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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. 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

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  1. 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

  2. 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

  3. 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.

  4. Where are they? • 54 in United States • Louisiana • LifeShare Blood Centers • Medical Center of Louisiana University Hospital • The Blood Center

  5. 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)

  6. Table of blood group systems ISBT Human Blood Group Systems

  7. From www.bloodindex.com

  8. 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

  9. 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

  10. 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--)

  11. 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

  12. 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

  13. Other Rh Variants: e • hrs/Hr • hrb/HrB

  14. 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

  15. 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.

  16. 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

  17. 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

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

  19. 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.

  20. Duffy System • Chromosome 1 • 5 antigens: Fya, Fyb, Fy3, Fy5, Fy6 (Fy4 is now obsolete) • Located on Duffy glycoprotein (DARC)

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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)

  26. 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?)

  27. 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)

  28. 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)

  29. 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

  30. 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.

  31. 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.

  32. 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)

  33. 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

  34. 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)

  35. 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

  36. 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)

  37. 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!

  38. 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

  39. Lewis System • Chromosome 19 • 6 Antigens • Lea, Leb • Leab, LebH, ALeb, BLeb

  40. 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

  41. Dombrock System • Chromosome 12 • 7 antigens • Doa, Dob • Gya • Hy • Joa • DOYA • DOMR • Antigens located on GPI-linked glycoprotein. Function unknown

  42. 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

  43. 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

  44. Dombrock, cont. • Enzymes: • Resistant to ficin, papain • Sensitive to trypsin, DTT • Antibodies: • IgG: Clinically significant • Can cause HTR’s (but not HDFN)

  45. Cromer System • Chromosome 1 • 16 Antigens, including: • Cra • Tca, Tcb, Tcc • Dra • Wesa, Wesb • Located on DAF (CD55), a complement regulatory glycoprotein

  46. 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

  47. 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

  48. 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

  49. Lutheran, cont. • Lutheran null phenotypes • Homozygous recessive for LU gene • Dominant suppressor gene, In(Lu) - Also suppresses P1, AnWj • X-linked suppressor gene, XS2

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