Kell, Duffy, Kidd and Lutheran Blood Groups

General Reminders

• Antigens in blood group systems are designated with letters (usually A and B).
• When writing phenotypes or antigens, include the corresponding blood group system symbol to differentiate from the ABO blood group system.
• Example: Duffy A antigen is written as Fya and the corresponding phenotype is Fy(a+b-).

Common Blood Groups

• Includes Kell, Duffy, Kidd, and Lutheran blood groups.
• Antibodies are usually IgG, can cross the placenta, and may cause hemolytic disease (HDFN and HTR).

Kell System 006 (KEL) & Kx Systems 019 (XK)

• Named after Mrs. Kelleher (1946), who had anti-Kell antibodies causing hemolytic disease in her newborn.
• Similar to Rh, featuring both high and low-incidence antigens.
• High prevalence antigens are common in the population, while low incidence antigens are less common.
• KEL gene is located on Chromosome 7.

Major Kell Antigens

• K (Kell) has prevalence <9% (low incidence).
• k (cellano) has prevalence >90% (high prevalence).
• Antigens are only found on RBCs and are abundant in the testes.

Kell Antigen Development

• Antigens are well-developed at birth.
  • K is present at 9% at 10 weeks of gestation.
  • k is present at 99.8% at 7 weeks of gestation.
• The K antigen is highly immunogenic, second only to the D antigen, and can cause severe hemolytic disease.
• Glycoproteins have disulfide-bonded regions linked with the XK protein.

Kell Antigen Sensitivity

• Sensitive to sulfhydryl reagents, which easily break disulfide bonds:
  • 2-mercaptoethanol (2-ME)
  • Dithiothreitol (DTT)
  • 2-aminoethylisothiouronium bromide (AET)
  • ZZAP (DTT + enzyme)

Kellnull and K0

• Does not express all Kell antigens, except Kx.
• Kx antigen is embedded in the cell membrane and is the only exposed antigen when Kell antigens are absent, with no RBC abnormality.
• Anti-Ku (KEL5) recognizes universal Kell antigens (Ku) present on all RBCs, except Kellnull and can cause HDFN and HTR.
• Rare Kell negative units should be given to Kellnull individuals.

Other Kell Antigens

Kp Antigens

• Kpa is a low frequency antigen (2%), also known as Penney, with antibody Anti-Kpb.
• Kpb is a high frequency antigen (99.9%), also known as Rautenberg, with antibody Anti-Kpa.

Js Antigens

• Jsa is present in 20% of blacks and 0.1% in whites, also known as Sutter, with antibody Anti-Jsb.
• Jsb is highly frequent in blacks (80-100%), also known as Matthews, with antibody Anti-Jsa.

Kell Antibodies

Anti-K

• Produced by individuals with the small "k" antigen (Kell(K-k+)).
  • IgG, reacts well at AHG phase, and can cross the placenta.
• Antibody is immune-mediated from transfusion or pregnancy and clinically significant as may cause HDFN and severe HTR.
• Most common antibody due to the immunogenicity of the K antigen and the high prevalence of the small "k" antigen.

Differentiating Anti-K vs Anti-D

• Anti-K destroys erythroid precursor cells of the fetus, while Anti-D does not harm erythroid precursor cells.

• Anti-K causes suppression of erythropoiesis, reticulocytopenia, and anemia.

• Anti-D causes hemolysis, reticulocytosis, hyperbilirubinemia, and anemia.

• k, Kpb, and Jsb antibodies are rare due to the high prevalence of these antigens.

Kpa and Jsa

• Low prevalence antigens, are also rare.
• Few donors have the antigens, resulting in low incidence of stimulation.
• Kx Antigen 019 (XK): ISBT 019; membrane transport protein.

XK1 Gene

• Located on the X chromosome and not part of the Kell system, though related.
• Acts as a transport protein spanning the membrane 10 times.
• Present in all RBCs except McLeod phenotype.
• Kell antigen expression depends on the presence of the XK protein, and Kx antigens are increased in K0 individuals when Kell antigens are denatured.

McLeod Syndrome

• Absence of Kx & Km antigen, almost exclusive in white males with X-linked inheritance. The mother is the carrier.

• Mcleod has no Kx antigen expressed while Kellnull has Kx antigen to be expressed

• Associated with mutations in the XK locus.

• McLeod phenotypes written with superscript "W", indicating weak Kell antigens.

• Causes abnormal red cell morphologies (acanthocytic RBCs) and decreased red cell survival, leading to compensated, chronic hemolytic anemia with reticulocytosis, bilirubinemia, splenomegaly, and decreased haptoglobin.

• There is association with chronic granulomatous disease.

  • WBCs can engulf but cannot kill; inability of the phagocyte to produce NADPH oxidase needed for hydrogen peroxide production. They die early due to overwhelming infection.
  • Not all males with McLeod syndrome have CGD, and not all CGD patients have McLeod phenotype.

• Antibodies produced are Anti-Kx and Anti-Km, strongly reacting with the K0 phenotype RBCs due to abundant Kx antigens.

Duffy Blood Group System 008 (FY)

• Discovered in 1950 in a hemophilia patient with anti-Fya after multiple transfusions.
• A year later, anti-Fyb was discovered in a woman with 3 pregnancies.
• Duffy genes (ACKR1) are located at chromosome 1, with Fya and Fyb coding for antigens and Fy a silent allele prevalent in Blacks.
• Formally known as DARC.

