The Rh Blood Group
Brian Poirier, MD
UCDavis Medical Center
1
Topics
•
•
•
•
Terminology systems
Rh antibodies
Consequences of Rh incompatibility
Unusual phenotypes
2
Objectives
• Explain the derivation of the term Rh
• Differentiate Rh from LW
• Compare and convert the major
genotypes among Fisher-Race,
Wiener, and Rosenfield terminologies
• Define the basic biochemical structure
of Rh
3
Objectives (Continued)
• Describe and differentiate three
mechanisms that result in weak D
expression on rbcs
• Describe 3 characteristics of Rh
antibodies
• Describe how to prevent Rh D
immunization
4
5
Rh Blood Group
• Second most important blood group (after
ABO)
6
History of the Rh System
• 1939 Levine described a HTR in an OB
patient:
– After delivery of a still born infant, a woman
required transfusions.
– After receiving her husband’s blood (ABO
compatible), she demonstrated the acute
HTR.
– An antibody was isolated from mom’s serum
that reacted both at 37 C and 20 C with
father’s rbcs.
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History of the Rh System
(continued)
8
History of the Rh System
(continued)
• 1940 Landsteiner and Wiener reported:
– An antibody made by guinea pigs and rabbits
when they were transfused with rhesus
monkey rbcs.
– The antibody agglutinated 85% of human rbcs,
was named “Rh.”
– The antibody was renamed as anti-LW
(Landsteiner and Wiener).
– The name Rh was retained for humanproduced antibody.
9
Nomenclatures of the Rh
system
•
•
•
•
Fisher-Race: The DCE Terminology
Wiener (Rh-Hr): The Rh-Hr Terminology
Rosenfield: Alpha/Numeric Terminology
ISBT (International Society of Blood
Transfusion): Numeric Terminology
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Fisher-Race (DCE or CDE)
• 5 major antigens: D, C, E, c, e
– Rh positive really means D positive.
– Absence of D designated “d” (later found not
to be a real antigen- an “amorph”).
• 8 potential haplotypes named based on
presence of genes for above antigens (eg,
Dce, dce).
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Wiener (Rh-Hr)
• Different names for the 5 main antigens
– Rho=D
– rh’=C
– rh”=E
– hr’=c
– hr”=e
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Wiener (Rh-Hr) (continued)
• Gave shorthand names to the 8 potential
combinations alluded to above; still in use
R1=DCe
r’=dCe
R2=DcE
r”=dcE
Ro=Dce
r=dce
Rz=DCE
ry=dCE
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Converting Wiener (Rh-Hr)
to Fisher-Race
Fisher-Race terminology is easier to use:
• R=D, r=d
• 1 or prime=C
• 2 or double prime=E
• 0 or blank=ce
• any superscript letter =CE
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Rosenfield Terminology
(alpha/numeric)
• Rosenfield system has no genetic basis, only
demonstrates the presence or absence of the
antigen on the red cells.
• A minus sign preceding a number designates
absence of the antigen. The absence of the
number indicates the antigen has not been
typed.
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Rosenfield Terminology
(Continued)
• D is assigned Rh1; C is assigned Rh2; E is
assigned Rh3; c is assigned Rh4; e is
assigned Rh5
• Example 1: D+ C- E+ c+ e+ would be: Rh: 1, 2, 3, 4, 5
• Example 2: DCe/dcE would be: Rh: 1, 2, 3, 4,
5
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ISBT Terminology
• ISBT adopted a six-digit number for each blood
goup specificiy.
• First 3 numbers represent the system and the
remaining 3 the antigen specificity.
• 004 was assigned to the Rh blood group
system; each antigen assigned to the Rh
system was given a unique number to complete
the 6-digit computer number.
• Example: “D” antigen would be “004001”
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“The Big Four Rh
Phenotypes
• R1, R2, R0, and r are most frequently
encountered phenotypes.
• R0 most common in blacks, least
common in whites.
• R 1> R 2
• r is always second in frequency
• Whites: R1 > r > R2 > R0
• Blacks: R0 > r > R1 > R2
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Gene Frequency of Rh
Antigens
Gene
D
d
C
E
c
e
Frequency %
85
15
70
30
80
98
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Common Rh Types by 3
Nomenclatures
Wiener
%
R1r
33
R1R1
rr
R1R2
11
R2r
R2R2
Fisher-Race
Rosenfield
DCe/dce
Rh: 1,2,-3, 4,5
DCe/DCe
dce/dce
DCe/DcE
Rh: 1,2,-3, -4,5
Rh: -1,-2,-3, 4,5
Rh: 1,2,3, 4,5
18
15
DcE/dce
DcE/DcE
Rh: 1,-2,3, 4,5
Rh: 1,-2,3, 4,-5
9
2
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Rh Antigens
• Non-glycosylated proteins in the red cell
membrane.
