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The Rhesus (Rh)
Blood Group
system
The Rh(D) Antigen
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Rh is the most complex system,
with over 45 antigens
The complexity of the Rh blood
group Ags is due to the highly
polymorphic genes that encode
them.
Discovered in 1940 after work on
Rhesus monkeys
The 2nd most important after ABO in
the crossmatch test
Only the most clinically significant
Ags will be discussed
Rh Genetics
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The genes that control the system
are autosomal codominant located
on the short arm of chromosome 1.
Rh blood group antigens are
proteins
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The antigens of the Rh blood group are
proteins.
The RhD gene encodes the D antigen,
which is a large protein on the red blood
cell membrane, & the most important.
Proteins
RHD gene
RHCE gene
Chromosome 1
Rh Antigen Frequency
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D antigen – 85%
d antigen – 15%
C antigen – 70%
c antigen – 80%
E antigen – 30%
e antigen – 98%
Rh Positive
Rh Negative
The presence or absence of D Ag
determines if the person is Rh+ or Rh-
Nomenclature of the RH system
3 Different nomenclatures:
1- Fisher-Race
2- Weiner
3- Rosenfield Nomenclature
Fisher-Race Theory
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Rh inheritance is controlled by 3 closely
linked loci on each chromosome of a
homologous pair
Each locus has its own set of alleles which
are: Dd , Cc , and Ee .
The D gene is dominant to the d gene, but
Cc and Ee are co-dominant.
The 3 loci are so closely linked that
crossing over does NOT occur, and the 3
genes on one chromosome are always
inherited together.
Fisher-Race
D
Produces D antigen
D
d
C
c
E
d
3
closely
linked
genes
C
c
E
e
“d” antigen not
produced
e
Produces C/c antigen
Produces E/e antigen
Fisher-Race
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There are 8 gene
complexes at the
Rh locus
Fisher-Race uses
DCE as the order
Others alphabetize
the genes as CDE
DCe
dCe
DcE
dCE
Dce
dcE
DCE
dce
Fisher-Race Nomenclature
Gene
Combination
Dce
DCe
DcE
DCE
dce
dCe
dcE
dCE
Antigens
D, c, e
D, C, e
D, c, E
D, C, E
c,e
C,e
c,E
C,E
Fisher-Race Example:
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DCe/DCe individual is homozygous
for D, C, and e genes
DCe/dcE individual is heterozygous
for D, C, e, d, c, and E genes
Fisher-Race:
Genetics/Terminology
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Rh phenotype is designated by the
presence or absence of Rh antigens: D, C,
c, E, e
• little d: Indicates the ABSENCE of the D
antigen and nothing more.
• There is NO little d antigen or allele.
• Many blood bankers today are leaving
the ‘d’ out the the nomenclature
entirely.
• Phenotype example: R1 phenotype is D,
C, e
In the Fish-Race theory the D gene codes for the
D antigen. The C gene codes for the C antigen,
etc.
Wiener Theory
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Good for describing phenotype
There is one Rh locus at which occurs one Rh
gene, but this gene has multiple alleles.
For example, one gene R1 produces one
agglutinogen (antigen) Rh1 which is composed of
three "factors"
The three factors are analogous to C, D, and e
respectively
The main difference between the Fisher-Race and
Wiener theories is that the:
• Fisher-Race theory has three closely linked
loci,
• the Wiener theory has only one gene locus at
which multiple alleles occur.
Wiener Theory
Produces
D antigen
on RBC
r”
R0
R”
R’
Produces C
antigen on
RBC
r’
Single gene at Rh
locus
Wiener
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Wiener further theorized that 8
major genes led to different
combinations of antigens (D, C, E, c,
e):
• R0, R1, R2, Rz
• r, r′, r″, ry
2- Weiner Nomenclature
Nomenclature expressed by the use of a single letter.
R
D present
r
D absent
Prime ′ or 1
C
Double ″
or 2
E
Conversion of Wiener to FisherRace
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R in Wiener = D in Fisher-Race
r is absence of D (d)
0 or no symbol implies c and e
1 or ′ implies C and e
2 or ″ implies c and E
z or y implies C and E
Fisher-Race and Wiener Nomenclature
Fisher-Race
Dce
DCe
DcE
DCE
dce
dCe
dcE
dCE
Antigens
D, c, e
D, C, e
D, c, E
D, C, E
c,e
C,e
c,E
C,E
(Weiner Gene)
0
R
1
R
2
R
z
R
r
r′
r″
y
r
Converting Wiener into FisherRace or vice versa
RD
r  no D
1 and ′  C
2 and ″  E
Written in shorthand
Example: DcE  R2
r″  dcE
Rosenfield Nomenclature
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Each antigen assigned a number
Rh 1 = D
Rh 2 = C
Rh 3 = E
Rh 4 = c
Rh 5 = e
In writing the phenotype, the prefix “Rh” is
followed by colon, then number (if negative,
number is preceded by -)
e.g. D+, C+, E-, c+, e+ is written as
Rh:1,2,-3,4,5
Significance
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After ABO, the Rh system is the second most
important system. This is because:
The D antigen is extremely immunogenic.
