Biological mechanisms of Drug-induced haemolytic anaemia

(DIHA)

Tamia NguyenHaematology Discussion

Group 26/07/2016

Outline• Why talk about DIHA?• The proposed biological mechanisms of DIHA

Drug-induced immune haemolytic anaemia • A blood disorder that occurs when a drug triggers the

body’s immune system to attack its own red cells.

• DIHA is Rare – ~12% IHA

• But:– Can be under-recognised

• Similar serological features as IHA by other causes

– Potentially life-threatening if left untreated – Haemolysis resolved rapidly upon drug cessation

The proposed mechanisms of DIHA– Less emphasised area but interesting– Sufficient data to call for a reclassification– Some freaky behaviours

Traditional mechanisms:– Drug dependent Ab: only react in the

presence of drug• Hapten hypothesis• Immune complex hypothesis

– Drug independent Ab: true autoAb• Altered self antigen hypothesis• Immune dysregulation hypothesis

– Non-immunological protein adsorption

UNIFYING HYPOTHES

IS

Hapten hypothesis1. Drug firmly attaches to RBC membrane

2. Membrane-bound drug elicits an immune response

Prototype drug: penicillin – covalently bind RBC

Limitation: Most drugs do not form stable bond with RBC

Immune complex hypothesis

1. The body produces Ab against the drug

2. Antibodies binds to drug and form an immune complex

3. The complex adsorbs to RBC membrane and activate C’

Prototype drug: quinidineLimitations: - Drug-antibody complexes have never been demonstrated experimentally- Ab binds RBC via their FAB domain - Ab appear to be cell line-specific

1. DAT doesn’t become positive until 3-6 months after drug 2. Haemolysis can take up to 4 months to develop but

resolves quickly after drug cessation (~2 weeks)3. Seemingly no immune memory when patient is

rechallenged with drug ie again, take long time to develop Ab

4. Codevelopment of other autoantibodies (anti-nuclear Ab, lupus-like syndrome)

Prototype drug: methyldopa (Aldomet)

Drug independent Antibodies have some unusual features

Altered self antigen hypothesis Immune dysregulation hypothesis

- Drugs alters RBC antigen in a way that they are no longer recognised as self

- Can explain: The delay in DAT becoming positive if drug is incorporated into normoblasts or retics

- Cannot explain: Everything else Plus, binding between Methyldopa and RBC has never been demonstrated consistently

- Methyldopa cause an aberration in lymphocyte proliferation, allowing proliferation of auto-Ab producing cells.

- Can explain: almost everything: a delay in DAT change, delay in haemolysis, even in repeated challenge

- However:Experiments that supported this hypothesis could not be reproducedFurther studies yield inconclusive or contradicting conclusions.

Unifying hypothesis1. Drug first interact with the cell membrane2. Then, this drug-membrane structure can induce

the production of drug-dependent or drug-independent Ab

Limitation:- Many drug only provoke one type of Ab: drug-dependent

OR drug-independent- Fail to explain the co-development of other autoAb

Non-immunological protein adsorption

Drug modifies RBC membrane so that normal plasma proteins are non-specifically adsorbed onto the red cell.

Traditionally thought to cause positive DAT but not haemolysis BUT now shown to also cause haemolysis (if IgG is absorbed) Prototype drug: cephalosporinLimitation: limited study

SummaryTraditional mechanisms:– Drug dependent Ab• Hapten hypothesis• Immune complex hypothesis

– Drug independent Ab• Altered self antigen hypothesis• Immune dysregulation hypothesis

– Non-immunological protein adsorption Many difficulties in studying DIHA…

UNIFYING HYPOTHESIS

Supplementary slides

Serological characteristicsDrug-dependent Ab Drug-independent Ab

Penicillin-type Non-penicillin type Methyldopa-induced AutoAb

NIPA

Require large dose of drug

Require a small amount of drugs

10-30% develop pos DAT but only 0.5% develop HA

positive DAT but rarely haemolysis

Develop over 7-10 days

Acute onset, many patients have renal failure

Develop up to months after therapy

 

DAT +, usually with IgG

IAT ±, elution suggestive but not characteristics

DAT +, usually with C’  

IAT ±, elution suggestive but not characteristics

DAT + with IgG

IAT , eluate (indistinguishable from WAIHA)

DAT + with multiple proteins on RBC (eg: albumin)IAT , eluate

High titre of penicillin Ab in the serum (~1000)