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The Rhesus (Rh) Blood Group system
Mohammed Laqqan
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.
Mohammed Laqqan
Rh Genetics
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The genes that control the system are autosomal
codominant located on the short arm of
chromosome 1.
Mohammed Laqqan
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
Mohammed Laqqan
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 RhMohammed Laqqan
Nomenclature of the RH system
3 Different nomenclatures:
1- Fisher-Race
2- Weiner
3- Rosenfield Nomenclature
Mohammed Laqqan
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 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.
Mohammed Laqqan
Fisher-Race
D
Produces D antigen
D
d
C
c
E
e
3
close
ly
linke
d
genes
d
“d” antigen not
produced
c
Produces C/c antigen
C
E
e
Produces E/e antigen
Mohammed Laqqan
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
Mohammed Laqqan
Fisher-Race Nomenclature
Gene Combination
Antigens
Dce
D, c, e
DCe
D, C, e
DcE
D, c, E
DCE
D, C, E
dce
c,e
dCe
C,e
dcE
c,E
dCE
C,E
Mohammed Laqqan
Fisher-Race Example:
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DCe/DCe individual is homozygous for D, C, and
e genes
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DCe/dcE individual is heterozygous for D, C, e,
d, c, and E genes
Mohammed Laqqan
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
Rh genes are codominant.
Mohammed Laqqan
In the Fish-Race theory the D gene codes for the D
antigen. The C gene codes for the C antigen, etc.
Mohammed Laqqan
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:
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Fisher-Race theory has three closely linked loci,
the Wiener theory has only one gene locus at which multiple
alleles occur.
Mohammed Laqqan
Wiener Theory
Produces
D antigen
on RBC
r”
R0
R”
R’
Produces C
antigen on
RBC
r’
Single gene at Rh locus
Mohammed Laqqan
Wiener
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Wiener further theorized that 8 major genes led to
different combinations of antigens (D, C, E, c, e):
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R0, R1, R2, Rz
r, r′, r″, ry
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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
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Conversion of Wiener to Fisher-Race
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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
Mohammed Laqqan
Fisher-Race and Wiener Nomenclature
Fisher-Race
Antigens
(Weiner Gene)
Dce
D, c, e
R0
DCe
D, C, e
R1
DcE
D, c, E
R
DCE
D, C, E
Rz
dce
c,e
r
dCe
C,e
r′
dcE
c,E
r″
dCE
C,E
2
ry
Mohammed Laqqan
Converting Wiener into Fisher-Race or vice versa
RD
r  no D
1 and ′  C
2 and ″  E
Written in shorthand
Example: DcE  R2
r″  dcE
Mohammed Laqqan
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
Mohammed Laqqan
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
Mohammed Laqqan
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
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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
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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)
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,
Stomatocytosis.
When transfusion is necessary ONLY Rh Null blood can be used to
transfuse.
Mohammed Laqqan
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
Significant
Yes
Abs class
IgG
Thermal range
4 - 37
HDNB
Yes
Transfusion Reactions
Extravascular
Intravascular
Yes
No
Mohammed Laqqan
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.
Mohammed Laqqan
Hemolytic disease of the Newborn (HDN)
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Usually related to D antigen exposure and the formation of
anti-D
Usually results from D negative female and D positive male
producing and offspring.
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The baby will probably be D positive.
1st pregnancy not effected, the 2nd pregnancy and on will be
effected-results in still birth, severe jaundice, anemia related
to HDN.
To prevent this occurrence the female is administered RHIG.
Mohammed Laqqan
Rh factor
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Rh factor can cause
complications in some
pregnancies.
First pregnancy
Placenta
Rh+ antigens
Mother is exposed to Rh
antigens at the birth of
her Rh+ baby.
Mohammed Laqqan
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Mother makes anti-Rh+
antibodies.
Anti-Rh+
antibodies
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Possible
subsequent
pregnancies
During the mother’s next
pregnancy, Rh
antibodies can cross the
placenta and endanger
the fetus.
Mohammed Laqqan
Weak D Phenotype
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Most D positive rbc’s react macroscopically with Reagent
anti-D at immediate spin
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These patients are referred to as Rh positive
Reacting from 1+ to 3+ or greater
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.
Mohammed Laqqan
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
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Categories of Du red cells
1- Acquired Du (Position Effect)
2- Du Variant (Partial D)
3- Hereditary Du (Genetically Transmissible)
Mohammed Laqqan
1- Acquired Du (Position Effect)
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C allele in trans position to D allele
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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)
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Does NOT happen when C is in cis position
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Example: DCe/dce
Can safely transfuse D positive blood components.
–
Mohammed Laqqan
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
Mohammed Laqqan
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
Mohammed Laqqan
using routine anti-D typing reagents..
3- Hereditary Du (Genetically Transmissible)
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The RHD gene codes for weakened expression of D antigen
in this mechanism.
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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.
Agglutinate weakly or not at all at immediate spin phase.
Agglutinate strongly at AHG phase.
Can safely transfuse D positive blood components.
Mohammed Laqqan