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ABO System


In the 1901, Karl Landsteiner discovered the ABO blood group antigens. By
systematically mixing the RBC from a number of individuals with the sera
from others, he found that the RBCs from some individuals were agglutinated
by the sera from others. A pattern of four major groups emerged- A, B, AB, or
O. Individuals have either A or B antigen on their cells, a combination of A&B,
or neither (group O).

Subtle differences distinguish the A and B blood group antigens. An

individual lacking one or both of these antigens will have serum Abs to
the missing Ag(s). A type O individual is missing both A and B Ags on
the cell and therefore has anti-A and anti-B Abs in the serum.

Antibodies are usually not present at birth but are present in most
individuals by about 6 mons of age. During this period the infant is
exposed to a variety of microorganisms and foodstuffs which have
antigenic determinants that are cross reactive with the blood group
substances and which can thus provide the stimulation for isoantibody
formation (ie E. coli has type B like Ag). These cross reacting Ags
induce formation of Abs in individuals lacking these antigens. An
individual with type A blood however does not respond to A like
epitopes on intestinal microorganisms because these A-like epitopes are
too similar to self and a state of self tolerance to these epitopes should
exist. Therefore, even though induced by microbial Ags, the Abs react to
similar oligosaccharides on RBCs. Natural isoAbs are usually of the
IgM class. Abs arising as a result of a mismatched transfusion are
usually of the IgG class.

The blood group antigens are genetically determined with each antigen
controlled by two alleles, with A & B alleles codominant to the O allele.

The A blood type appears to have the most variation in subgroups;

several have been found for O's; B subgroups exist but are extremely
rare; and AB's have a wide variety, as they can inherit all the
possibilities of the A group. There are about 20 different known
subgroups of group A. A1 equals approximately 80% of the entire A
blood type population, and A2 makes up the remaining 20%, under
current data. This means that all other subgroups must be rare. The A1
allele is dominant to the A2 allele and occurs about 5 times more

Genotype-Phenotype Correlations: US% (caucasian)

A1A2, A1A1, A1O A1 A=40

A2A2, A2O A2

BB, BO B B=10

A1B A1B AB=4


OO O O=46

The blood group substances A & B are found in the body secretions
(saliva, semen, gastric juices, sweat) of about 75% of persons (secretors)
with these blood groups. The secretion is also genetically determined
and controlled by two alleles: Se and se with Se being dominant. The
blood group antigens are also found on liver, muscle, spleen, kidney and
lung cells. It is therefore possible to determine the blood type of an
individual by examination of any tissue.

The ABO RBC antigens are cell surface heterosaccharides. ABO Ags
are not primary gene products but instead they are enzymatic reaction
products catalyzed by enzymes called glycosyltransferases. All normal
individuals synthesize a common core glycan called the H Ag (type O)
that is attached to a polypeptide backbone. Individuals who possess an A
allele gene product form an enzyme that adds a terminal N-
acetylgalactosamine to some of their O Ags for the A Ag. The B allele
enzyme adds a terminal galactose. Type O blood does not lack Ag-
instead have H substance.

A1 red blood cells have about one million A antigens per cell. A2 red
cells have only 250,000 A antigens per cell, or one-fourth the amount
that A1 cells have.

The 'A' antigen on A1 and A2 subgroup blood cells is named 'Type 2 A'
antigen; however, A1 subgroup blood cells also have two additional
forms of antigen as well, 'Type 3 A' and 'Type 4 A', neither of which
appear on A2 subgroup blood cells.

The H antigen (fucose) is a precursor of A and B antigens. It is present

on the surface of all ABO types red blood cells - A, B, AB, and O. Adult
O's have 1.7 million copies of H antigen per red blood cell. The A1 gene
is a much better converter of H (or the 'O' antigen) than is the A2 gene.
Therefore, A2 red cells have much more H antigen than do A1 red cells.

Other blood group systems have been discovered recently. Today some 20
human systems, which include 60 different blood group factors are known.
The antigens of one of these the Lewis system are involved in the chemical
structure of the ABO system antigens. In general, differences in minor blood
groups lead to red cell lysis only after repeated transfusions produce a
secondary Ab response.

Transfusion Reaction

The chief danger from incompatible transfusions lies in the fate of the
injected cells. The patient may suffer a transfusion reaction if there is sufficient
Ab in his circulation to cause agglutination or hemolysis of the donor’s RBCs.

Despite the presence of anti-A and anti-B agglutinins in the

sera of group O individuals, their blood can often be given
to persons of any group.

The titer of normal isohemagglutinins is normally

low, and

they are diluted by the blood of the recipient to such

an extent that they do not agglutinate or hemolyze
the patient’s cells.

Therefore, members of group O are called

universal donors-they have no blood antigens that
can be recognized by the recipient.

Group AB individuals are likewise called universal

recipients because they have no Abs in their serum.

