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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


Objectives

Objectives

  • 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)


A closer look at the blood group systems an irl

Table of blood group systems

ISBT Human Blood Group Systems


A closer look at the blood group systems an irl

From www.bloodindex.com


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


Other rh variants e

Other Rh Variants: e

  • hrs/Hr

  • hrb/HrB


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


A closer look at the blood group systems an irl

RhAG

  • 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


A closer look at the blood group systems an irl

http://www.pnas.org/content/105/23/8026/F6.expansion.html


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 ways1. 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

Kell

XK (Kx)


Kell cont

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


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

Kell

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!


    Phentoypes

    Phentoypes

    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

    • Doa67%

    • Dob82%

    • Gya, Hy, JoaHighs


    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, 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 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:

      • Coahigh incidence

      • Coblow incidence (8-10% in whites)

      • Co3high incidence

      • Co4high 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


  • A closer look at the blood group systems an irl

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


    Gerbich cont

    Gerbich, cont.

    • 3 rare “Gerbich negative” phenotypes:

      • Ge:-2,3,4Yus

      • Ge:-2,-3,4Gerbich

      • Ge:-2,-3,-4Leach (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

      • Ytahigh incidence

      • Ytblow 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


    References

    References

    • 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.


    References1

    References

    • 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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