Management and treatment of auto immune hemolytic anemia
HDG presentation_pathogenic mechanisms of DIHA
1. Biological mechanisms of Drug-
induced haemolytic anaemia
(DIHA)
Tamia Nguyen
Haematology Discussion Group
26/07/2016
2. Outline
• Why talk about DIHA?
• The proposed biological mechanisms of DIHA
3. 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
4. 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
HYPOTHESIS
5. Hapten hypothesis
1. 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
6. 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: quinidine
Limitations:
- Drug-antibody complexes have never been demonstrated experimentally
- Ab binds RBC via their FAB domain
- Ab appear to be cell line-specific
7. 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
8. 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
reproduced
Further studies yield
inconclusive or contradicting
conclusions.
9. Unifying hypothesis
1. Drug first interact with the cell membrane
2. 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
10. 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: cephalosporin
Limitation: limited study
11. Summary
Traditional 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
14. Serological characteristics
Drug-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)
Editor's Notes
Drug-induced immune haemolytic anaemia is what the name say: that the administration of a drug can lead to an immune response against the red cell and cause their destruction
DIHA can be under-reported, reason being its serologic results can mimic those of autoimmune haemolytic anaemia or haemolytic transfusion reactions, thus DIIHA may go undetected in some cases.
Some pretty unusual behaviour that you wouldn’t expect from a normal immune reaction.
So if you stay with me for the next 10’, I promise you some interesting questions that will make you scratch your head and pull your hair.
Drug dependent antibodies are those that will only react in vitro in the presence of drug
Drug independent Ab are those that can be detected in vitro without adding any drug, they are essentially true autoantibodies.
Drugs are small molecules and by themselves, they are not sufficient to elicit an immune response. So naturally, hapten hypothesis is the first one to be suggested.
The immune complex mechanism was first proposed to explain drug-induced thrombocytopenia and was later extended to apply to RBCs
… binds via their Fab domain (while if it were nonspecific adsorption, we would expect binding through both the Fab and Fc domain)
… appear to be cell line-specific (this feature is again in consistent with the assumption that the immune complex is absorbed non-specifically to the red cells)
Lupus-like syndrome – which suggest a more systematic alteration of the immune system
Retics… which can takes months to mature into RBC
For about 10 years, life was good, the questions were answered
With the fallen of the traditional mechanisms, a new theories was proposed. It is based on the observation that some drug can cause both drug-dependent and drug-independent Ab
In Summary, I attempted to describe the traditional mechanisms of DIHA and discuss their limitations.
However, I want to acknowledge that it’s very hard to study DIHA. For one thing, they’re very rare. And there are a number of diagnostical pitfalls that occur on the patient’s side, at patient bedside and in the lab. It’s also never easy to undercover the exact mechanism. So there are still a lot that we cant explain about DIHA.
But to end my presentation on a positive note, I want to quote Leonard Cohen: There’s a crack in everything, that’s how the light gets in
