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Modern Blood Banking & Transfusion Practices

6th Edition

Chapter 7

The Rh Blood Group System

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Introduction
Rh specific antigens reside on proteins versus the
carbohydrate antigens ABO and Hh.
Rh antigens are very immunogenic.
Rh antibodies are produced after exposure to
foreign red blood cells. This is distinct from ABO
antibodies.
Production is caused when person lacking antigen is
exposed to antigen foreign to their system.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Introduction
Rh is the second most important blood group
system after ABO.
It is a complex blood group system composed of
over 50 different RBC antigens.
Individuals who lack RhD are Rh negative.
Individuals who possess RhD are Rh positive.
Determining the presence or absence of RhD is
critical in pretransfusion testing.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

History
Levine and Stetson described a hemolytic transfusion
reaction in an obstetrical patient.
Landsteiner and Wiener reported on an antibody made
by guinea pigs and rabbits when they were transfused
with Rhesus macaque monkey RBCs.
Further research resulted in defining Rh as a primary
cause of hemolytic disease of the fetus and newborn
(HDFN or erythroblastosis fetalis) and a significant
cause of hemolytic transfusion reactions.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Fisher-Race: DCE Terminology


Fisher and Race postulated that the antigens of the
system were produced by three closely linked sets of
alleles.
Each gene was responsible for producing a product (or
antigen) on the RBC surface.
The phenotype (antigens expressed on the RBC detected
by typing) of a given RBC is defined by the presence of
D, C, c, E, and e expression.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Fisher-Race: DCE Terminology


Rh antigen frequency in the Caucasian population
D: 85% (Rh positive)
Absence of D: 15% (Rh negative)
C: 70%
E: 30%
c: 80%
e: 98%

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Fisher-Race: DCE Terminology


Haplotype: the complement of genes inherited from
either parent
See table 7-2 in textbook for Haplotypes
DCe most common haplotype for whites and asians
Dce most common haplotype for blacks
Consideration of Rhnull and Rhmod phenotypes
Rhnull = a person expressing NO Rh antigens on their RBCs.
Rhmod = a person with weakened expression of Rh antigens.
Expressed with parenthesis. (Ie. (D), (C), (e))

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Wiener: Rh-Hr Terminology


Wiener believed there was one gene responsible for defining
Rh that produced an agglutinogen containing a series of blood
factors.
This Rh gene produced at least three factors within an
agglutinogen.
The agglutinogen may be considered the phenotypic
expression of the haplotype.
Each factor is an antigen recognized by an antibody.
Antibodies can recognize single or multiple factors or antigens.
Fisher-Race nomenclature may be converted to Wiener
nomenclature and vice versa.
Copyright 2012 F.A. Davis Company
Modern Blood Banking & Transfusion Practices
6th Edition

Wiener: Rh-Hr Terminology


Review Table 7-4 (page 152) from textbook
Weiner Haplotype Terminology

R = represents presence of D
r = represents absence of D

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Rosenfield & Coworkers: Alphanumeric Terminology


In the early 1960s Rosenfield and associates proposed a system
that assigns a number to each antigen of the Rh system in order of
its discovery or recognized relationship to the Rh system.
This system demonstrates the presence or absence of the antigen
on the RBC.
A minus sign preceding a number designates absence of the
antigen.
If an antigen has not been typed, its number will not appear in the
sequence.
For the five major antigens, D is assigned Rh1, C is Rh2, E is Rh3,
c is Rh4, and e is Rh5.
Copyright 2012 F.A. Davis Company
Modern Blood Banking & Transfusion Practices
6th Edition

International Society of Blood Transfusion Committee (ISBT)


ISBT formed the Committee on Terminology for Red Cell Surface
Antigens.
The mandate was to establish a uniform nomenclature that is both eye-
and machine-readable and is in keeping with the genetic basis of blood
groups.
The ISBT adopted a six-digit number for each authenticated antigen
belonging to a blood group system.
The first three numbers represent the system and the remaining
three the antigenic specificity.
Number 004 was assigned to the Rh blood group system, and then
each antigen assigned to the Rh system was given a unique number
to complete the six-digit computer number.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Overview of Rh Terminologies

Tables 74, 75, and 76 summarize the data


presented in this section.
Table 77 correlates Rh phenotypes with the
most probable or predicted genotype in a
designated population.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Overview of Rh Terminologies
Determining probably or predicted genotypes was useful for
parentage studies (relationship testing)

Considerations for zygosity testing (molecular testing)


There are substantial differences in phenotypes and
predicted genotypes of various populations.
These differences must be remembered when trying to
locate compatible blood for recipients with unusual or
multiple Rh antibodies.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Overview of Rh Terminologies
For consistency of use, RHD and RHCE, all upper
case and in italics, will be used from this point
forward in the text to indicate genes.
RhD, RhCe, RhcE, Rhce, and RhCE will be used to
designate proteins on which the Rh antigens reside.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Molecular Genetics
Two theories of Rh genetic control were initially
postulated to explain genetically the results of
serologic and biochemical studies in the Rh
system.
Wiener postulated that a single gene produces a
single product that contains separately
recognizable factors.
Fisher and Race proposed that the Rh locus
contains three distinct genes that control
production of their respective antigens.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

RH Genes
Tippett correctly proposed that two closely linked genes located on
chromosome 1 control expression of Rh proteins; namely, RHD and
RHCE.
The gene RHD codes for the presence or absence of the RhD
protein.
The gene RHCE codes for either RhCe, RhcE, Rhce, or RhCE
polypeptides.
Another gene important to Rh antigen expression is RHAG on
chromosome 6.
The product of this gene is Rh-associated glycoprotein (RhAG).
RhAG is termed a coexpressor and must be present for successful
expression of the Rh antigens.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

RH Genes
By itself RhAG does not express any Rh antigens.
When mutations in the RHAG gene occur, it can
result in missing or significantly altered RhD and
RhCE proteins, affecting antigen expression.
Consideration of the Rhnull phenotype.

