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Other Blood Groups
Lewis, Kell, Duffy, Kidd, Ii, MNSs & P
IntroductionIntroduction
Over 500 blood group antigensOver 500 blood group antigens
““High incidence”, “public” or “high High incidence”, “public” or “high frequency” frequency” antigensantigens are those present on are those present on almost every person’s red blood cellsalmost every person’s red blood cells
““Low incidence”, “private” or “low Low incidence”, “private” or “low frequency” frequency” antigensantigens are present on very, are present on very, very few individuals red blood cellsvery few individuals red blood cells
IntroductionIntroduction
Each known Each known antigenantigen initially identified initially identified through the detection of its specific through the detection of its specific antibodyantibody in the serum. in the serum.
Knowledge of serologic behavior and Knowledge of serologic behavior and characteristics of blood group characteristics of blood group antibodiesantibodies is is CRITICAL for identificationCRITICAL for identification
IntroductionIntroduction
Essential when evaluating antibody screen Essential when evaluating antibody screen and panel studies.and panel studies.
Considerations given to:Considerations given to: Phase of reactivityPhase of reactivity
Antibody class involvedAntibody class involved
Ability to cause HDFN and HTRAbility to cause HDFN and HTR
Major Blood Group Systems Lewis
I
P
MNSs
Kell
Kidd
Duffy
Lewis SystemLewis System
Major antigens LeMajor antigens Leaa and Le and Lebb , other antigens , other antigens include Leinclude Lecc, Le, Ledd and Le and Lexx
Antigens ARE NOT intrinsic to RBCs but are Antigens ARE NOT intrinsic to RBCs but are absorbed from the plasma and inserted absorbed from the plasma and inserted into RBC membrane.into RBC membrane.
Lewis SystemLewis System
Antigenic DevelopmentAntigenic Development Genetic control reside in single gene “Le”Genetic control reside in single gene “Le”
Amorph le, if homozygous will not have Lewis antigensAmorph le, if homozygous will not have Lewis antigens
LeLea a formed first, then modified to form Leformed first, then modified to form Lebb which is which is adsorbed preferentially over Leadsorbed preferentially over Leaa
Lewis phenotype of RBC can be changed by Lewis phenotype of RBC can be changed by incubating with plasma containing Leincubating with plasma containing Leaa or Le or Lebb glycoplipid.glycoplipid.
Lewis SystemLewis System
Lewis Phenotypes and Their FrequenciesLewis Phenotypes and Their Frequencies
WhiteWhite BlackBlack
Le (a+b-)Le (a+b-) 22%22% 23%23%
Le (a-b+)Le (a-b+) 72%72% 55%55%
Le (a-b-)Le (a-b-) 6%6% 22%22%
Le (a+b+)Le (a+b+) RareRare rarerare
Lewis SystemLewis System
Lewis antigens in infantsLewis antigens in infants Antigens absent or extremely weak at birthAntigens absent or extremely weak at birth
Expression of Leb gradualExpression of Leb gradual Birth Le (a-b-)Birth Le (a-b-) 2 months Le(a+b-)2 months Le(a+b-) 12 to 18 months Le(a+b+)12 to 18 months Le(a+b+) 2 to 3 years Le (a-b+)2 to 3 years Le (a-b+)
Lewis SystemLewis System
Lewis antigens and pregnancyLewis antigens and pregnancy Antigen strength may decline dramaticallyAntigen strength may decline dramatically
Transiently Le (a-b-) may produce Lewis Transiently Le (a-b-) may produce Lewis antibodies during pregnancyantibodies during pregnancy
Antigens return after delivery and antibodies Antigens return after delivery and antibodies disappeardisappear
Lewis SystemLewis System
Interaction of Le, Se and H GenesInteraction of Le, Se and H Genes lele will not have Lewis antigens, but if Se lele will not have Lewis antigens, but if Se
present will have A, B and H in secrectionspresent will have A, B and H in secrections
Genotype se/se and have one Lewis antigen Genotype se/se and have one Lewis antigen will have Lewill have Leaa in their secretions but no A, B or in their secretions but no A, B or H.H.
