is often discharged before the haemolysis appears
Risk proportional to transfusion burden and prior pregnancy
- Sickle cell disease and thalassaemia carry the highest risk (~10-30% alloimmunised) - the donor pool differs antigenically from the recipient population
Alloimmunisation rate ~1-3% per unit in the general population, higher in inflammatory states

The antibodies

System	Notable antibodies
Kidd (Jk-a, Jk-b)	*The classic cause - notorious for evanescence* (titre falls fast, undetectable at the next crossmatch)
Rh (E, c, C, e)	Common after transfusion and pregnancy
Kell (K)	Strongly immunogenic; also causes severe haemolytic disease of the fetus and newborn with marrow suppression
Duffy (Fy-a, Fy-b)	Common in alloimmunised patients of African ancestry
MNS, Lewis	Lewis rarely clinically significant

Why the crossmatch was negative

Antibody evanescence - titres fall below the detection threshold over months to years
- *Kidd antibodies are the archetype*
Historical antibody records may be held at a different hospital - this is why a national/shared antibody registry matters

Mechanism of destruction

IgG is monomeric and does not fix complement to completion
-> IgG-coated red cells bound by Fc receptors on splenic macrophages
-> extravascular haemolysis
-> unconjugated hyperbilirubinaemia, high LDH, low haptoglobin, spherocytes on film
*Little or no haemoglobinuria, no DIC, no shock* - the contrast with an acute ABO reaction

Clinical

Falling haemoglobin 2-10 days post-transfusion, or failure to achieve the expected increment
Low-grade fever, malaise, mild jaundice
Rarely: dark urine, back pain, AKI (with a strong antibody or a large transfused volume)

Laboratory

DAT positive - classically "mixed field", donor cells coated and recipient cells not
New alloantibody on repeat antibody screen that was absent pre-transfusion
Eluate from the patient's red cells identifies the antibody
LDH high, unconjugated bilirubin high, haptoglobin low, reticulocytes high
Film: spherocytes
Free plasma haemoglobin usually normal - extravascular destruction

Differential for a falling Hb a week after transfusion

Hyperhaemolysis syndrome - the dangerous variant

Almost exclusively in sickle cell disease
*Haemoglobin falls BELOW the pre-transfusion level* - both donor and recipient red cells are destroyed
Reticulocytopenia may accompany it
*Further transfusion makes it worse and can be fatal*
Treat with IV methylprednisolone + IVIG; eculizumab, rituximab and tocilizumab in refractory cases; avoid transfusion unless life-threatening

A. Supportive - most cases need nothing else

B. Transfusion if required

*Only antigen-negative, fully crossmatched units* - discuss with the transfusion medicine specialist
Extended phenotype or genotype matching (Rh and Kell as a minimum, extended in haemoglobinopathies)
Expect a delay - antigen-negative units may need to be sourced from the national inventory

C. Documentation - the part that prevents recurrence

*Issue the patient with an antibody card and enter the antibody on the hospital and state/national transfusion record*
Antigen-negative units are required for life, even after the antibody becomes undetectable
Inform the patient's GP and any other treating hospital
Report to the haemovigilance programme

D. Prevention

*Prophylactic extended red cell phenotype/genotype matching (Rh + Kell) in patients who will be transfused repeatedly*
- Sickle cell disease, thalassaemia, MDS, myelofibrosis, and women of childbearing potential
- Reduces alloimmunisation and later haemolytic disease of the fetus and newborn
Minimise transfusion overall - each unit carries an alloimmunisation risk
Check for historical antibodies at other institutions before crossmatching

Multiply transfused patients - sickle cell disease, thalassaemia, MDS, myelofibrosis, chronic renal failure
Previous pregnancy (alloimmunisation without transfusion)
Kidd antibodies (the archetypal evanescent antibody)
Hyperhaemolysis syndrome in sickle cell disease
Haemolytic disease of the fetus and newborn - the same antibodies (anti-D, anti-c, anti-Kell)
Autoimmune haemolytic anaemia (a differential, and can be triggered post-transfusion)
Post-transfusion purpura (a different alloimmune delayed reaction, against HPA-1a)
Passenger lymphocyte syndrome after transplant

Usually mild and self-limiting - haemolysis ceases once transfused antigen-positive cells are cleared (days to ~2 weeks)
Most patients recover without intervention
*The antibody is permanent in its clinical significance even though it becomes serologically undetectable*

Complications

Symptomatic anaemia; delayed or failed response to transfusion
Acute kidney injury (uncommon)
Hyperhaemolysis syndrome - potentially fatal, and worsened by further transfusion
Increasing difficulty finding compatible blood as antibodies accumulate
- A patient with multiple alloantibodies may take days to crossmatch in an emergency
Future pregnancy - haemolytic disease of the fetus and newborn

The lesson

*An unexplained fall in haemoglobin with jaundice about a week after transfusion is a delayed haemolytic reaction until proven otherwise* - send a DAT and repeat the antibody screen before transfusing again

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