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A Closer Look at the Blood Group Systems: An IRL’s Point of View. Jennifer Haywood, MLS(ASCP)SBB Regional Transfusion Services Coordinator Omega Diagnostics, LLC Shreveport, LA. Objectives. List and describe antigens of the major blood group systems

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A Closer Look at the Blood Group Systems:An IRL’s Point of View

Jennifer Haywood, MLS(ASCP)SBB

Regional Transfusion Services Coordinator

Omega Diagnostics, LLC

Shreveport, LA


  • List and describe antigens of the major blood group systems

  • Identify recent changes in P, Fy, Jk, Do, and RhAG systems

  • Identify the clinical significance of blood group antibodies

What is an IRL?

Immunohematology Reference Laboratories:

highly specialized laboratory that provides an essential service to patients who have specific serologic complexities and/or need rare blood components.

provide an exchange of information and consultation on rare blood group antibodies, component preparation and therapy, blood compatibility testing and research.

Where are they?

  • 54 in United States

  • Louisiana

    • LifeShare Blood Centers

    • Medical Center of Louisiana University Hospital

    • The Blood Center

Blood Group Systems

  • Named by International Society for Blood Transfusion (ISBT), Committee on Terminology for Red Cell Surface Antigens

  • All antigens fall into one of four classifications:

    1. systems

    2. collections

    3. low incidence antigens (700 series)

    4. high incidence antigens (901 series)

Table of blood group systems

ISBT Human Blood Group Systems

From www.bloodindex.com

Rh System

  • Chromosome 1

  • 2 genes: RHD and RHCE

  • Highly homologous (93.8%)

  • Genes located on short arm of chromosome 1

  • Head-to-Head configuration

Rh System

  • RHD gene: presence or absence of D antigen

  • RHCE gene: RHCe, RHcE, RHce, RHCE polypeptides

  • Each antigen is a mosaic of epitopes

  • Exchanges between RHD and RHCE cause variants

RhD Variants

  • Weakened D expression:

    • genetic weak D, C Trans, Partial D, Del

  • Enhanced D expression:

    • Some variants (DIIIC, DIVa)

    • Cells lacking RhCE proteins (D--)

RhD Negative

  • Whites:

    • most completely lack the RHD gene

    • Rare: some have the RHD gene, but have a mutation that causes a stop codon, therefore no expression

  • Blacks:

    • No RHD gene

    • Inactive gene due to a stop codon

    • RHD-CE-D hybrid

Rh Variants

  • Most common: r’s (C)ces

    • Codes for a C hybrid and a variant e.

    • (C) means weakened expression

    • Negative for Hrb

    • These individuals can make what appears to be Anti-C and Anti-e even though they are positive for these antigens.

    • Found in blacks that are VS+, V-

    • Hybrid gene: D-CE-D (Rh negative because the RHD gene is interrupted

Other Rh Variants: e

  • hrs/Hr

  • hrb/HrB

RhDeficiency Syndrome

  • Rhnull

    • Missing all Rhantigens

    • Fragile red cells, chronic anemia

    • Very rare, about 14 families

  • Rhmod

    • Partial suppression of Rh expression

    • Clinical symptoms less severe than Rhnull

Other antigens

  • Cw

    • Found in 2% of whites, rarely in blacks

    • Most Cw+ cells are C+, rarely C=

  • f

    • present when c and e are on the same haplotype (cis position)

    • If patient has antibody, give units negative for c or e

  • rhi

    • Present when C and e are in cis position

    • If patient has antibody, give units negative for C or e

  • G

    • Present on cells that have D and/or C antigens. Reacts as though it were a combination of anti-C plus anti-D

    • Antibody can be identified by adsorption/elution methods or by testing patient’s plasma with rG cell.

Rh Antibodies

  • Enhanced by enzymes

  • Mostly IgG / do not activate complement

  • Usually persist for many years

  • Anti-D, -c can cause severe HDFN

  • Anti-C, -E, -e cause mild or no HDFN

  • Auto antibodies can be Rh specific, mimicking alloantibodies


  • Chromosome 1

  • Rh-associated glycoprotein

  • Protein is part of a membrane channel.

