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4.1 Transfusion and Transplant Immunology > Auto-Immune Haemolytic Anaemia > Flashcards

Auto-Immune Haemolytic Anaemia Flashcards

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1
Q

What are the two types of AIHA?

A

Cold and warm

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2
Q

In general what is the main difference between cold and warm AIHA

A

Warm is more frequent then cold
However warm is rarely seen in the lab while cold is often seen
Warm doesnt really affect the patient

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3
Q

What are the four different types of AIHA that we will look at, classify AIHA?

A

Warm
Cold/Cold Agglutinin Disease (CAD/S)
PCH -> paroxysmal cold haemoglobinuria
Drug Induced haemolytic anaemia

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4
Q

Give a general overview of AIHA, incidence, what is it, causes
(7)

A

Incidence of 1/80,000 people
Occurs at all ages but more common in people over 40 with a peak in the 70s
Caused by autoantibodies direct against self antigens
Often due to a loss of T suppressor cells
Can be either primary/idiopathic or secondary
Red cell loss is either extravascular or intravascular

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5
Q

What is the incidence of AIHA?

A

1/80,000 people

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6
Q

Who is most likely to be affected by AIHA

A

Rarely seen in anyone under 40
Mostly in those over 40 with a peak in 70s
More common in females vs males
Higher frequency in males with CLL (10% develop AIHA)

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7
Q

Compare idiopathic vs secondary AIHA, compare the frequency

A

Primary or idiopathic AIHA means we dont know where the AIHA has arisen from
In secondary we know the cause and can treat it by treating the cause

Its 50/50 primar/secondary in warm AIHA
Its 90% secondary in cold

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8
Q

Compare the antibodies of warm vs cold AIHA

A

Cold = IgM
Warm = igG

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9
Q

How frequent are the different classifications of AIHA?

A

Warm is seen in 80% of cases
Cold is not as common as warm but has characteristic features in lab
Drug induced is very rare

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10
Q

Talk about anaemia in those with AIHA

A

Anaemia may not always occur due to compensatory mechanisms but there will always be a reduced red cell survival
AIHA requires patient to be anaemic but this only happens when compensation mechanisms fail
Drug induced AIHA tends to give the most severe anaemia, other types tend to be insidious and not as severe

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11
Q

Talk about characteristic agglutination in cold AIHA

A

Sample will come to the lab and look clotted - entire sample will look like a big blood clot
When sample is warmed up bood will look anticoagulated as normal
Very obvious in lab

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12
Q

Talk about the antibodies in warm AIHA

A

IgG autoantibodies which preferentially react at 37 dgrees

Causes increased red cell removal usually through extravascular haemolysis (liver and spleen)

Fix complement only to a level of C3, if at all

50% of cases are secondary/associated with other conditions such as CLL, SLE, transpants etc

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13
Q

what are the main sources of extravascular haemolysis in WAIHA?

A

Liver
Spleen

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14
Q

Talk about complement fixation in WAIHA

A

Not always complement fixing, if any it is only to the C3 level

Fc(IgG)/C3b complex on red cells are recognised by receptors on macrophages -> this is what causes the extravascular haemolysis

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15
Q

Give some examples of conditions which cause WAIHA

A

lymphoproliferative disorders e.g. CLL ((10%=AIHA)
autoimmune disordered e.g. SLE
Post transplant

50% of WAIHA are caused by these conditions

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16
Q

How might we detect a WAIHA in the lab?

A

Screen might be negative or weakly positive due to low levels of antibody in plasma
DAT will be positive

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17
Q

Why is the screen usually negative in AIHA?

A

Most of the autoantibody will be bound to red cells leavin very little left free in plasma

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18
Q

What will a AIHA blood film look like?

A

Spherocytes
Reticulocytes/polychromasia
RBC fragmentation
NRBCs

Will look like hereditary spherocytosis
Evidence of extravascular haemolysis but might see signs of intravascular haemolysis in severe disease

Film is typical of any kind of extravascular haemolysis e.g. transfusion reactions

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19
Q

How do we distinguish between AIHA and HS?

A

AIHA will be DAT+
HS will be DAT-

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20
Q

Why does WAIHA result in spherocytes?

A

Its from the extravascular haemolysis system attempting to destroy the red cells
This compresses the red cells into spherocytes

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21
Q

What does the degree of haemolysis in WAIHA depend on?

A

The level of haemolysis increases with the titre of the autoantibody

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22
Q

WAIHA only fixes complement to C3 level, why is this significant?

A

This is what haemolysis is only extravascular
Not enough complement fixing to warrent intravascular haemolysis

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23
Q

At what temperature does WAIHA antibodies bind?

