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HEM 2133

Immunohaematology I
Lesson 13:
Other Blood Group Systems

Blood Group System

A group of related chemical determinants
(antigens) residing on the red blood cell (RBC)
The antigens associated with each system are
produced by the action of genes at a single
locus or at loci situated so close together on
the chromosome that crossing over rarely

In most cases, the blood group antigens are

expressed as autosomal codominant traits
In some circumstances, the action of alleles at
separate loci may be required for the
production of the final antigenic determinant
E.g. the products of A and B genes cannot be
fully expressed without collaborative action at
the Hh locus to produce H substance

Most blood group system antigens are integral

part of the RBC membrane
However, some antigens are simply absorbed
onto the membrane from surrounding plasma
These are recognized as also belonging to
blood group system

Importance of red blood cell antigens

Antigens of the ABO and Rh systems
transfusion therapy
Hemolytic disease of the newborn
Autoimmune hemolytic anemia
Medicolegal serology aid in identification of
individuals in paternity testing as well as in
forensic investigation

The Lewis Blood Group System

Identified in 1946 by Mourant
Antigens in the Lewis system: Lea, Leb , Lec ,
Led , Lex
Three phenotypes commonly seen in the
system are Le(a-b+), Le(a+b-) and Le(a-b-)

Difference between the Lewis system and

other blood group system:
1. Lewis antigens are not intrinsic to the RBC
membrane produced during cell
The antigens are produced by tissue cells and
are found primarily in plasma and watery
RBCs subsequently acquire Lewis antigens by
adsorption from the surrounding plasma

2. An individuals Lewis phenotype is not

determined solely by genes at the Lele locus
but also by the action of genes at the Hh and
Sese loci.
3. The amount of Lewis antigen expressed on
the RBC varies according to the cells ABO

Genetics of the Lewis system

Interactions of three genetic loci influence
production of the Lea and Leb antigens
The Lewis gene locus, with alleles Le and le,
determines whether an individual will develop
Lewis antigens
The nature of the antigens expressed depends
on activity by the secretor genes (Se and se)
and the Hh genes

Individuals with the lele genotype do not

produce Lea or Leb antigens regardless of the
other genes present
They type as Le(a-b-) and have no Lewis
antigens in their plasma or secretions
Nonsecretors (genotype sese) who have at
least one Le gene produce only the Lea antigen
Their RBCs type as Le(a+b-) and their plasma
and secretions contain the Lea antigen

Expression of the Le(a-b+) RBC phenotype

depends on the presence of at least one Le
gene, one Se gene and one H gene
Le(a-b+) individuals have both Lea and Leb
antigens in their secretions
Because the Se gene is present, these
individuals also produce the appropriate A, B
and H antigens in their secretions

Acquisition of Lewis antigens by red blood cells

In the plasma, Lewis antigen activity is found
on glycolipids
RBCs acquire Lewis antigens by adsorbing
these Lewis-active glycolipids onto their
The Lewis phenotype of RBCs depends on the
phenotype of the plasma in which they are
suspended and can be changed by incubating
the cells in plasma containing different Lewisactive glycolipids

If Le(a-b-) cells are incubated with plasma

containing Lea or Leb glycolipid, they adsorb
the available antigen from the plasma and
subsequently type as Le(a+b-) or Le(a-b+)
Similarly, Le(a+b-) or Le(a-b+) cells incubated
in plasma from an lele individual lose Lewis
antigens and convert to Le(a-b-)
The same change in phenotypic expression is
observed with transfused cells, which convert
to the phenotype of the recipient

Lewis System Antibodies

A very common antibody that is often
naturally occurring
Produced almost exclusively by the Le(a-b-)
Le(a-b+) individuals do have small amounts of
Lea antigen in their plasma and RBCs, they
usually do not form anti-Lea
Usually IgM, reacts best at room temperature

Usually produced by Le(a-b-) individuals
May also be seen in Le(a+b-) phenotype
Usually an IgM, room temperature-reactive

Clinical significance of Lewis System

Hemolytic Disease of the Newborn
Lewis antibodies usually are not associated with
 Most examples of anti-Lea and anti-Leb are IgM and
are therefore incapable of crossing the placenta
 Even examples of Lewis antibodies that are IgG and
able to cross the placenta do not cause destruction
of fetal RBCs because Lewis antigens are poorly
expressed on these cells

Hemolytic transfusion reaction

The most commonly seen forms of anti-Lea and
anti-Leb are reactive at room temperature only
and are not associated with HTR
However, Lewis antibodies that demonstrate in
vitro hemolysis or that are reactive in
antiglobulin phase should be considered capable
of inducing increased clearance of transfused