  • Interacts with Rh antigens. Influences insertion of the Rh proteins into the red cell membrane

  • Antigens:

    • Duclos and Duclos-likeHigh incidence

    • OlaLow incidence


RhAG and Rh

  • Rhnull

    • Phenotype most often results from ‘regulator’ mutations in RhAG

  • Rhmod

    • One Japanese donor who is Rhmod was found to have the low Ola (also from mutation of RhAG)

  • RhAG relationship to Rh: Plays a critical role in trafficking RhCE and RhD proteins to the membrane.

Duffy System

  • Chromosome 1

  • 5 antigens: Fya, Fyb, Fy3, Fy5, Fy6

    (Fy4 is now obsolete)

  • Located on Duffy glycoprotein (DARC)

Duffy, cont.

  • Whites and Asians:

    • 2 antigens: Fya, Fyb

    • 3 phenotypes: Fy(a+b-), Fy(a+b+), Fy(a-b+)

  • Blacks

    • A third allele also exists: Fy

    • Codes for no Duffy glycoproteins on red cells

    • If homozygous for Fy, person will be Fy(a-b-)

    • Fyx: another allele that codes for a weak Fyb expression

GATA-1 and Duffy

  • A mutation of GATA can also cause a person to be Fy(a-b-)

  • This mutation, found in blacks, is on the same coding region as Fyb, therefore, no Fyb expression on red cells, but is expressed in other tissues

  • Person will not make anti-Fyb and rarely makes anti-Fy3/5

Other Fy Antigens

  • If a person has Fya and/or Fyb, they will also have Fy3/5

  • Remember GATA… Fyb is on tissues, so Fy3/5 is present

  • Resistant to enzymes!

  • Fy5 is also missing from Rhnull cells

Duffy Antibodies

  • IgG

  • Anti-Fya is 20 times more common than anti-Fyb… you know why!

  • Both cause delayed and acute HTR

  • Anti-Fy3 has been implicated in delayed and acute HTR, but anti-Fy5 only in delayed HTR

Kidd System

  • Chromosome 18

  • 3 Antigens: Jka, Jkb, Jk3

  • Null phenotype – Jk(a-b-), Jk:-3

    • Two ways1. homozygous for silent gene at

      JK locus (found in polynesians)

      2. dominant inhibitor gene In(Jk)

      (found in Japanese)

New Jk phenotype?

  • A study published in Immunohematology in Feb 2011 by Wester, Storry, and Olsson

    “Characterization of Jk(a+weak): a new blood group phenotype associated with an altered JK*01 allele”

    • 3 nucleotide changes

    • Weakened expression of Jka antigen on red cells

    • Routine serology could miss this weak expression (risk for HTR?)

Kidd Antibodies

  • Often found with other antibodies

  • Usually IgG1 or IgG3, can bind complement (can cause severe acute HTR)

  • Antibodies can be hard to detect and can cause delayed HTR (antibodies deteriorate quickly)

  • Kidd antigens are resistant to enzymes (useful for detecting weak antibodies)

Kell System

  • Chromosome 7

  • 32 Antigens

    • 5 pairs:

      • K/k

      • Jsa/Jsb

      • K11/K17

      • K14/K24

      • VLAN/VONG

    • 1 triplet: Kpa, Kpb, Kpc


XK (Kx)

Kell, cont.

  • Klow incidence, found in whites

  • khigh incidence

  • Jsalow incidence, found in blacks

  • Jsb high incidence

  • Kpalow incidence, found in whites

  • Kpbhigh incidence

  • Kpclow incidence, found in Japanese

  • K does not occur with Kpa – if RBCs are K+,Kpa+, they are in trans position

  • Kpa can suppress other Kell antigens

Ko and Kmod

  • Ko phenotype expresses no Kell antigens

  • Homozygous for an amorph gene

  • Antibody produced is called anti-Ku

  • Kmod phenotype has very weak expression of Kell antigens (may have to adsorb and elute to see). Antibody produced is like anti-Ku, except also will not react with other Kmod cells.

Kell Antibodies

  • Usually IgG1

  • Detected at IAT, but may occur at RT and 37o incubations

  • Anti-K most common alloantibody other than Rh

  • Kell antigens are destroyed by DTT, AET, and EGA (makes Ko cells), but they are resistant to enzymes.

XK System

  • On X chromosome

  • One antigen: Kx

  • Shares a disulphide bond with Kell protein

  • Kx antigen is enhanced:

    • Ko cells

    • Kmod cells

    • Kp(a+b-) cells


XK (Kx)

XK, cont.

  • McLeod phenotype

    • Red cells that lack Kx.