Lewis SystemLewis System
Lewis PhenotypeLewis Phenotype ABH SecretorABH Secretor Lewis SecretorLewis Secretor
Le (a+b-)Le (a+b-) All ABH NON-SecretorsAll ABH NON-Secretors All LeAll Leaa Secretors Secretors
Le (a-b+)Le (a-b+) All ABH secretorsAll ABH secretors All secretors of LeAll secretors of Leaa and and LeLebb
Le (a-b-)Le (a-b-) 80% ABH secretors80% ABH secretors
20% ABH NON secretors20% ABH NON secretors
NONENONE
Lewis SystemLewis System
Lewis AntibodiesLewis Antibodies Almost always IgM, react strongly at RT, may Almost always IgM, react strongly at RT, may
cause ABO discrepancy if reverse cells have cause ABO discrepancy if reverse cells have Lewis antigen.Lewis antigen.
Occur almost exclusively in Le (a-b-) and Occur almost exclusively in Le (a-b-) and production of anti-Leproduction of anti-Leaa AND –Le AND –Lebb not unusual not unusual
Anti-LeAnti-Leaa frequently encountered, anti-Le frequently encountered, anti-Lebb rarely rarely encountered.encountered.
Lewis SystemLewis System
Lewis AntibodiesLewis Antibodies Although most react at RT reactivity may be seen at Although most react at RT reactivity may be seen at
37C, but is weaker and may be weakly reactive at AHG37C, but is weaker and may be weakly reactive at AHG
Can bind complement and cause IN-VITRO hemolysis, Can bind complement and cause IN-VITRO hemolysis, most often with enzyme treated cellsmost often with enzyme treated cells
Because antibodies are IgM and antigens are poorly Because antibodies are IgM and antigens are poorly developed at birth antibodies NOT implicated in HDFN.developed at birth antibodies NOT implicated in HDFN.
Lewis SystemLewis System
Lewis antibodiesLewis antibodies Can be neutralized in-vitro by additions of Can be neutralized in-vitro by additions of
Lewis SubstanceLewis Substance Le antigens are present in secretionsLe antigens are present in secretions Add to serum with Lewis antibodies and the Add to serum with Lewis antibodies and the
antibodies will be bound to the soluble Lewis antigensantibodies will be bound to the soluble Lewis antigens Useful when multiple antibodies are present and 1 is Useful when multiple antibodies are present and 1 is
a Lewis, eliminates the activity of the antibodya Lewis, eliminates the activity of the antibody
Lewis Antibodies
Anti-Le a, Anti-Le b, Anti-Lex
Most react at room temperature or below -
Often fix complement
Some in vitro hemolysis
Le a may cause HTR
Lewis Antibodies
Anti-Le a
Found in Lea-b- secretors
best room temperature or below
Often fix complement
Some in vitro hemolysis
Le a may cause HTR
Lewis Antibodies
Anti-Le b
Often found with Anti-Lea
Most react at room temperature or below
Two types - Anti-LebH and Anti-LebL
Rare cause of HTR
Lewis Antibodies
Anti-Lex
Most react at room temperature or below -
Reacts with both Lea and Leb as a single antibody
Lewis Antibodies
Special Problems in the Blood Bank
Lewis antigens may be weaker during pregnancy and women produce antibodies
Can neutralize Lewis antibodies with Lewis plasma
Pregnant woman with room temperature antibodies, neutralize with Lewis antigen when testing for HDN antibodies
Lewis SystemLewis System
Transfusion PracticeTransfusion Practice Transfused RBCs will acquire the Lewis phenotype of the Transfused RBCs will acquire the Lewis phenotype of the
recipient within a few daysrecipient within a few days
Lewis antibodies in patient will be neutralized by Lewis Lewis antibodies in patient will be neutralized by Lewis substance in donor plasmasubstance in donor plasma
Lewis antibodies rarely cause in-vivo hemolysisLewis antibodies rarely cause in-vivo hemolysis
It is not necessary to phenotype donors for Lewis It is not necessary to phenotype donors for Lewis antigens prior to transfusion, give crossmatch antigens prior to transfusion, give crossmatch compatiblecompatible
The Kell Blood Group System
Background information The Kell blood group system was
discovered in 1946.
