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4.1 Transfusion and Transplant Immunology > Major Blood Group Systems Dependent on AHG > Flashcards

Major Blood Group Systems Dependent on AHG Flashcards

1
Q

What three blood group systems were discovered because of the IAT antiglobulin test

A

Kell
Duffy
Kidd

These are known as the ‘Big 3’
They are the most clinically significant after ABO and Rh

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2
Q

When was the IAT discovered?

A

1946

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3
Q

Why are Duffy, Kidd and Kell clinically significant?

A

They can all interact with complement

Duffy can also cause HDFN

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4
Q

Disovery of the Kell Blood group system
(5)

A

First defining antigen of the Kell Blood Group was discovered in 1946 (same year as IAT) by an antibody in the serum of a Mrs Kelleher

It was discovered by Lancer; Coombs, Mourant and Race

It was found that she had an antibody which reacted with her husbands, her daughters and newborns red blood cells

Her antibody also reacted with 9% of a random population -> antibody against antigen called K (K1)

In 1949 (3 yrs later) the allelic partner/corresponding antigen k (K2) was discovered

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5
Q

Origin of the Kell Blood group system
(5)

A

First defining antigen of the Kell Blood Group was discovered in 1946 (same year as IAT) by an antibody in the serum of a Mrs Kelleher

It was discovered by Lancer; Coombs, Mourant and Race

It was found that she had an antibody which reacted with her husbands, her daughters and newborns red blood cells

Her antibody also reacted with 9% of a random population -> antibody against antigen called K (K1)

In 1949 (3 yrs later) the allelic partner/corresponding antigen k (K2) was discovered

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6
Q

When was the K antigen discovered, when was k discovered?

A

K was discovered in 1946 in a Mrs Kellaher by Lancet; Coombs, Mourant and Race

k was disocvered in 1949

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7
Q

What are the four most common Kell antigens?

A

K (K1)
k (K2)
Kpa
Jsa

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8
Q

What is an anti-k antibody known as and why?

A

This is known as Cellano as it was found in a Ms. Cellano

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9
Q

Why is a Cellano difficult to work up and why?

A

An anti-k will usually cause a pan reactive panel

This is because 99.8% of the population are either Kk or kk
-> only 0.2% of people are KK => panreactive panel as we rarely get K- cells as part of our screen

It just means it can be more difficult to rule out other antibodies, might have to elute of anti-k etc etc

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10
Q

What chromosome is Kell located on?

A

Chromosome 7

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11
Q

Why did Ms Kellaher’s anti-K react with 9% of red cells?

A

This is because:
- 8.8% of people are Kk and 0.2% of people are KK

=> 9% of people have a K which her antibody would react against

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12
Q

What is the percentage of each Kell phenotype?

A

91% are kk (K/Kell negative)
8.8% are Kk
0.2% are KK

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13
Q

How immunogenic is K antigen?

A

1 in 10 produce an antibody if exposed to K antigen
-> since 90% of people are K- this can be seen

There are many reports of anti-K in transfused patients and multiparous women

Hence why women get K- blood in ireland

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14
Q

How many antigens are there in the Kell system, why so many?

A

There are 27 antigens total

Due to multiple allelic system giving rise to antithetical antigens

There is actualy so many possible combinations that not all possible genotypes have been found yet e.g. Kpa and Jsa have occured on separate chromosomes in patient but never on the one gene

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15
Q

What Kell antigens are found in nearly 100% of people?

A

k, Kpb and Jsb are found in nearly everyone

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16
Q

What are the 11 Kell antigens you need to be concerned with?

A

K and k
Kpa, Kpb and Kpc (Kpa most common in caucasions)
Jsa and Jsb (Jsa in Blacks)
K11 and K17
K14 and K24

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17
Q

What Kell phenotype will any Kpa+ be?

A

They will all be k+

i.e. Kpa+ only occurs in k+

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18
Q

Why might it be that weve never recorded a Kpa and Jsa on the same chromosome?

A

This is because Kpa is predominantly found in whites (2.3% of caucasians)

While Jsa is found in predominantly blacks (20%)

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19
Q

Other than Kpa and Jsa what is another Kell group antigen combination that has never been recorded, white might this be?