A

Igs will bind at all temperature but 37 degrees is preffered

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24
Q

What kind of antibodies are seen in WAIHA primary/idiopathic type

A

IgG antibodies directed against a single RBC membrane protein
They will appear as non specific i.e. will react with most rbc samples but wont react against Rhnull cells -> Rh associated glycoprotein antibodies

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25
What kind of blood do we give for WAIHA patients?
Blood is consequently difficult to find as antibodies are often against Rh glycopeptide antigens -> only Rhnull blood in IBTS will come up crossmatch negative but we dont have this available to give to paients We usually ABO, Rh and K type the patient and give back their groups Very important to ask if patient has been transfused or pregnant though as these could possibly have other antigens such as Kidd antibodies or duffy
26
Why do we use the DAT for WAIHA?
As the DAT indicates in vivo red cell coating
27
How do we treat WAIHA?
Treat the primary condition Steroids, splenectomy, transfusions, typical courses of treatment for primary conditions etc Steroids = gold standard for WAIHA - very successful - antibodies usually disappear after a few weeks
28
Talk about transfusions in AIHA
WAIHA rarely warrents need for a transfusion In WAIHA patients Hb usually drops really slowly, over a long period of time, eventually patient will present to GP with tiredness and maybe jaudice if really anaemic Patient Hb can be as low as 5 but since it is a gradual drop in Hb steroids are still the gold standard for treatment and not transfusion Difficult to get blood for these patients and steroid tretment will begin to see increase in Hb immediately
29
How do patients present with WAIHA
Anaemia Severe pallor Weakness Dyspnoea Fever Sometimes jaundice
30
How does WAIHA affect ABO and Rh typing?
No affect on ABO typing usually Used to cause problems with our Rh control - used to come up positive due to high levels of potentiators used in RhD antisera - improvements in antisera (now use monoclonal) in recent years has meant we no longer see this positive Rh control (potentiator - Rhantisera) - cleaner reagent requiring less enhancement
31
Talk about the use of DAT in WAIHA
DAT is usually positive 20% are IgG only DAT positive 67% are IgG and C3 positive 13% are C3 only positive
32
How does the type of antibody affect complement fixation in WAIHA?
Some types of antibodies are better at complemen fixing then others: IgG1+IgG3 are better than IgG2 or IgG4 Its based on the affinity for FcR and increased complement activation IgG1 and 3 are more haemolytic then 2 and 4
33
What would you do with a warm AIHA in the lab?
Antibody screen - will be positive if enough free antibody DAT - will be positive Adsorptions - adsorb autoantibodies out of patient plasma so that you can look for alloantibodies Elutions of limited value as eluate will react against everything
34
Why is it important to do adsorptions for WAIHA?
There are allo antibodies in 40% of cases -> increased if patient has been transfused or pregnant
35
Why is it important to do adsorptions for WAIHA?
There are allo antibodies in 40% of cases -> increased if patient has been transfused or pregnant
36
Why is it important to do adsorptions for WAIHA?
There are allo antibodies in 40% of cases -> increased if patient has been transfused or pregnant
37
How do you carry out an adsorption
adsorb autoantibody from patients plasma React patient red cells with their own plasma -> red cells will be coated in the autoantibody Separate out plasma again Now react plasma - autoantibody againist antibody panel to look for other alloantibodies
38
WAIHA antibodies are produced against what?
Rh related glycoprotein Band-3 Glycophorin A
39
Talk about steroid treatment for WAIHA
Corticosteroids/glucocorticoids e.g. prednisone Decreased FcR on macrophages Mainstay treatment??? 20% will go into complete remission - no evidence of disease 10% will have no response to treatment at all i.e. Hb will continue to drop
40
List the treatment methods for WAIHA
Steroids Splenectomy MABS e.g. Rituximab Immunosuppressive therapy Plasmapheresis IVIG
41
Talk about splenectomy for WAIHA
Splenectomy only considered if patient is young Patient will require lifelong antibioti treatment Corticosteroid treatment is preferred Decreases destruction and autoantibody production Will need 6x the antibody titre to produce the same amount of haemolysis without a spleen
42
Talk about rituximab for AIHA
Monoclonal antibody treatment against CD20 Affects B cells - decreases B cells Thus decreasing amount of monoclonal antibody production
43
Talk about Immunosuppressive therapy for AIHA
Only used if all other drugs have failed Azothioprine, cyclophosphamide etc -> cytotoxic immunosuppressants If all else fails then chemo drugs such as methatrexate are considered
44
Talk about IVIG for WAIHA
Were not 100% sure how it works Think it works by flooding macrophage Fc receptors - macrophages unable to detect that rbcs have been coated with antibodies Known as liquid gold - very expensive and rarely used
45
When is transfusion given for WAIHA