Number of Kell antigens: > 20
These antigens are the third most potent, after those of the ABO and Rh blood groups, at triggering an immune reaction.
Molecular information The KEL gene is found on chromosome 7 The KEL gene is highly polymorphic, with
different alleles at this locus encoding the 25 antigens that define the Kell blood group.
The Kell protein is a polypeptide chain of 732 amino acids in length that becomes glycosylated at five different sites. It makes a single pass through the RBC membrane.
Kell Blood Group System XK gene produces Kx substance, which is a
precursor of of Kell Ags Kel genes convert Kx substance into the Kell Ags
on RBCs K (Kell) & k (cellano) are produced by allelic genes,
this results into 3 phenotypes: K+k- (genotype KK) K+k+ (genotype Kk) K-k+ (genotype kk)
Other allelic genes include: Kpa/Kpb, Jsa/Jsb
Kx
XK Gene (Chromosome X)
Kell system glycoprotein: Kell Ag’s reside here.
KEL Gene
RBC
Frequency of Kell phenotypes
Phenotype Caucasians Blacks
K-k+ 91 % 98 %
K+k- 0.2 % Rare
K+k+ 8.8 2
Kx Substance Kx substance is present on RBCs & WBCs Kell genes convert Kx substance into the Kell Ags
on RBCs
Kell genes do not convert Kx on WBCs
McLeod Phenotype Absence of Kx proteins in
RBCs membrane lead to McLeod Phenotype
This absence cause: abnormal RBCs shape
(acanthocytes)
& reduced in-vivo survival
Chronic Granulomatous Disease Absence of Kx proteins in WBCs cause
CGD Leukocytes are able to phagocytose but
not to kill bacteria Patients with CGD have recurrent bacterial
infections Patients who lack Kx on RBCs & WBCs
have both Mcleod and CGD
Kell Antibodies K- individuals produce anti-K when
exposed to K+ cells Frequency of K+ is low (9%), easy to find blood
On the other hand frequency of k is 99.9% k- individuals produce anti-k when exposed to
k+ cells Difficult to find blood
Antibodies produced against Kell antigens
Kell AbsClinically
Significant
Yes
Abs class
IgG (rarely) IgM
Thermal range
4 - 37
HDNB
Yes
Transfusion Reactions
Extravascular Intravascular
Yes Rare
Duffy Blood Group System
Duffy Blood Group System The Duffy blood group was discovered in 1950. The Duffy glycoprotein is encoded by the FY gene,
found on chromosome 1 , of which there are two main alleles, FYA and FYB. They are codominant.
The Duffy gene codes for a glycoprotein also found in other tissues: brain, kidney, spleen, heart and lung.
The Duffy glycoprotein is a transmembrane protein Five alleles at Duffy locus, the most important: Fya,
Fyb & Fy (Silent Allele) Fya is more immunogenic than Fyb
Duffy Antigens
Phenotype Frequencies
Phenotype Caucasians % Blacks
%
Fy (a+b+) 49 2
Fy (a+b-) 18 14
Fy (a-b+) 33 19
Fy (a-b-) rare 65
Different genes Fy(a-b-) blacks do not produce anti-Fya or
anti-Fyb following transfusion with Fy(a+) or Fy(b+) blood
Fy(a-b-) Caucasians become sensitized
following transfusion with Fy(a+) or Fy(b+) blood
This suggest that Fy(a-b-) phenotype arises from different genes in the two populations
Duffy Antigens Fya, Fyb antigens are Destroyed by enzymes
Abs DO NOT agglutinate enzyme treated cells
Moderately immunogenic Fya is more immunogenic than Fyb
Duffy Antibodies
IgG antibodies and can activate complement
Anti- Fya is more frequently encountered
Anti- Fyb is more frequently found in patients produced multiple alloantibodies
Duffy AbsClinically
Significant
Yes
Abs class
IgG
Thermal range
4 - 37
HDNB
Yes
Transfusion Reactions
Extravascular Intravascular
Yes Yes
Duffy and Malaria
Black people with the Duffy phenotype of Fy(a–b–) appear to have resistance to Plasmodium vivax & Plasmodium knowlesi causative agents of Malaria.