A

K and Kpa
Might be due to the realtively low frequency of both antigens
Only (9% of people have a K and only 2.3% of people have a Jsa)

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20
Q

What is the Kell null state?

A

Ko

This is due to a lack of K gene or Kx gene (covalently bonded on rbc surface)

They produce an anti-Ku

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21
Q

Describe the Kell glycoprotein, how does it express the antigens, what protein

A

A 93kD transmembrane, single-pass protein which carries the Kell antigens

It is an endothelin-3-converting enzyme

The Kell antigens are expressed in Low Desnity on the cell

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22
Q

What is the function of Kell glycoprotein?
(3)

A

It is an endothelin-3-converting enzyme

It cleaves an inactive precursor called big-endothelin-3 to create active endothelin-3

This is a potent constrictor of blood vessels

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23
Q

What kind of antigen is both Kell and Kx?

A

They are both glycoproteins (different though)

Kell is a single pass while Kx is a multipass (passes membrane 10 times)

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24
Q

What treatments can affect Kell antigen expression?

A

Daratumumab and ZAP
-> No K expression after dara treatment - hence ehy typing is required before starting treatment

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25
Q

What treatments can affect Kell antigen expression?

A

Daratumumab and ZAP
-> No K expression after dara treatment - hence ehy typing is required before starting treatment

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26
Q

What method is in place to negate daratumumab interference?

A

Send sample to IBTS for DTT treatment -> negates DARA interference

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27
Q

What chromosome is Kx antigen encoded on?

A

X chromosome - hence why its called Kx

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28
Q

What chromosome is Kx antigen encoded on?

A

X chromosome - hence why its called Kx

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29
Q

What can affect the Kell glycoprotein, how does this affect it?

A

Thiol degradation of double disulphide bonds (s-s-disulphide bonds)

These are needed for structural integrity

But this fact can be used in serologica investigations e.g. where there is an anti-K and an anti-Fya
-> it means we can remove Kell antigens if we need to investigate other antibodies

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30
Q

What are three methods of thiol degradation that can be used on Kell antigens?

A

DTT
ZZAP
AET

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31
Q

What are three methods of thiol degradation that can be used on Kell antigens?

A

DTT
ZZAP
AET

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32
Q

When might thiol degradation of Kell be needed?

A

If we have an anti-k -> we rarely will have an anti-K well rarely have a K- cell to use in panel -> often pan reactive

To rule out any other antibodies we can treat the red cells with a thiol degradation method - we can then rerun the panel to check for other antibodies

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33
Q

What is the molecular basis of the K and k antigens?

A

k and K are the two major codominant alleles

They result from a SNP (698C ->T)

The corresponding k and K antigens differ by a single amino acid change (thr193Met)

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34
Q

What is Kmod?

A

Kmod is a weakened expression of the Kell antigens

It is similar to weak D caused by point mutations

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35
Q

How is Kel affected by enzymes

A

Kell is not mean to be affected by enzymes

It is not destroyed by enzymes

In practice you might see that K is actually weakened by enzymes but this is more to do with the actual reagents used and not the actual enzyme activity

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36
Q

How immunogenic is K, why is this significant?

A

1 in 10 chance of making an anti-K if K+ blood given to K-

It is IgG, it reacts at 37 degrees, it is not complement binding

Because of this all K- women of childbearing age are given K- blood

it can cause a severe haemolytic transfusion reaction

It can occur naurally

Anti-K and anti-Ku are capable of causing a severe reaction

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37
Q

Comment on the immunigenicity of the different Kell antibodies

A

Anti-K and Ku are caoable of causing a severe reaction (severe haemolytic transfusion reaction)

Anti-k, anti-Kpa, anti-Kpb and anti Jsa and anti-Jsb cause milder reactions

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38
Q

Why is it thought that anti-K is so immunogenic?

A

The K antigens develop early on in erythropoiesis

This means anti-K can destroy rbc before they even get a chance to form haemoglobin

Because of this bilirubin is not considered a good measurement of a transfuion reaction involving anti-K, haemoglobin should be measured directly e.g. Dopler ultrasound or cordocentesis in HDFN etc

For the same reason, anti-K titre is considered not reliable measurement of the actual in vivo situation

39
Q

How can anti-K caused HDFN result in foetal death?