Routine (37C) compatibility testing should be

used to select appropriate donors for patients
with these potentially significant Lewis
Selection of antigen-negative units for
transfusion does not appear to be necessary
The elution of Lewis antigens from cells
incubated in Le plasma may contribute to the
relative insignificance of Lewis system
antibodies in transfusion practice

If antigen-positive cells are transfused to an

antibody marker, the transfused cells readily
lose their antigens and are no longer a target
for destruction by Lewis antibodies
Further, the antigens released from donor
cells into the plasma can neutralize Lewis
antibodies present in the recipient plasma

The I Blood Group System

I antigen is present on all red cells of all
human adults, but only a small amount is
present at birth
Its allele i is present in the red cells at birth,
and changes from i to I during the first 18
Adult cells show a very small amount of i

The i antigen also serves as a marker for

maturation of red cells
If a large number of immature red cells are
being released into circulation, the i activity is
As a rare exception, the maturation of i
antigen to I does not take place and such i
adult individuals remain strongly positive for i
throughout life and show only traces of I

Antibodies Defining the I System Antigens

Usually seen as a benign, naturally occurring,
cold-reactive autoantibody
Encountered when testing is conducted at
room temperature or below
Can be detected in the sera of most normal
adults if the serum is tested at 4C
Almost exclusively IgM and binds complement

The antibody elutes when the mixture is

incubated at 37C but the bound complement
remains and reacts with a polyspecific
antiglobulin serum
Occasional examples of anti-I are strongly
reactive autoantibodies that can cause a cold
autoimmune hemolytic anemia
Individuals of the adult i phenotype may
develop a strong alloanti-I that may be
strongly hemolytic

A rare antibody
Usually an IgM cold agglutinin
Development of a potent autoanti-i is
sometimes associated with infectious
mononucleosis and may cause a transient
hemolytic anemia

Clinical Significance of Anti-I and Anti-i

Hemolytic Disease of the Newborn
I system antibodies are primarily IgM in nature
They cannot cross the placenta to cause HDN
The weak expression of the I antigen on fetal
RBCs protects those cells from anti-I-mediated
IgG anti-i has been implicated in at least one
case of HDN

Hemolytic Transfusion Reaction

The normally encountered benign autoanti-I
does not cause increased clearance of
transfused cells
More potent examples of anti-I and anti-i,
such as those associated with hemolytic
anemias, may destroy transfused cells as well
as autologous cells
If transfusion is required in these instances,
the blood should be warmed and the patient
kept warm during the transfusion

The P Blood Group System

Discovered in 1927 when Landsteiner and
Immunized rabbits with human RBCs and
used the resulting immune sera to test for
antigenic differences among individual RBC

Antigens of the P blood group system

Most common phenotypes: P1 and P2
analogous to the A1 and A2 phenotypes seen
in the ABO system
P1 individuals have two antigens on their
RBCs: P1 and P
P2 individuals have only the P antigen and can
produce anti-P1
The P1 antigen is poorly developed at birth,
but the P antigen is well developed

In adults, expression of the P1 antigen varies

widely from individual to individual
The strength of the antigen can deteriorate on
3rd antigen Pk
P1k phenotype expressing both P1 and Pk
P2k phenotype P1 negative and Pk positive
Pk positive cells always lack the P antigen
p phenotype negative for P1, P and Pk antigens

Antigens of the P Blood Group System

Antibodies of the P Blood Group System

Frequently encountered in the serum of P2
Usually is naturally occurring as an IgM coldreactive agglutinin
Does not react above room temperature and
may often go undetected in samples tested by
routine techniques

Produced only by individuals of the P1k or P2k
A potent hemolysin and must be considered
significant when selecting blood for transfusion
Associated with an autoimmune hemolytic
anemia known as paroxysmal cold
Potent IgG hemolysin

Produced by all individuals with the p
A potent, naturally occurring hemolysin that
may be either IgM or IgG
Women of the p phenotype have an increased
incidence of spontaneous abortion

Clinical Significance of P System Antibodies

Anti-P1 has little clinical significance
Usually an IgM antibody
P1 antigen is poorly expressed on fetal cells
has not been associated with HDN
Anti-P1 may be an in vitro hemolysin but it is
not reactive above room temperature
Rare examples of Anti-P1 that are reactive at
37C are capable of causing in vivo hemolysis
and have been associated with HTR

Anti-P and anti-PP1Pk

- produced by individuals with rare P system
- more potent antibodies and can be clinically
- each can be hemolytic, both in vitro and in
vivo, and both have been associated with HDN
and HTR

The MNSs Blood Group System

Discovered in 1927 by Landsteiner and Levine
They used rabbit immune anti-human RBC
sera, they identified a second blood group
system, calling the two antigens M and N
The MNSs blood group system rivals the Rh
system for number of antigens and complexity
Major antigens: M, N, S, s and U

