Rh Blood Group System Notes

History

• 1940: Levine & Stetson linked Rh to HDFN.

• Landsteiner & Wiener discovered "anti-Rh" agglutinating 85% RBCs, 15% didn't.

• Human anti-Rh was similar to guinea pig/rabbit antibodies from Rhesus monkey RBCs; later found different, but "Rh" name remained.

  • Guinea pig/rabbit antibody targeted LW antigen.

Genetics and Biochemistry

• Current theory: 2 linked genes control Rh antigens (codominant).

  • RHD gene: expresses D antigen.

  • RHCE gene: expresses C, c, E, e antigens.

• Other theories by:

  • Fisher-Race: 3 linked loci (D/d, C/c, E/e) control Rh antigens.

  • Wiener: Rh antigens controlled by alleles at one gene locus.

Common Rh Antigens

Fisher-Race Terminology

• Each gene expresses an antigen with the same letter (e.g., C gene → C antigen).

• Absence of D antigen: “d”.

• Gene order: usually DCE, sometimes CDE.

Wiener Terminology

• Wiener: 8 alleles at one Rh gene locus: R0, R1, R2 , Rz, r, r′, r″, ry

• Each gene encodes an agglutinogen (factors) correlating with Rh antigens. Example 1: R1 → Rh1(Rh0, rh′ , hr″) → D, C, e

  • Note: Long hand notation is outdated and rarely used.

• Wiener to Fisher-Race:

  • R  D

  • r  no D

  • 1 and ′ C

  • 2 and ″ E

  • 0  ce

  • Z or y  CE

  • Example: R2 → DcE

Rosenfield Terminology

• Suited for computerized data entry.

• Antigens designated by number:

  • Rh1:D

  • Rh2:C

  • Rh3:E

  • Rh4:c

  • Rh5:e

• Example: D+, C+, E–, c+, e+ = Rh:1,2,–3,4,5

ISBT Terminology

• International Society of Blood Transfusion.

• Standardizes nomenclature.

• Six-digit numbers for each blood group specificity.

• 004 = Rh system.

• The other numbers refer to the Rosenfield system (e.g., C antigen is RH2).

• Example: C antigen ISBT number = 004002.

Genotype

• Phenotype: result of RBCs reacting with antisera.

• Genotype: genetic makeup, predicted by phenotype and race.

• True genotype: family studies or molecular testing.

• Common genotypes:

  • Caucasians: R1, r, R2, R0

  • Blacks: R0, r, R1, R2

  • r′, r″ , Rz , and ry are rarely encountered.

Rh Genotypes and Phenotypes

D Antigen

• Most immunogenic in Rh system.

• D-negative individuals get D-negative blood.

• D-negative individuals may produce anti-D if given D-positive blood.

Weak D Antigens

• RBCs test positive only by IAT.

• Newer monoclonal reagents enhance detection without IAT.

Genetics of Weak D Antigens

• More common in black population.

• Weaker form of D, often cDe haplotype.

• IAT usually needed.

• Patients are weak D positive, can receive D-positive blood.

Position Effect of Weak D Antigens

• D antigen appears weak when C antigen is trans to D.

• Ce (r′) gene paired with Cde (R1) or cDe (R0).

• Patients are weak D positive, can receive D-positive blood.

Weak D: Partial D Antigens

• Individuals D positive but missing parts of D antigen.

• Exposed to “whole D antigen,” may produce anti-D to missing part.

• Partial D antigen reacts strongly with monoclonal reagents.

• Suspect partial D when D-positive makes anti-D not reactive with own RBCs.

Significance

• AABB requires donor cells be tested for weak D if initially nonreactive.

• Recipient samples don't need weak D testing; classified as D-negative, transfused with D-negative blood.

Compound Antigens

• Also called cis-product antigens.

• Two genes on same chromosome may form additional antigen products.

• Example: c and e antigens cause “f” to be inherited.

G Antigens

• Almost all genes coding for C or D code for G antigen.

• Anti-G antibody mimics anti-D and anti-C antibodies.

• If negative for D/C and receive D-positive/C-positive blood, may produce anti-G (appears as anti-D or anti-C).

• If anti-G present, give D-negative and C-negative blood.

Unusual Phenotypes

• D-deletion:

  • -D- or D--

  • No reactions with anti- E, anti-e, anti-C, or anti-c

  • Stronger D antigen activity

  • Transfuse only D- deleted cells

• Rhnull:

  • No Rh antigens

  • Two possible genetic mechanisms

    • Regulator gene: RHAG

    • Amorph (r=)

• Rhmod:

  • Similar to Rhnull

  • Most Rh antigen expression is missing; the RHAG gene also controls this phenotype

Rh Antibody Facts

• Usually RBC stimulated

• Most are IgG1

• Agglutination best observed by IAT

• Potentiators useful for identification

• Antibodies to C, c, E, e react stronger to homozygous antigens (dosage)

• Do not activate complement

• E-negative and c-negative blood sometimes given when anti-E is identified (weak anti-c often seen with anti-E).

Clinical Considerations

• Transfusion reactions

  • Rh antibody levels may be undetectable for years but produce a rapid response upon exposure to the antigen

  • Antigen-negative RBCs should be transfused if Rh antibodies are identified

• Hemolytic disease of the fetus and newborn

  • HDFN may occur when a woman is Rh negative and the fetus/infant is Rh positive

  • Antibodies may form during the first pregnancy

  • Maternal antibody may destroy fetal RBCs in subsequent pregnancies

  • Rh immune globulin will protect the mother from forming anti-D antibody

LW Blood Group System

• LW antigens/antibodies similar to Rh but not genetically related.

• Anti-LW antibody reacts with D-positive (strong) and D-negative (weak) cells.

• Alleles: Lwa , LWb , and LW

• Most common phenotype: LW