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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
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? 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
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
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-like High incidence • Ola Low 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 ways 1. 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 Kell XK (Kx)
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
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 Kell 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!
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 • 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 • Doa 67% • Dob 82% • Gya, Hy, Joa Highs
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, 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, 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