Antibodies of the MNSs Blood Group System

Relatively common specificity in normal sera
Usually a naturally occurring antibody reacting
at room temperature or below
May be either IgM or IgG
Many examples of anti-M show dosage by
reacting stronger with homozygous (MM) cells
than with heterozyggous (MN)

Some weak antibodies may react only with

homozygous cells at room temperature
Many examples of anti-M react more strongly
in an acidified test system
Occasional examples of anti-M that are
reactive at 37C or in the antiglobulin test may
be clinically significant
Anti-M has rarely been reported to cause HDN
or HTR

An uncommon antibody
Usually a weak, cold-reactive, naturally
occurring IgM agglutinin produced by
individuals who are M+N- and who are
positive for S or s
Many anti-N sera demonstrate antigen dosage
on RBCs
It is not considered clinically significant unless
antibody reactions occur at 37C

Anti-S and anti-s

Uncommon antibodies usually seen as
immune antibodies reactive in the
antiglobulin phase
Anti-S is usually IgG, but IgM may also be seen
Anti-s is almost always IgG
Some anti-S sera may demonstrate antigen
dosage on the RBCs
Both specificities are considered clinically

A rare antibody reactive at 37C and the
antiglobulin phase with the cells of most
normal individuals
Should be considered clinically significant and
has been associated with severe HDN and HTR
Identification can be difficult due to the
scarcity of U-negative cells for testing

Clinical Significance of MNSs System

Anti-M and anti-N
Not usually associated with HDN or HTR
because they are normally reactive at
temperature below 37C
Examples of MNSs antibodies reactive at
higher temperatures or in the antiglobulin
phase of testing are considered clinically

Anti-S, anti-s and anti-U

All have been associated with severe HDN and
Must be considered clinically significant
Antigen-negative blood should be selected for
transfusion to patients with one of these

The Kell Blood Group System

First new blood group system discovered after
the development of the antiglobulin test
Antigens: K, k, Kpa, Kpb, Jsa, Jsb
Null phenotype K0 lack all Kell system
McLeod phenotype weakened expression of
Kell system antigens is associated with
structural and functional abnormalities of
RBCs and leukocytes

Antibodies of the Kell Blood Group System

The Kell system antibody most commonly
encountered in routine blood bank practice
K antigen is a powerful immunogen, second
only to D in its potential to induce
Once stimulated, the immune system can
continue to produce detectable levels of antiK for years

Usually seen as an immune-mediated IgG

antibody reactive only in the antiglobulin
phase of testing
Autoanti-K has been reported

Other Kell System Antibodies

Antibodies to k, Kpa, Kpb, Jsa, Jsb share the
serologic characteristics and clinical
significance of anti-K but occur much less
often because of the frequencies of these
Kell system antibodies should be considered
whenever a serum reactive with most or all
cells is encountered

Clinical Significance of Kell System

Hemolytic Disease of the Newborn
Kell system antibodies are usually IgG and Kell
antigens are well expressed on fetal cells
- Must be considered capable of causing HDN
Anti-K is particularly potent causing disease
severe enough to require transfusion therapy
in 50% of cases in one study

Hemolytic Transfusion Reaction

Anti-K has been the cause of many transfusion
The reactions can be immediate or delayed
Other antibodies in the Kell blood group
system also have caused HTRs

The Duffy Blood Group System

Antigens: Fya, Fyb, Fyx, FY3, FY4, FY5 and FY6
Antibodies defining the Duffy system
Anti-Fya and anti-Fyb
Most likely to be encountered in routine blood
Often seen in combination with other RBC
Usually are IgG antibodies produced after
transfusion or pregnancy and must be considered
clinically significant

Reacted equally well in with enzyme-treated or
untreated cells
Immune mediated, but transfusion appears to be a
much stronger stimulus than pregnancy
Resembles anti-FY3, reacted equally well in with
enzyme-treated or untreated cells
Reacted only with cells having normal Rh antigens and
Fya or Fyb antigens
Like FY3 and FY4, the FY5 antigen is not destroyed by
proteolytic enzyme

Clinical Significance of Duffy System

Hemolytic Disease of the Newborn
Anti-Fya is an uncommon cause of HDN,
usually resulting in a mild disease
Occasional cases severe enough to require
exchange transfusion have been reported and
rare fatalities have occurred
Anti-Fyb has been implicated in only one case
of HDN, in which the infant is only mildly

Anti-FY3 has been associated with a mild HDN,

whereas anti-FY4 and anti-FY5 have not been
implicated in HDN
Hemolytic transfusion reaction
Anti-Fya has often been implicated in
immediate and delayed HTR, which
occasionally have been fatal
Anti-Fyb has also been implicated in
immediate and delayed HTR, occasionally
causing severe cell destruction or death