    • Causes suppression of all Kell antigens

    • McLeod Syndrome - X-linked condition assoc. with acanthocytosis and late-onset muscular, neurologic, and psychiatric symptoms

MNS System

  • Chromosome 4

  • 46 Antigens! Lots of recombination between closely linked genes.

  • Glycophorin A: M, N antigens

    • Much more GPA on red cell than GPB

    • GPA assoc. with protein band 3, which affects expression of Wrb (of the Diego System)

  • Glycophorin B: S, s, U, antigens (and ‘N’)

    • GPB appears to be assoc. with Rh protein and RHAG (Rhnull RBC’s have greatly reduced S, s expression)

  • MNS, cont.

    • U neg found in blacks (2%)

      • U neg because of a partial or full deletion of GPB.

      • U variants: some examples of anti-U react with apparent U neg cells. Assorption/elution techniques can prove U antigen presence.

      • Approx. 16% of S-s- are weakly U+

  • What about patients with anti-U and anti-N?

  • Enzymes:

    • M, N, S, s, He, ‘N’ are destroyed(S and s can be variable)

    • U is resistant

  • MNS Antibodies

    • Exhibit dosage

    • Anti-M: IgM, common, naturally occurring

    • Anti-N: IgM, rare due to ‘N’ found on GPB.

    • Anti-S, -s, -U: IgG, can cause HTR and HDFN

    • Anti-Ena: antibodies to regions of GPA. Made by rare individuals who lack all or part of GPA. (Can cause severe HTR and HDFN)

    P1Pk System (formerly P System)

    • Chromosome 22

    • 2 Antigens!

      • P1 and Pk

    • Globoside System: P is the only antigen

    • Globoside Collection: PX2 and LKE antigens

    • More changes to come based on molecular technology!


    P1 and P2 phenotypes account for >99% of population. Both synthesize Pk and P antigens.

    3 rare phenoypes:

    1. p

    2. P1k

    3. P2k

    Lewis System

    • Chromosome 19

    • 6 Antigens

      • Lea, Leb

      • Leab, LebH, ALeb, BLeb

    Lewis, cont.

    • Can a person be Le(a+b+)?

      • Infants

      • Japanese (16%)

  • Antibodies

    • IgM, naturally occurring

    • Seen in pregnant women

    • Rarely seen at AHG phase

  • Dombrock System

    • Chromosome 12

    • 7 antigens

      • Doa, Dob

      • Gya

      • Hy

      • Joa

      • DOYA

      • DOMR

    • Antigens located on GPI-linked glycoprotein. Function unknown

    Dombrock, cont.

    • Gya is the null of the Dombrock system (found in Eastern Europeans & Japanese)

    • Hy and Joa neg found in blacks

    • Doa67%

    • Dob82%

    • Gya, Hy, JoaHighs

    6th Dombrock Antigen

    • DOYA

      • Study published in Transfusion, Volume 50, Issue 6 (June 2010) by Mayer, et al.

      • A patient’s DO genes have a single nucleotide change. DOYA (possible high incidence antigen) not present.

      • Causes no expression of Doa and weakened expression of Hy, Joa, and Gya antigens

    Dombrock, cont.

    • Enzymes:

      • Resistant to ficin, papain

      • Sensitive to trypsin, DTT

  • Antibodies:

    • IgG: Clinically significant

    • Can cause HTR’s (but not HDFN)

  • Cromer System

    • Chromosome 1

    • 16 Antigens, including:

      • Cra

      • Tca, Tcb, Tcc

      • Dra

      • Wesa, Wesb

    • Located on DAF (CD55), a complement regulatory glycoprotein

    Cromer, cont.

    • Cra, Dra, Tca, Wesbhigh incidence

    • Tcb, Tcc, Wesalow incidence

    • Inab phenotype

      • Null of Cromer System. People with Inab phenotype can make Anti-IFC, a mixture of antibodies that reacts with all cells except other Inab cells.

  • Dra neg cells have weak expression of all other Cromer antigens because of a qualitative difference in DAF

  • Cromer, cont.

    • Enzymes:

      • Resistant to: ficin, papain, trypsin

      • Weakened with DTT

    • Antibodies:

      • Mostly IgG, some IgM

      • Not usually considered clinically significant

      • No evidence of HTR or HDFN

    Lutheran System

    • Chromosome 19

    • 20 antigens, including:

      • Lua, Lub

      • Lu6, Lu9

      • Lu8, Lu14

      • Aua, Aub

  • Antigen strength is variable

  • Located on Lu glycoproteins, which belong to the immunoglobulin superfamily. Lu glycoprotein binds to laminin

  • Lutheran, cont.