Rhnull no Rh antigens expressed on RBCs

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Rh-Positive Phenotypes
Rh-positive individuals inherit one or two
codominant RHD genes, which result in expression
of RhD antigen and are typed Rh-positive.
In addition to the RHD gene(s), two RHCE genes are
inherited, one from each parent.
<Insert Figure 74>

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Rh-Negative Phenotypes
Rh-negative individuals can arise from at least
three different mutations.
These mutations are most often found in
individuals falling into three different ethnic
backgrounds.
European ethnicity
African ethnicity
Asian ethnicity

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Biochemistry
Rh antigens are non-glycosylated (no carbohydrates)
proteins.
Rh antigens reside on transmembrane proteins and are an
integral part of the RBC membrane.
Only small loops of Rh proteins are exposed on the surface of
the RBC.
The number of D antigen sites vary depending on Rh
phenotype.
RhD and RhCE proteins and RhAG are exclusively on red blood
cells.
As transmembrane proteins, they play a role in maintaining
the structural integrity of the RBC.
They may also act as molecular transporters.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Weak D: Variations of D Antigen Expression


Some individuals RBCs possess weaker expression of D
antigen that requires an indirect antiglobulin test to
detect the D antigen.
Referred to as Du (Weak D)
Individuals with altered D antigen are categorized into
different phenotypes defined as weakened D.
C in trans to RHD
Weak D (fewer D antigens in number)
Partial D (D epitope is missing or altered)
Del (Common in Asians, rare in whites)

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Detection of Rh Antibodies and Antigens


Most Rh antibodies are IgG and react optimally at 37C
or after AHG testing.
Rh antibodies are usually produced following
exposure to foreign RBCs.
Rh antibodies may show dosage.
Rh antibodies are enhanced when testing with
enzyme-treated RBCs.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Detection of Rh Antibodies and


Antigens (contd)
IgG1, IgG2, IgG3, and IgG4 subclasses of Rh antibodies
have been reported.
IgG1 and IgG3 are of the greatest clinical significance;
RBCs coated with IgG1 and IgG3 are rapidly cleared from
the circulation by the RES.
Rh antibodies often persist for years.
Rh antibodies do not bind complement.
Rh antibodies can cross the placenta.
Copyright 2012 F.A. Davis Company
Modern Blood Banking & Transfusion Practices
6th Edition

Rh Typing Reagents
The goal is to use a reagent anti-D that will
allow for typing individuals RBCs as quickly
and accurately as typing for ABO.
The reagents may be high-proteinbased or
low-proteinbased, saline-based, chemically
modified, monoclonal, or blends of
monoclonals.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Clinical Considerations:
Transfusion Reactions
The D antigen is the most immunogenic antigen
outside the ABO system.
Careful review of the medical history for pregnancy or
transfusion of products containing RBCs
Unexplained fever, a mild bilirubin elevation, and a
decrease in hemoglobin and haptoglobin
The DAT is usually positive
Antibody screen may demonstrate circulating antibody
Elution studies may be helpful

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Hemolytic Disease of the Fetus and Newborn


HDFN caused by Rh antibodies is often severe; the Rh
antigens are well developed on fetal cells, and Rh
antibodies are transplacental IgG.
Rh-immune globulin, a purified preparation of IgG
anti-D, is given to D-negative woman during
pregnancy and after delivery of a D-positive fetus.
Rh-immune globulin is effective only in preventing
RhD HDFN.

Copyright 2012 F.A. Davis Company


Modern Blood Banking & Transfusion Practices
6th Edition

Rh Deficiency Syndrome:
Rhnull and Rhmod
Individuals who lack all Rh antigens on their RBCs
are said to have Rhnull syndrome
Individuals of the Rhmod phenotype have a partial
suppression of RH gene expression caused by
mutations in the RHAG gene
When the resultant RhAG protein is altered, normal Rh
antigens are also altered often causing weakened
expression of the normal Rh and LW antigens
Copyright 2012 F.A. Davis Company
Modern Blood Banking & Transfusion Practices
6th Edition

The Landsteiner Weiner (LW) Blood Group System


The LW system dates from the time when Rh antigens were first
recognized.
Many years later, it was recognized that the two antibodies were not
identical; the anti-rhesus described by Landsteiner and Wiener was
renamed anti-LW in their honor.
Phenotypically, there is a similarity between the Rh and LW systems.
Anti-LW reacts strongly with most D-positive RBCs, weakly (sometimes
not at all) with Rh-negative RBCs, and never with Rhnull cells.
Anti-LW usually shows stronger positive reactions with D-positive RBCs
than with D-negative adult RBCs.
Anti-LW reacts equally well with cord cells regardless of their D type.

Copyright 2012 F.A. Davis Company