• Inherited as codominant alleles.
• Are transmembrane polypeptides and are an
integral part of the red cell membrane.
• All Rh antigens (D,C,E) are very similar; differ
by only 44 base pair.
• C and c differ in 4 a.a.
• E and e differ in 1 a.a.
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Rh Antigens
Hillyer et al 2009
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Rh Antigens (continued)
• Rh antigens are highly immunogenic:
D>c>E>C>e
• The D antigen is the most immunogenic
antigen outside the ABO system.
• As little as 0.5 ml will elicit anti-D alloimmunization in healthy volunteers
(Gunson et al 1970).
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Rh Antibodies
•
•
•
•
Do not bind complement
Extravascular
IgG
Can cross placenta and cause
HDFN
• HTR
• Exposure required (pregnancy or
transfusion)
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Consequences of Rh
Incompatibility
• Unexposed: 80% of healthy D negative
individuals make anti-D with one unit
transfused. Approximately 22% of
hospitalized (non-oncology) patients
(Yazer et al 2007).
• Exposed: HTRs with extravascular
hemolysis
• Most severe HDFN
25
Prevention of D Immunization:
RhIgG
• Macro dose (300 g): protect against 30
mL of WB or 15 mL of packed RBCs
• Micro dose (50 g): protect against 5 mL
of WB; sufficient for abortion,
amniocentesis, and ectopic rupture at up
to 12 weeks gestation
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Unusual Rh Phenotypes
• Weak D phenotype Du
• Rhnull phenotype
• Compound Rh antigens
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Weak D phenotype (Du)
• Some D positive individuals require AHG
phase to demonstrate D antigen
• Reasons:
– C opposite chromosome to D (C in trans
position): eg, Dce/dCe
– Genetic weak D (weakened D
expression)
– Partial D (“Mosaic”)
• (most prone to making anti-D)
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Determination of D Status
• Donors: D neg donors must be confirmed
by AHG test
• Recipients: D neg recipients do not need
to be confirmed by AHG (though most are)
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Rh antigen typing reagents
•
•
•
•
•
Saline anti-D (IgM, can’t be used for Du)
High protein anti-D (requiring Rh control)
Chemically modified anti-D (low protein)
Monoclonal anti-D
Blend of Monoclonals (anti-IgM and antiIgG anti-D)
31
Rhnull Phenotype
• Lacks all Rh antigens
• Rhnull syndrome demonstrates a mild
compensated hemolytic anemia with
stomatocytosis, spherocytosis and
reticulocytosis
• Transfuse with Rhnull blood
• The clinical symptoms of Rhmod
phenotype are less severe and rarely
clinically remarkable.
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Compound Rh Antigens
• f = antigen present when c and e are on
the same chromosome
• G: G is present on most D pos and all C
pos RBCs. Anti-G originally appeared to
be anti-D+C; further investigation showed
that anti-G was directed toward D+G.
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The LW System
• LW antigens
• Anti- LW
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LW Antigens (normal
pathway)
Precursor substance
DCE genes
normal Rh antigens
LWa LWb genes
LW pos
 LW genes
LW neg
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Anti- LW:
– Reacts strongly with most D pos rbcs.
– Reacts weakly with D neg rbcs.
– No reaction with Rhnull rbcs.
– Reacts equally well with cord cells regardless
of D typing.
– Rarely clinically significant.
36
Objectives
• Explain the derivation of the term Rh
• Differentiate Rh from LW
• Compare and convert the major genotypes
among Fisher-Race, Wiener, and
Rosenfield terminologies
• Define the basic biochemical structure of
Rh
37
Objectives (Continued)
• Describe and differentiate three
mechanisms that result in weak D
expression on rbcs
• Describe 3 characteristics of Rh antibodies
• Describe how to prevent Rh D
immunization
38
39
THANKS TO
• Rosemary Howard, CLS
• Dr Chris Gresens
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References
• Transfusion Medicine and Hemostasis, Hillyer et al,
2009, Elsevier Pub.
• Yazer et al, (2007), Detection of anti-D in D- recipients
transfused with D + red cells, Transfusion 47 21972201
• Avent ND, Reid (2000) The Rh blood group system: a
review Blood 95 375-387.
• Gunson et al (1970) The Anti-Rh0(D) Responses of
Immunized Volunteers following Repeated
Antigenic Stimuli, BJH
41