A

Causes anti-K foetal anaemia due to suppression of erythropoesis not foetal RBC destruction

40
Q

Talk about the Kx gene
(4)

A

Kx gene locus on X Chr Xp21

It gives rise to the Kx antigen

It is found on the glycoprotein to which the kell antigen attache covalently

Kx is not affected by DTT or AET unlike K

Even Ko cells will still have Kx expression (different gene)

41
Q

Talk about deletions in the Kx gene

A

Deletions in this gene give rise to a number of disorder
Depending on the size of the deletion, the severity differs

42
Q

Talk about deletions in the Kx gene

A

Deletions in this gene give rise to a number of disorder
Depending on the size of the deletion, the severity differs

43
Q

List the conditions associated with Xp21 gene deletions, ie. Kx deletions
(4)

A

Retinitis pigmentosa
Duchenne’s muscular dystroph
X-linked Chronic Granulomatous Disease (CGD)
Mc Leod Syndrome - Lack of Kx

These are x-linked conditions, only affecting men

44
Q

What is Mc Leod Syndrome?
(6)

A

A very rare x-linked condition affecting only 60 males

It is a complete lack of Kx

It results in weakly expressed Kell antigens

It causes reduced rbc survival, acanthocytes and decreased rbc permeability to eater

Patients suffer from a compensated anaemia

These patients often have an anti-Kx

45
Q

What are the symptoms of Mc Leod syndrome?

A

Muscular wasting
Seizures
Cardiomyopathy
Psychiatric disorders

46
Q

What are the symptoms of Mc Leod syndrome?

A

Muscular wasting
Seizures
Cardiomyopathy
Psychiatric disorders

47
Q

What is the history of the Duffy Blood Group System, what are the antigens?

A

It was discovered in 1950 in a multi-transfused Haemophiliac Mr Duffy who had an anti-Fya

In 1955 is was discovered that many black populations lacked the Duffy antigens enitrely i.e. were Fy(a-b-)

Fya, Fyb, Fy3, Fy4, Fy5, Fy6, Fyx antigens

Fya is much more common than Fyb

The Duffy gene was the first blood group to have its gene located

48
Q

Talk about anti Duffy antibodies

A

These antibodies are IgG

They are rarely found on their own -> they tend to occur in the multi-transfused or mothers of multiple children etc

49
Q

How difficult is it to get blood for someone with an anti-Fya?

A

1 in 3 units is Fya negative -> easy to find

50
Q

How difficult is it to get blood for someone with an anti Jka?

A

1 in 4 units are Jka negative

Relatively easy to get blood for

51
Q

What is Fyx?

A

Fyx is a weakened version of the Duffy blood group system

The Fyx allele encodes the Fyb antigen where B is only weakly expressed and is not always detected by anti-Fyb

Fy(b+x)

52
Q

What is the frequency of each duffy phenotype?

A

49% Fy(a+b+)
33% Fy (a-b+)
17% Fy (a+b-)

Fy(a-b-) is rare in Caucasians but seen in 68% of Blacks

53
Q

Comment on the action of enzymes on Duffy antigens

A

Fya and Fyb are destroyed by enzymes

Fy3, 4 and 5 are not destroyed and may be enhanced

54
Q

What kind of antibodies are Fya and Fyb?
(5)

A

They are IgG antibodies

They are complement binding

They are involved in HDN and Haemolytic Transfusion Reactions (HTR)

They are associated with Delayed HTR in SCDPs

Antigen deterioration can cause problems in panels

55
Q

What blood groups might a serum sample be required for the investigation of antibodies?