    • Lutheran null phenotypes

      • Homozygous recessive for LU gene

      • Dominant suppressor gene, In(Lu)

        - Also suppresses P1, AnWj

      • X-linked suppressor gene, XS2

    Lutheran, cont.

    • Enzymes:

      • Resistant to: ficin, papain

      • Sensitive to trypsin

      • Weakened by DTT

  • Antibodies:

    • Usually IgM, but also IgG and IgA

    • Can be naturally occurring

    • Can cause mild delayed HTR, no HDFN

  • Colton System

    • Chromosome 7

    • 4 Antigens:

      • Coahigh incidence

      • Coblow incidence (8-10% in whites)

      • Co3high incidence

      • Co4high incidence

  • Located on aquaporin-1, a water channel forming protein

  • Colton, cont.

    • Extremely rare Colton null phenotype

    • Enzymes: Resistant to all

    • Antibodies:

      • IgG (and rarely IgM)

      • Causes HTR and mild to severe HDFN

    Gerbich System

    • Chromosome 2

    • 11 Antigens

      • 3 highs: Ge:2, Ge:3, Ge:4, Ge:10, Ge:11, Ge:12

      • 5 lows: Wb, Lsa, Ana, Dha, GEIS

  • Located on glycophorins C and D

  • www.bloodsystemslaboratories.org/images/bbt-5.jpg

    Gerbich, cont.

    • 3 rare “Gerbich negative” phenotypes:

      • Ge:-2,3,4Yus

      • Ge:-2,-3,4Gerbich

      • Ge:-2,-3,-4Leach (Ge null phenotype)

    Gerbich, cont.

    • Enzymes:

      • Ge3

        • Resistant to: ficin, papain

        • Sensitive to trypsin, DTT

      • Ge2, Ge4

        • Resisitant to DTT

        • Sensitive to ficin, papain, trypsin

    Gerbich, cont.

    • Antibodies:

      • Mostly IgG, but can be IgM

      • Can be naturally occurring (autoantibodies have also been reported)

      • Have not caused HTRs, but Anti-Ge3 has caused HDFN

    Cartwright System

    • Chromosome 7

    • 2 Antigens

      • Ytahigh incidence

      • Ytblow incidence (8%)

  • There is no Yt null phentoype

  • Cartwright, cont.

    • Enzymes:

      • Resistant to trypsin

      • Sensitive to DTT

      • Variable with ficin, papain

  • Antibodies:

    • IgG

    • Have been implicated in acute and delayed HTRs

    • No HDFN

  • Vel Antigen

    • Antigen strength is variable

    • Vel neg found in 1:4000 whites

    • Enzymes: Resistant to all

    • Anti-Vel:

      • IgM

      • Causes severe, immediate HTR (fixes complement)

      • No HDFN

      • Rare autoantibody

    Ata Antigen

    • High incidence. Ata neg found only in blacks

    • Enzymes: Resistant to all

    • Anti-Ata

      • Mostly IgG

      • Has caused mild delayed HTR and mild HDFN


    • Scott ML. The complexities of the Rh System. Vox Sang 2004;87(Suppl. 1):58-62.

    • Wester ES, Storry JR, Olsson ML. Characterization of Jk(a+weak): a new blood group phenotype with an altered JK*01 allele. Transfusion 2011;51:380-392.

    • Daniels G, Reid ME. Blood groups: the past 50 years. Transfusion 2010;50:281-289.

    • Roback JD, et al. Technical Manual. 16th ed. Bethesda, MD: AABB, 2008.

    • Harmening DM. Modern Blood Banking and Transfusion Practices. 5th ed. Philadelphia, PA: F. A. Davis Co., 2005.

    • Daniels G. Human Blood Groups. 2nd ed. Cambridge, MA: Blackwell Science, 2002.

    • Tilley L, et al. A new blood group system, RHAG: three antigens resulting from amino acid substitutions in the Rh-associated glycoprotein. Vox Sang 2010;98(2):151-9.


    • Reid ME, Lomas-Francis C. Blood Group Antigens and Antibodies. New York: SBB Books, 2007.

    • Storry JR, Castilho L, et al. International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Berlin Report. Vox Sang 2011.

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