Of course homologous blood is always the best due to other

minor blood groups.
Transfusion reactions may trigger an immediate hemolytic reaction, resulting in
both intravascular lysis of RBCs, mediated by the C' system and extensive
phagocytosis of Ab and C' coated RBCs by MOs of the liver and spleen.

Immediate reactions are most commonly associated with ABO blood

group incompatibilities.

Lysis of the RBCs lead to free hemoglobin that can be detected in the
plasma and it is filtered through the kidneys.

Hemoglobin can be present in quantities that may be toxic for

kidney cells, producing acute tubular cell necrosis and renal

High fevers, chills, nausea, pain in the lower back, shock,

hemoglobin in the urine and disseminated intravascular
coagulation may also develop (suggestive of massive cytokine
release ie TNF).

Some of the hemoglobin gets converted to bilirubin which at high

levels is toxic.

Treatment involves

prompt termination of the transfusion and

maintenance of urine flow with a diuretic because the

accumulation of hemoglobin in the kidney can cause acute
tubular necrosis.

The disseminated intravascular coagulation consumes clotting factors

faster than they can be synthesized and the patient may paradoxically die
of bleeding.

More delayed hemolytic reactions may result from incompatibilities of

minor blood group antigens.


The Rh factor is not the single entity as originally thought but a complex
system of antigens. Initially 3 pairs of closely linked allelic genes were
postulated by Fisher and called Cc,Dd, and Ee. There are actually more than 30
subgroups of these factors but for practical purposes the D ( or Rho in the
Weiner system) antigen proved to be the strongest and most potent
antigenically and therefore the most important in hemolytic disease and in
transfusion reactions.

There are antigens for each of these factors so there is antiserum available for
each one except anti-d so we have to employ statistical studies to determine
zygosity of D.

If a person upon agglutination testing, is homozygous for Big C or Big E

(that is they reacted with big C and/ or E but not anti-c or anti-e) then
that person is most likely homozygous for big D.

DCe / _Ce= homozygous for D.

If a person has Big C and Big E present, regardless of the zygositiy, then
most likely that person is homozygous for D.

DCe / _ cE = homozygous for D

DcE / _ce= heterozygous for D

Hemolytic Disease of the Newborn or Erythroblastosis Fetalis

Anti-Rh antibodies normally are not present in the serum. Consequently,

sensitization is necessary for an Rh antigen-antibody reaction.

Sensitization typically occurs when an Rh negative woman carries an Rh

positive fetus which inherited this antigen from the father.

The fetal Rh antigen rarely enters the mother's circulation during

pregnancy but can leak across the placenta during delivery, miscarriage,
or abortion. The Rh negative mother's immune system then becomes
sensitized to the Rh antigen and can produce anti-Rh antibodies of the
IgM isotype.

Because sensitization usually occurs at delivery, the first Rh+ child of an

Rh- mother rarely suffers from hemolytic disease.

The problems occur with each successive Rh+ fetus. Fetal antigens can
leak into the mother's circulation which can result from hard coughing or
sneezing. This triggers a secondary Ab response (activates memory B
cells) so IgG is produced this time. IgG can cross the placenta and
attack the RBC of the fetus and cause jaundice due to excessive bilirubin
in their blood.

Hemolytic disease can now be prevented by giving Rh negative mothers

injections of Rhogam (anti-Rh Abs) within 72 hours of delivery. The Abs bind
to circulating Rh+ fetal RBC and destroy them before they can act to sensitize
her specific immune system.

Coomb’s test

Unlike the ABO system, the corresponding antibodies for the Rh antigens
do not occur naturally, but as the result of immunization.

In addition, the antibodies which do occur do not always behave

as do the conventional saline agglutinins which is what we call the
ABO Abs. Instead they are often called incomplete or blocking

They do agglutinate cells suspended in a serum albumin or after

cells are treated with trypsin - apparently the Rh antigen resided
beneath the stromal surface of the red cell and it is revealed by

The Rh Ags are also widely spaced on the RBC surface, the IgG
anti Rh Abs cannot fix complement and cause lysis of the RBC in

The most important means of demonstrating incomplete antibodies is the

Coombs test. If the RBC are sensitized by incomplete antibodies they can be
agglutinated by anti-Ab serum. Anti-Ab serum would have no effect on
unsensitized RBC.

*This test is used to detect in vivo sensitization of RBC of an erythroblastic

infant by passively acquired maternal Rh antibodies.

Direct Test- The infants RBC are washed and anti-globulin serum is added-
agglutination will occur if the mother’s Ab is coating the RBC as is seen in
Erythroblastosis Fetalis.

Indirect Test- maternal serum which potentially contains the anti-Rh Ab is incubated
with Rh+ test cells. Then anti-Ab is added. If anti-Rh Abs are present on the RBCs then
agglutination will occur.