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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

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
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
Where are they?
  • 54 in United States
  • Louisiana
    • LifeShare Blood Centers
    • Medical Center of Louisiana University Hospital
    • The Blood Center
blood group systems
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

rh system
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 system1
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
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
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
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
rh deficiency syndrome
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
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
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-like High incidence
      • Ola Low incidence
rhag and rh
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
Duffy System
  • Chromosome 1
  • 5 antigens: Fya, Fyb, Fy3, Fy5, Fy6

(Fy4 is now obsolete)

  • Located on Duffy glycoprotein (DARC)
duffy cont
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
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
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
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
Kidd System
  • Chromosome 18
  • 3 Antigens: Jka, Jkb, Jk3
  • Null phenotype – Jk(a-b-), Jk:-3
    • Two ways 1. homozygous for silent gene at

JK locus (found in polynesians)

2. dominant inhibitor gene In(Jk)

(found in Japanese)

new jk phenotype
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
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
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
Kell, cont.
  • K low incidence, found in whites
  • k high incidence
  • Jsa low incidence, found in blacks
  • Jsb high incidence
  • Kpa low incidence, found in whites
  • Kpb high incidence
  • Kpc low 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
k o and k mod
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
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
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
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
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
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
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
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
Lewis System
  • Chromosome 19
  • 6 Antigens
    • Lea, Leb
    • Leab, LebH, ALeb, BLeb
lewis cont
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
Dombrock System
  • Chromosome 12
  • 7 antigens
    • Doa, Dob
    • Gya
    • Hy
    • Joa
    • DOYA
    • DOMR
  • Antigens located on GPI-linked glycoprotein. Function unknown
dombrock cont
Dombrock, cont.
  • Gya is the null of the Dombrock system (found in Eastern Europeans & Japanese)
  • Hy and Joa neg found in blacks
  • Doa 67%
  • Dob 82%
  • Gya, Hy, Joa Highs
6 th dombrock antigen
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 cont1
Dombrock, cont.
  • Enzymes:
      • Resistant to ficin, papain
      • Sensitive to trypsin, DTT
  • Antibodies:
      • IgG: Clinically significant
      • Can cause HTR’s (but not HDFN)
cromer system
Cromer System
  • Chromosome 1
  • 16 Antigens, including:
    • Cra
    • Tca, Tcb, Tcc
    • Dra
    • Wesa, Wesb
  • Located on DAF (CD55), a complement regulatory glycoprotein
cromer cont
Cromer, cont.
  • Cra, Dra, Tca, Wesb high incidence
  • Tcb, Tcc, Wesa low 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 cont1
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
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, cont.
  • Lutheran null phenotypes
    • Homozygous recessive for LU gene
    • Dominant suppressor gene, In(Lu)

- Also suppresses P1, AnWj

    • X-linked suppressor gene, XS2
lutheran cont1
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
Colton System
  • Chromosome 7
  • 4 Antigens:
      • Coa high incidence
      • Cob low incidence (8-10% in whites)
      • Co3 high incidence
      • Co4 high incidence
  • Located on aquaporin-1, a water channel forming protein
colton cont
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
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
gerbich cont
Gerbich, cont.
  • 3 rare “Gerbich negative” phenotypes:
    • Ge:-2,3,4 Yus
    • Ge:-2,-3,4 Gerbich
    • Ge:-2,-3,-4 Leach (Ge null phenotype)
gerbich cont1
Gerbich, cont.
  • Enzymes:
      • Ge3
        • Resistant to: ficin, papain
        • Sensitive to trypsin, DTT
      • Ge2, Ge4
        • Resisitant to DTT
        • Sensitive to ficin, papain, trypsin
gerbich cont2
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
Cartwright System
  • Chromosome 7
  • 2 Antigens
      • Yta high incidence
      • Ytb low incidence (8%)
  • There is no Yt null phentoype
cartwright cont
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
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
at a antigen
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.