The Rhesus (Rh)

Blood Group
system
 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
 Rh Genetics
 The genes that control the system
are autosomal codominant located
on the short arm of chromosome 1.
 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
 Rh Antigen Frequency
 D antigen – 85% RhPositive
Rh Positive
 d antigen – 15% RhNegative
Negative
Rh
 C antigen – 70%
 c antigen – 80%
 E antigen – 30%
 e antigen – 98%

 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
 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 D Produces D antigen

d d “d” antigen not

produced

C 3 C
closely Produces C/c antigen
c linked c
genes

E E
Produces E/e antigen
e e
 Fisher-Race
 There are 8 gene
complexes at the DCe dCe
Rh locus DcE dCE
 Fisher-Race uses
DCE as the order Dce dcE
 Others alphabetize DCE dce
the genes as CDE
Fisher-Race Nomenclature
Gene
Antigens
Combination
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
 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
 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.
In the Fish-Race theory the D gene codes for
the D antigen. The C gene codes for the C
antigen, etc.
 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.
 Wiener Theory

Produces
D antigen
r” on RBC

R0
R”
R’
Produces C r’
antigen on
RBC
Single gene at Rh
locus
 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
 2- Weiner Nomenclature
Nomenclature expressed by the use of a single letter.

R D present

r D absent

Prime ′ or 1 C
Double ″
E
or 2
 Conversion of Wiener to Fisher-
Race
 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 Antigens (Weiner Gene)

0
Dce D, c, e R
1
DCe D, C, e R
DcE D, c, E R2
z
DCE D, C, E Rz
dce c,e r
dCe C,e r′
dcE c,E r″
y
dCE C,E r
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
 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
 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
 Weak D Phenotype
 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

 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
• 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 D red cells
u

1- Acquired Du (Position Effect)

2- Du Variant (Partial D)
3- Hereditary Du (Genetically
Transmissible)
 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.
 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
 Partial D: Multiple epitopes make up D antigen. Each
color represents a different epitope of the D antigen.

A.

Patient B lacks
B. 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
anti-D typing reagents..
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.
 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
 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.
 Rh antibodies
 Result from the Rh Abs
exposure to Rh Clinically Abs class
antigens Significant IgG
Yes
• IgG form
Thermal HDNB
• Bind at 37°C range Yes
• Form agglutination 4 - 37
in IAT phase Transfusion Reactions
Extravascul Intravascul
ar ar

Yes 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 re-exposure.
 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.
 Rh factor
 Rh factor can First pregnancy
cause
complications in Placenta
some Rh+ antigens
pregnancies.

 Mother is
exposed to Rh
antigens at the
birth of her Rh+
baby.
 Mother makes
anti-Rh+ Anti-Rh+ Possible
subsequent
antibodies
antibodies. pregnancies
 During the
mother’s next
pregnancy, Rh
antibodies can
cross the placenta
and endanger the
fetus.