The Rhesus (Rh) Blood

Group system

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The Rh(D) Antigen

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
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Rh Genetics
The genes that control the system are
autosomal codominant located on the
short arm of chromosome 1.

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Rh blood group antigens are

proteins
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
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Rh Antigen Frequency

D antigen 85%
d antigen 15%
C antigen 70%
c antigen 80%
E antigen 30%
e antigen 98%

RhPositive
Positive
Rh
RhNegative
Negative
Rh

The presence or absence of D Ag determines if

the person is Rh+ or RhM. Zaharna Blood Bank

Nomenclature of the RH system

3 Different nomenclatures:
1- Fisher-Race
2- Weiner
3- Rosenfield Nomenclature

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Fisher-Race Theory
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.
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Fisher-Race
D

Produces D antigen

D
d

C
c

3
closely
linked
genes

C
c

E
e

d antigen not
produced

Produces C/c antigen

Produces E/e antigen

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Fisher-Race
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

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Fisher-Race Nomenclature
Gene
Combinati
on

Antigens

Dce
DCe
DcE
DCE
dce
dCe
dcE

D, c, e
D, C, e
D, c, E
D, C, E
c,e
C,e
c,E

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Fisher-Race Example:
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

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Fisher-Race:
Genetics/Terminology
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.
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In the Fish-Race theory the D gene codes for

the D antigen. The C gene codes for the C
antigen, etc.
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Wiener Theory
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.

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Wiener Theory
Produces
D antigen
on RBC

r
R0
R

R
Produces C
antigen on
RBC

r
Single gene at Rh
locus

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Wiener
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

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2- Weiner Nomenclature
Nomenclature expressed by the use of a single letter.

D present

D absent

Prime or 1

Double or 2

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Conversion of Wiener to FisherRace

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

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Fisher-Race and Wiener Nomenclature

Fisher-Race Antigens

(Weiner Gene)

Dce
DCe

D, c, e

R0

D, C, e

R1

DcE

D, c, E

R2

DCE

D, C, E

dce
dCe
dcE
dCE

c,e
C,e
c,E
C,E
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R
r
r
r
ry

Converting Wiener into FisherRace or vice versa

RD
r no D
1 and C
2

and E
Written in shorthand

Example: DcE R2
r dcE
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Rosenfield Nomenclature
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

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Significance
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
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Weak D Phenotype
Most D positive rbcs react macroscopically with
Reagent anti-D at immediate spin
These patients are referred to as Rh positive
Reacting from 1+ to 3+ or greater

HOWEVER, some D-positive rbcs 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.
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Variants of D
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 D red cells

u

1- Acquired Du (Position Effect)

2- Du Variant (Partial D)
3- Hereditary Du (Genetically Transmissible)

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1- Acquired Du (Position Effect)

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.

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.
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2- Du Variant (Partial D)
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
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Partial D: Multiple epitopes make up D antigen. Each

color represents a different epitope of the D antigen.
A.

Patient B lacks
one D epitope.

B.

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 cells using routine
anti-D typing reagents..
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3- Hereditary Du (Genetically Transmissible)

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.

Agglutinate weakly or not at all at immediate

spin phase.
Agglutinate strongly at AHG phase.
Can safely transfuse D positive blood
components.
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Rh Deleted
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
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.

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Rh antibodies
Result from the
exposure to Rh
antigens
IgG form
Bind at 37C
Form agglutination in
IAT phase

Rh Abs
Clinically
Significant
Yes

Abs class
IgG

Thermal
range
4 - 37

HDNB
Yes

Transfusion Reactions
Extravascular Intravascular

Yes
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No

Clinical Significance of Rh
antibodies
Related to Hemolytic transfusion reactions
Re-exposure to antigen cause rapid
secondary response
Always check patients history for previous
transfusion or pregnancy to avoid reexposure.

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Hemolytic disease of the Newborn

(HDN)
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.
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.
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Rh factor
Rh factor can
cause
complications in
some
pregnancies.

Firstpregnancy

Mother is exposed
to Rh antigens at
the birth of her Rh+
baby.
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Placenta
Rh+antigens

 Mother makes antiRh+ antibodies.

AntiRh+
antibodies

During the mothers

next pregnancy, Rh
antibodies can cross
the placenta and
endanger the fetus.

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Possible
subsequent
pregnancies