Duffy Antigen

• Identified at 6 weeks gestation and well-developed at birth.
• Destroyed by enzymes like Ficin, Papain, Bromelin, Chymotrypsin, and ZZAP, but not by Dithiothreitol (DTT), AET, or glycine acid EDTA treatment.
• Shows dosage and are only found on RBCs and other tissues like brain, colon, endothelium, lungs, etc.

Fy3

• Antigenic precursor to both Fya and Fyb and must be present for them to exist.
• Not destroyed by enzymes.
• Anti-Fy3 is an inseparable anti-FyaFyb, discovered in a Fynull individual.

FyX

• Inherited weak form of Fyb that does not produce a distinct antigen and may type as Fy(b-), reacting weakly with some anti-Fyb.
• The antigens are transmembrane proteins that traverses the cell membrane 7 times
• no anti-FyX exists since it does not produce a distinct antigen.
• the differentiation of Fya and Fyb comes fromthe 42nd position while in the glycoprotein:
• 42nd = Glycine for Fya
• 42nd = Aspartate for Fyb

Chemokine Receptor

• The duffy antigens are membranes of the chemokine receptor known as ATYPICAL CHEMOKINE RECEPTOR 1 (ACKR1)
• Previously known as DARC; receptor for proinflammatory chemokines and Plasmodium Vivax
• Individuals lacking antigens are protected from Plasmodium Vivax as the parasite lacks a receptor to enter cells.

Duffy Phenotypes

• Blacks: Fy(a+b-) 9%, Fy(a+b+) 1%, Fy(a-b+) 22%, Fy(a-b-) 68%.
• Whites: Fy(a+b-) 17%, Fy(a+b+) 49%, Fy(a-b+) 35%, Fy(a-b-) very rare.
• Fy is the silent allele responsible for Fy(a-b-) expression, making Fynull individuals unable to create Anti-Fyb.

Duffy Antibodies

• IgG, showing dosage and reacting best in AHG phase.
• Rarely bind complement and is clinically significant.
• Cause delayed and acute HTR and HDFN.
• Do NOT react with enzyme-treated RBCs.
• Useful in antibody screening is useful

Duffy and Malaria Connection.

• Most African-Americans are Fy(a-b-) and are resistant from malarial infections because Fya and Fyb are receptors for malaria (P. Vivax & P. Knowlesi).

Kidd Blood Group System 009 (JK)

Kidd Genes

From Mrs. Kidd who had an antibody in her serum causing HDFN to her infant named John Kidd Reacted with 77% of the Bostonians Discovered after two years later Jka and Jkb(co-dominant alleles) Jk(silent genes located on Chromosome 18)

Kidd Phenotypes

JkaJka is detected 26.3% for whites and 51.1% for blacks JkaJkb is detected 50.3% for whites and 40.8% for blacks JkbJkb is detected 23.4% for whites and 8.1% for blacks JkJk is detected for Asians and are rare in both whites and blacks

Kidd Antigens

• Only present in RBCs and are not found on any other tissues
• Are not very immunogenic
• Jka is detected at 11 weeks in gestation
• Jkb is detected at 7 weeks in gestation
• Enhanced by enzymes
• Not very accessible in RBC membranes

Kidd Antibodies

• IgG, crosses placenta and cause delayed and acute HTR and HDFN.
• Kidd antibodies decline rapidly in the body, undetectable shortly after a transfusion, but can cause hemolytic transfusion reaction.
• Weak but are notorius with the following:
• LISS/PEG is required for detection
• dosage may show nonreactive to antihuman globulin testing
• binds complement
• check patients card if they had a previously treated antibody
• it should be noted that a Kidd antibody was present
• Anti-Jk3 is Implicated in severe, immediate and delayed and HTR (hemolytic transfusion reaction) and mild HDFN (hemolytic disease of the fetus of new borns)
• found in those who are jk (a-b)(null phenotype)and is more common in those in the far east and pacific islanders

Lutheran System 005(Lu)

####Lutheran Genes/Antigen

• Discovered in 1945, 11 years after Anti-Lub was discovered
• Composed of 27 antigens located with codominant alleles on the Chromosome 19
• Lutheran 22,10,15 are already obsolete due to dominant recessive inhibitor
• Found in high(Lumost common) and low incidents, Blood bank generally deals with Lutheran bloods because some traits have questionable immunogenicity
• Dominant: the phenotype should have the Lub dominant antigens, thus the red cell should inherit an antigen that is either Lua and/or Lub

####Lutheran Antibodies

• Made by individuals with Lub antigens, IgM and and rarely IgA and are naturally occurring at room temperature(25) . Some may not bind to compliment but are generally mild to the point which that they are not significant
• Can be destroyed from treating enzymes (anti-Lob)
• Dominant recessive blood type (Lu(a+b-)) expression is in a suppressed by the in(Lu) gene(inhibitor to luthern)
• The Dominant has a trace amount of Lutheran antigens, unlike the (Lu(a-b-)), the recessive lacks all Lutheran antigens.
• The recessive are X-linked inhibitor types Lu(a-b-) where all affected individuals are male that carried traces of Adsorption-elution(Lub). This type will NOT result in an Anti-Lub red cell treatment.

###Other Lutheran Gene Facts

• Lumost common as a Lua-negative phenotype
• Made when you have Lub antigens
• Not found in placenta and hepatocytes
• Can also be a Recessive X-linked inhibitor Type of Lutheran