A

Anti Duffy and anti Kidd

56
Q

What is considered the gold standard for Duffy antibody investigation?
(3)

A

Serum sample prefferred as EDTA anti-coagulant will bind calcium and complement which reduces the strength of the Duffy reaction

Serum samples will have double the strength of the reaction due to both complement and antibody binding

You will also have to get a fresh set of reagent red cells for a panel as Duffy antigen expression deteriorates with time and causes weaker reactions

57
Q

Write a note on the genetics of the Duffy blood group system

A

Duffy locus is on chromosome 1 -> its syntenic to the Rh locus - it was the first gene assigned to a specific locus

It encodes a glycosylated protein with 7 trans-membrane domains of 339 AA with 63 being extracellular (potentially antigenic)

DARC appears to be a receptor for IL-8 and other chemokines

FYA and FYB differ by a single nucleotide at positiion 125 (G->A)

Fya and Fyb antigens differ by a single amino acid at residue 42 (glycine -> aspartic acid)

58
Q

Write a note on the genetics of the Duffy blood group system

A

Duffy locus is on chromosome 1 -> its syntenic to the Rh locus - it was the first gene assigned to a specific locus

It encodes a glycosylated protein with 7 trans-membrane domains of 339 AA with 63 being extracellular (potentially antigenic)

DARC appears to be a receptor for IL-8 and other chemokines

FYA and FYB differ by a single nucleotide at positiion 125 (G->A)

Fya and Fyb antigens differ by a single amino acid at residue 42 (glycine -> aspartic acid)

59
Q

What chromosome is the Duffy locus encoded on?

A

Chromosome 1

60
Q

What does the Duffy gene encode?

A

It encodes a glycosylated protein with 7 trans-membrane domains of 339 AA with 63 being extracellular (potentially antigenic)

61
Q

What is DARC?

A

Duffy-Antigen Receptor Chemokine (DARC)

62
Q

What is the function of DARC?

A

Its a receptor for IL-8 and other chemokines

It is also the entry point for malaria (Fy6)

63
Q

What exactly are the Duffy antigens Fy3-Fy6?

A

They represent variations in the Fya and Fyb epitopes

64
Q

How is Fya different from FyB?
(2)

A

FyA differs from FyB by a single nucleotide at position 125 (G->A)

FyA differs from FyB antigens by a single amino acid at residue 42 (glycine -> aspartic acid)

65
Q

What strain of plasmodium does Fya-b- confer resistance against?

A

Plasmodium Knowlesi and Plasmodium vivax

66
Q

What is the site of plasmodium invasion into cells?

A

Fy6
(which is absent on Fy(a-b-) cells)

67
Q

Talk about antigen expression in the Fy(a-b-) individuals
(3)

A

This phenotype is caused by mutation in the erythroid promoter region of the FYB gene

This results in the lack of Fy expresson on the RBCS only

Fyb proteins are normal and expressed in other non-erythroid tissues

68
Q

What antibodies are produced by an Fy(a-b-) individual, why is this significant?

A

These individuals would produce an anti-Fya but not an anti-Fyb as this phenotype still produces FyB on non erythroid tissues

-> this means we can give then Fya-b+ blood

-> this is great because we very rarely have Fya-b- blood available

69
Q

What is the history on the Jk (Kidd) blood group system?

A

This system was discovered in 1951 in a John Kidd born to a Mrs Kidd (anti-Jka)

John was the 6th child of Mrs Kidd

John was a case of HDFN

Mrs Kidd also have an anti-K

In 1953 the predicted anti-Jkb was found in a transfusion reaction patient who also had an Fya

In 1959 the third (and final) antigen of this system Jk3 was discovered

70
Q

What are the three antigens of the Kidd system?

A

Jka
Jkb
Jk3

71
Q

When was Jka, Jkb and Jk3 found?

A

Jka in 1951
Jkb in 1953
Jk3 in 1959

72
Q

What is Jk3?

A

Jk3 is found in Jka-b- people

73
Q

What is the frequence of Jkab phenotypes in Caucasians?

A

50% Jka+b+
27% Jka+b-
23% Jka-b+

74
Q

What is the frequence of Jkab phenotypes in Blacks?

A

51% Jka+b-
41% Jka+b+
8% Jka-b+

75
Q

Genetics of the Kidd Blood group
(3)

A

Kidd locus is HUT11 gene on Chromosome 18

Jka and Jkb are antigen products of two alleles inherited in a co-dominant fashion

It is a urea transporter

76
Q

Who is Jka-b- seen in?

A

Its very very rare

Only seen in Polynesiand - 1% and Finish

77
Q

What is Jk(a-b-), how does it occur?

A

Homozygous inheritence of a silent Jk allele at the JK locus
- two damaged alleles together = no expression

OR (amorph type) inheritence of a dominant inhibitor gene In(Jk) unlinked to the JK locus

78
Q

What is the inhibitor Jk gene In(Jk)?

