The Rh Blood Group

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The Rh Blood Group

• Brian Poirier, MD
• UCDavis Medical Center

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Topics

• Terminology systems
• Rh antibodies
• Consequences of Rh incompatibility
• Unusual phenotypes

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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

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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

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Rh Blood Group

• Second most important blood group (after ABO)

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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 husbands blood (ABO
  compatible), she demonstrated the acute HTR.
• An antibody was isolated from moms serum that
  reacted both at 37 C and 20 C with fathers rbcs.

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History of the Rh System (continued)
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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 human-produced
  antibody.

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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
• RhoD
• rhC
• rhE
• hrc
• hre

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Wiener (Rh-Hr) (continued)

• Gave shorthand names to the 8 potential
  combinations alluded to above still in use
• R1DCe rdCe
• R2DcE rdcE
• RoDce rdce
• RzDCE rydCE

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Converting Wiener (Rh-Hr) to Fisher-Race

• Fisher-Race terminology is easier to use
• RD, rd
• 1 or primeC
• 2 or double primeE
• 0 or blankce
• 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.
• R1gt R2
• r is always second in frequency
• Whites R1 gt r gt R2 gt R0
• Blacks R0 gt r gt R1 gt R2

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Gene Frequency of Rh Antigens

• Gene Frequency
• D 85
• d 15
• C 70
• E 30
• c 80
• e 98

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Common Rh Types by 3 Nomenclatures

• Wiener Fisher-Race Rosenfield
• R1r DCe/dce Rh 1,2,-3, 4,5 33
• R1R1 DCe/DCe Rh 1,2,-3, -4,5 18
• rr dce/dce Rh -1,-2,-3, 4,5 15
• R1R2 DCe/DcE Rh 1,2,3, 4,5 11
• R2r DcE/dce Rh 1,-2,3, 4,5 9
• R2R2 DcE/DcE Rh 1,-2,3, 4,-5 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 gt c gt E gt C gt e
• The D antigen is the most immunogenic antigen
  outside the ABO system.
• As little as 0.5 ml will elicit anti-D
  allo-immunization 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

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Prevention of D ImmunizationRhIgG

• 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, cant 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 anti-IgG
  anti-D)

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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-DC
  further investigation showed that anti-G was
  directed toward DG.

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The LW System

• LW antigens
• Anti- LW

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LW Antigens (normal pathway)

• Precursor substance
• ÜDCE genes
• normal Rh antigens
• LWa LWb genesß à LW genes
• LW pos 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.

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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

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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

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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 2197-2201
• 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