It causes the production of anti-D in 50 - 70% of
Rh(D) negative people who are exposed to the D
antigen.
Moreover, anti-D is the most common cause of
severe HDN and can cause in Utero death.
Because of this, in blood transfusion, the patient
and donor are matched for Rh(D) type as well as
ABO groups.
The C and E Ags are not as immunogenic as D,
routine typing for these Ags is not performed
Weak D Phenotype
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Most D positive rbc’s react macroscopically
with Reagent anti-D at immediate spin
• These patients are referred to as Rh positive
• Reacting from 1+ to 3+ or greater
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HOWEVER, some D-positive rbc’s DO
NOT react (do NOT agglutinate) at
Immediate Spin using Reagent Anti-D.
These require further testing (37oC and/or
AHG) to determine the D status of the
patient.
Variants of D
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Weak expression of the Rh system
on the RBC, (Du)
Du red cells can be classified into
three categories according to the
mechanism that account for the
Weak D antigen
Categories of Du red cells
1- Acquired Du (Position Effect)
2- Du Variant (Partial D)
3- Hereditary Du (Genetically
Transmissible)
1- Acquired Du (Position Effect)
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C allele in trans position to D allele
• Example: Dce/dCe, DcE/dCE
In both of these cases the C allele is in the
trans position in relation to the D allele.
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D antigen is normal, C antigen appears to
be crowding the D antigen. (Steric
hindrance)
Does NOT happen when C is in cis
position
• Example: DCe/dce
Can safely transfuse D positive blood
components.
2- Du Variant (Partial D)
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The D- Ag consists of at least 4
parts
Missing one or more PARTS
(epitopes) of the D antigen
remaining Ag is weakly expressed
Alloantibodies are produced to the
missing parts
Du variants should receive Rh –ve
blood when transfused
Partial D: Multiple epitopes make up D antigen. Each
color represents a different epitope of the D antigen.
A.
B.
Patient B lacks
one D epitope.
The difference between Patient A and Patient B is a single
epitope of the D antigen. The problem is that Patient B can make
an antibody to Patient A even though both appear to have the
entire D antigen present on their red blood cell’s using routine antiD typing reagents..
3- Hereditary Du (Genetically Transmissible)
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The RHD gene codes for weakened
expression of D antigen in this
mechanism.
• D antigen is complete, there are just fewer D
Ag sites on the rbc. Quantitative!
• Common in Black population (usually Dce
haplotype). Very rare in White population.
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Agglutinate weakly or not at all at
immediate spin phase.
Agglutinate strongly at AHG phase.
Can safely transfuse D positive blood
components.
Rh Deleted
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Red cells that express no Ags at the
C & E loci ( D )
Number of D Ags greatly increase
Anti-D IgG Abs can agglutinate these
cells
Rh null
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RH null: individual that appears to have no Rh
antigens
RBC has fragile membrane- short lived
Must use autologous blood products
• No D, C, c, E, e antigens present on the RBC
membrane
Demonstrate mild hemolytic anemia (Rh antigens
are integral part of RBC membrane and absence
results in loss of membrane integrity)
• Stomatocytosis.
When transfusion is necessary ONLY Rh Null
blood can be used to transfuse.
Rh antibodies
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Result from the
exposure to Rh
antigens
IgG form
Bind at 37°C
Form agglutination
in IAT phase
Rh Abs
Clinically
Abs class
Significant
IgG
Yes
Thermal
HDNB
range
Yes
4 - 37
Transfusion Reactions
Extravascul Intravascul
ar
ar
Yes
No
Clinical Significance of Rh
antibodies
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Related to Hemolytic transfusion
reactions
Re-exposure to antigen cause rapid
secondary response
Always check patients history for
previous transfusion or pregnancy to
avoid re-exposure.
Hemolytic disease of the Newborn
(HDN)
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Usually related to D antigen exposure and the
formation of anti-D
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Usually results from D negative female and D
positive male producing and offspring.
• The baby will probably be D positive.
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1st pregnancy not effected, the 2nd pregnancy and
on will be effected-results in still birth, severe
jaundice, anemia related to HDN.
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To prevent this occurrence the female is
administered RHIG.
Rh factor
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Rh factor can
cause
complications in
some
pregnancies.
Mother is
exposed to Rh
antigens at the
birth of her Rh+
baby.
First pregnancy
Placenta
Rh+ antigens
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Mother makes
anti-Rh+
antibodies.
During the
mother’s next
pregnancy, Rh
antibodies can
cross the placenta
and endanger the
fetus.
Anti-Rh+
antibodies
Possible
subsequent
pregnancies