A

an inhibitor gene which results in lack of expression of Jk a and b

A similar inhibitor is seen in the Lutheran system

This gene doesnt affect the actual gene as with RhD or Kidd null types but instead affects the assembly of the protein into the red cell membrane i.e. the actual gene protein is completely fine it just cant be expressed correctly

79
Q

What is the antibody produced by Rhnull individuals?

A

Its anti-Rh 29

80
Q

What is significant about anti-Jk antibodies?

A

Jk antibodies can cause severe reactions

Jk antibodies also tend to disappear -> have been seen to dissappear in as little as two weeks

This can be scary as it means you will not see the antibody when doing a screen or panel

If you dont have patient history of antibody you will not pick it up

Hence why they are commonly seen in transfusion reactions

Hence need for Medlis

81
Q

What is significant about anti-Jk antibodies?k

A

Jk antibodies can cause severe reactions

Jk antibodies also tend to disappear -> have been seen to dissappear in as little as two weeks

This can be scary as it means you will not see the antibody when doing a screen or panel

If you dont have patient history of antibody you will not pick it up

Hence why they are commonly seen in transfusion reactions

Hence need for Medlis

82
Q

Where are Jk antigens expressed?

A

Mostly rbcs and the vasa recta of the kidney

83
Q

Where are Jk antigens expressed?

A

Mostly rbcs and the vasa recta of the kidney

84
Q

What exactly does the Kidd gene produce, what is its function?

A

Gene produces an integral membrane protein (389 aa) which spans the membrane 10 times

The Kidd antigen is a urea transporter

85
Q

How does Jka differ from Jkb?

A

There is only a single nucleotide difference

838G->A transition from Jka to Jkb

This results in an aspartic acid->asparagine at aa 280

86
Q

What affects does Jknull have on patient?

A

No pathological effects

87
Q

Write a little about anti Kidd antibodies

A

They are responsibly for 30% of DHTRs

Antigen deterioration as well as antibody dosage possibly contribute to missing anti-Jk antibodies

They are partially IgG/IgM

They can activate complement causing significant haemolysis

Occassionally causes AIHA

HDN is rare but Kidd antigen are found on foetal cells as early as week 11

Serum sample gold standard for antibody investigation

88
Q

What percentage of DHTR are caused by Kidd antibodies, why is this?

A

30% of DHTRs

Anti-Kidd antibodies are effervessent antibodies i.e. they disappear from blood after 2 weeks they are undetectable

89
Q

What was lecturers interaction with Kidd antibodies?

A

Fabian only seen 1 fatality
- Associated with Jk
- Woma had a GIT bleed - needed 6 units of blood
- She was anaemic - low haemoglobin - lots of blood needed to bring it up
- Following day her haemoglobin fell quickly 10,8,6, etc etc
She died at 54 -> she was also a Ms. Kidd (what are the chances)

90
Q

Can Kidd cause HDFN?

A

Yes, but rarely

Kidd antigens are expressed on faetal cells from 11 weeks

91
Q

What are the two things Kidd antibodies are known for

A

Causing delayed transfusion reactoins

For being found with other antiodies

92
Q

What are the two things Kidd antibodies are known for

A

Causing delayed transfusion reactoins

For being found with other antiodies

93
Q

What was the IBTS experience with anti-JK3

A

Woman had a miscarraige, she was panreactive but DAT and auto negative

There was no evidence of rouleaux

Panel was done in tubes and was not resolved

Sample was sent to IBTS for full typing where she was typed as Jka-b-

Patient was a suspected anti-Jk3 but there was not enough sample to continue as patient had left hospital

Patient came back the following year with another miscarriage when we got another sample

Using imported blood we were able to identify the presence of anti-Jk3 i.e. she had an anti-Jka, jkb and jk3

The following year the patient returned but pregnant

Adsorption techniques used to exclude any other antibodies

Jka-b- units were imported on a monthly basis from UK and Finland until baby was delivered via C section -> happy healthy baby

Baby was Dat positive though as he was Jka-b+, eluate contained an antiJk3

4.1 Transfusion and Transplant Immunology (24 decks)

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