In the short term where anaemia is sudden and severe Fabian has never seen this been done Usually cant get crossmatch neg blood -> just give ABO and Rh matched Clinican is responsible for transfusion, they will take accountability Nuissance to investigation, lot of work for one patient, follow ups must be done every week
46
Talk about CAIHA/CHAD antibodies
Environmentally stimulated IgM cold agglutinins They have a low thermal range They do not cause clinical problems usually Abnormal cold aggs can have an extended thermal range, i.e. they may be active at 30-32 degrees which can cause clinical symptoms in periphary (where body temp is lower) Autoantibodies prefer low temperatures but some IgM can bind up to 30 degrees -> called high titre cold agglutinins Can cause intravascular haemolysys by complement activtion
47
What are abnormal IgM cold aggs
CAIHA antibodies with an extended thermal range These function at 30-32 degrees Thus cause symptoms when peripheral blood reaches these temperatures e.g. when patient's hands or feet get cold etc
48
What are high tire cold aggs in CAIHA?
Auto antibodies which prefer low temperatures e.g. 4 degrees but can also bind to rbcs at 30 degrees
49
What is the preferred temperature for cold aggs?
4 degrees
50
Talk about complement activation in CAIHA
Can cause intravascular haemolysis by complement activation known as cold haemolysins But this is much less common Typically only complement is found on rbcs
51
What percentage of CAIHA is secondary?
90% of CAIHA is secondary to other conditions
52
Talk about cold aggs
these are only an affect of our testing - only reactive at room temperature not at body temperature Dont actually affect the patient These antibodies will disappear at 37 degrees Not true Cold agglutinin disease
53
CAIHA antiobdies are specific to what?
They are often anti-i or anti-I (Ii are antigens found on rbcs structures bearing ABH antigens)
54
Talk a little abobut Ii blood group, when would you see this
i has no branches, I has many branches A fucose is added on to end of branch to become a H antigen Cannot tell if an antibody is anti-H or anti-i - same specificity really All cord blood is little-i, i.e. I- i is converted to I as you get older
55
What are the two kinds of CAIHA
Chronic or transient
56
What is transient CAIHA
This is a phenomenom that occurs in children infected ith Mycobacterium pnneumonia or infectious mononucleosis It is a secondary type of CAIHA The antibodies produced are acute but transient i.e. high titre but will disapear when infection is cleared
57
What antibody specificity is the transient CAIHA antibody in infectious mono vs M. pneumonia?
IM = anti-i M. pneumo = anti-I
58
How do we demonstrate high titre cold agglutinins, i.e. cold aggs that react at 30 degrees?
ABO and typing must be carried out at 37 degrees, sample must be transported to lab in flask etc etc Specimen will demonstrate rough agglutination at room temperature ABO group carried out with washed cells (prewarmed saline) at 37 degrees Rh and DAT carried out DAT + with C3d Can do a serial dilution afterwards to quantify titre of antibody but usually this isnt done, patient is just treated A cold autoadsorption could also be possible if query any alloantibodies
59
How do you know if your 37 degrees investigation has worked/failed?
Your reagent controls are vital in this scenario Everything will remain positive if youve faileed i.e. if not everything at 37 degrees These are really hard to read though and clinicians dont like transfusing off these results due to the interpretive nature etc
60
How are cold auto adsorptions carried out now?
You could use patients own cells at low 30 degrees or below or use REST - Rabbit erythrocyte stroma ? - will adsorb out any anti H or I present
61
How is CAIHA treated?
Keep warm - no affects if body temp doesnt reach 30 degrees etc Corticosteroids - not as effective as in WAIHA Transfusion - must prewarm blood - not often required - crossmatch at 37 degrees and use anti-IgG - tend to give scruffy results - tend to not transfuse Treat underlying disorder e.g. pneumoniae Plasmapheresis if acute
62
What exactl is drug-induced immune haemolytic anaemia?
Rare anaemia as a consequence of therapy with a particular drug
63
What drugs are associated with Drug induced immune haemolyic anaemia?
There are over 125 drugs implicated in DAIHA Historically: - 67% = Methyldopa - 23% = IV penicillin Nowadays: - 2nd and 3rd generation cephalosporins (80-90%) especially cefotetant (72%) and ceftriaxone (10%)
64
What cephalosporins are most indicated in DAIHA nowadays?
72% cefotetan 10% ceftriaxone
65
What is the mortality of DAIHA?
40% of reported DAIHA are fatal
66
What antibodies are causative of DAIHA?
Mostly IgG -> simply antiobodies produced against the drug
67
Compare DIHA to AIHA in terms of eluate reactivity and seum
Eluate - Drug dependent antibody (DDA) negative or weak - Warm auto antibody (WAA) will be strongly positive Serum - DDA disappears within days if drug is discontinued e.g. with penicillin or quinolone whereby DDA disappears immediately after stoping treatment - WAA persists -> body will continue to produce it
68
Why would the eluate be negative in DIIAHA?
Red cells coated in DDA DAA washed off red cells Antibodies are directed only against drugs such as penicllin which is obviously not found on our reagent red blood cells - hence why panel will be negative
69
Describe how we would carry out an acid elution
Wash x4 to remove unbound protein Add acid to lower pH to dissociate bound antibodies Centrifuge Transfer supernatant to new tube Buffer to neutral pH Test to determine specificity of antibody
70
How exactly does Drug induced anaemia occur?
Drugs provoke antibody production through one of three methods Antibodies bind to red cells Coated red cells are removed by spleen or liver resulting in anaemia
71
How do we treat DAIHA
Anaemia is corrected by removal of drug from patient
72
What are the three mechanisms of Drug-induced immune haemolytic anaemia?
Drug adsorption mechanism Immune complex mechanism True autoimmune mechanism
73
What is the drug adsorption mechanism of DIIHA, give examples of drugs which cause this?
Drug binds firmly to rbc surface and stimulates production of an antibody which targets the drug when bound to rbcs Examples: - penicillins - cephalosporins
74
What is the immune complex mechanism of DIIHA, give examples of drugs which cause this?
Drug binds transiently to red cell membrane and together they form an epitope The antibody binds to this forming an immune complex This is what also happens in HIT Examples: - Quinidine - Quinine - Isoniazid
75
What is HIT
Heparin Induced thrombocytopenia A disorder caused by antibodies that recognise complexes of platelet factor 4 and heparin When on heparin therapy patients experience thrombocytopenia
76
What is the autoimmune mechanism of DIIHA, give examples of drugs which cause this?
This is where drugs cause production of autoantibodies These autoantibodies react with normal red cells Cross reactivity of antibody causing an autoimmune reaction They are usually indistinguishable from WAIHA Eluate will be positive Examples: - methyldopa - Ibuprofen
77
How exactlydoes immune complex or drug dependent antibody mechanism cause anaemia
Drug binds to and reacts with red cell surface proteins creating a neo-epitope Antibodies recognise altered protein/drug complex as foreign Antibodies bind and initiate process leading to red cell destruction Red cells removed as "innocent bystander" of destrucion of immune complexes Only occurs when drug is in the system C3 bound mainly -> hence serious anaemia
78
In short what are the three types of DIIAHA antibodies
Hapten-specific -> antibody specific to hapten (drug) Neonatigen -> antibody specific to hapten and membrane components together Crossreactive autoantiody produced to hapten-modified RBC membrane -> antibody mainly produced against membrane components (autoantibody)
79
In short what are the three types of DIIAHA antibodies
Hapten-specific -> antibody specific to hapten (drug) Neonatigen -> antibody specific to hapten and membrane components together Crossreactive autoantiody produced to hapten-modified RBC membrane -> antibody mainly produced against membrane components (autoantibody)
80
What is the fourth, non-immune, form of haemolytic anaemia?
Drugs alter red cell surface charge Nonimmunologic adsorption of proteins onto RBCs Drugs might change the rbc membrane so that many proteins attach to the membrane Results in red cell removal Leading to a positive DAT and possibly DIIHA without the production of any antibodies
81
How might we detect a DIHA in the lab?
Can be hard to spot, wouldnt expect them, overall rare DAT positive with IgG Hb as low as 2-4g/dl -> hence 40% mortality Drug treatment and transfusion history Clinically significant drug induced antibody titre>100 Eluate might be reactive against untreated cells in 15% of cases
82
What is DIIAHA often mistaken as?
Can appear like an autoantibody with anti-e specificity -> anto-immune anti-e is actually quite common particularl in Black individuals so it could easily be mistaken for this
83
The eluate will be positive in what percentage of DAIHA?
15% of cases are eluate positive
84
What is Paroxysmal cold haemoglobinuria, what kind of antibodys involved, when seen, effects etc
A transient acute AIHA Seen usually in children following viral infection Caused by IgG with anti-P specificity Causes complement fixation Reactive at 30 degrees i.e. low peripheral body temperature Causes mild HA, fabian has never seen one requiring transfusion
85
What antibody causes PCH, what is it often called?
IgG anti-P Also called Donath-Landsteiner antibody
86
What are the signs of PCH in the lab?
DAT positive - positive with C3b/d patient details history - child with viral infection - historically assocaited with syphilis - anti-P associated with living with pigeons
87
How is PCH treated
Corticosteroids Warm climate Transfusion - fabian never seen one required
88
How frequent is PCH
Is causes aout 30% of immune haemolytic anaemia - as it is associated with viral infection - actually quite commonly seen
89
What disease was PNH associated with?
Syphilis

4.1 Transfusion and Transplant Immunology (24 decks)

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