Duffy antigens appear to be a receptor for the P. vivax organism and when the antigen is not present on the red blood cell membrane P. vivax is unable to access the red blood cell
Some area’s of West Africa are 100% Fy(a–b–).
Plasmodium falciparum binds to RBCs at integral glycophorin A & B
Duffy and Malaria
Kidd Blood Group System
Kidd Blood Group System
The Kidd blood group was discovered in 1950.
The Kidd gene is located on chromosome 18
Three alleles: Jka, Jkb, Jk Codominant Inheritance
Jk is a silent allele (amorph)
The Kidd protein is an integral protein of the RBC membrane.
Kidd Phenotype Frequencies
Phenotype Caucasians (%)
Jk (a+ b-) 29
Jk (a+ b+) 49
Jk (a- b+) 22
Jk (a- b-)Exceedingly rare
(COMMON IN FILIPINOS)
Phenotype Frequencies
What is the purpose of learning the phenotype frequencies of each blood group antigen?
– When crossmatches are required it helps the Tech know how many units to crossmatch or antigen type to find compatible blood.
If a patient has anti-Jka antibody how many RBC units need to be antigen typed to find 2 compatible units?
78% of the population is positive for the antigen therefore 22% are NEGATIVE for the antigen. Approximately 2 out of 10 units are compatible. Need to antigen type 10 units.
Kidd Antigens & Antibodies Ags are well developed at birth
Have tendency to drop to low or undetectable levels following formation.
Abs are of IgG type & can activate complement (Anti-Jka, Anti-Jkb )
Produced following transfusion or pregnancy
Can cause HDNB
They are also a very common cause of delayed HTRs
KID ANTIBODY
Ii Blood Group
Found nearly on all RBCS
Their products are transferase enzymes that attach repeating units of Gal and GlcNAc to the ABO Precursor Substance.
Big I gene codes for branching of the Precursor Substance.
Ii Antigens
Little i antigen is LINEAR Found on cord cells, predominantly
Big I antigen is BRANCHED Gradually convert from i to I during the
first 18 months of life. Not all i converted to I, some i still present on adult cells, normally.
Rare adult individuals termed iadult do not express i Ag on their red cells
The I and i antigen sites are considered uncompleted ABH active chains.
When ABH are removed from RBCs more I Ags are expressed
I structure located beneath the ABH Ags
I Antibodies: Anti-I Anti-I is naturally
occurring often due to a Mycoplasma pneumoniae infection
Anti-I reacts with all adult cells (including patient’s own, all reagent cells, all donor cells)
Anti-I does not react with cord cells
Auto-anti-I is a common “cold agglutinin”
Anti-I AbsClinically
Significant
Rare
Abs class
IgM
Thermal range
4 - 10
HDNB
No
Transfusion Reactions
Extravascular Intravascular
No rare
Antii Antibodies
Antii is rarely found in healthy individuals
Reacts preferably with cord cells
anti-i can be found secondary to Infectious Mononucleosis. Transient: Only present with active disease
MNSs Blood Group System The antigens M and N are produced by
co-dominant alleles closely linked to the S and s genes,
which are also co-dominant. Chromosome 4 contains these linked
genes Genes produce two distinct
glycophorins or sialyglycoproteins (SGP) on the RBC membrane.
MN Genetics
MN Locus genes produce Glycophorin A (GPA) M-GPA’s 1st five aa’s = Serine-Ser-Thr-Thr-Glycine
N-GPA’s 1st five aa’s = Leucine-Ser-Thr-Thr-Glutamic acid
Amino acids (aa) 2, 3 & 4 are the same for both
Glycophorin A (GPA) is a glycoprotein also known as MN-sialoglycoprotein
MN Genetics
MN Genotypes & Phenotypes
Phenotype Genotype Frequency %
M+N- MM 30
M+N+ MN 50
M-N+ NN 20
MNSs Antigens
RBC
Glycophorin A
Glycophorin B
M
N
SsU
M & N only differ in their amino acid
sequence at positions 1 and 5
S & s only differ in their amino acid
sequence at position 29
….5, 4, 3, 2, 1 (NH2 end)COOH end …..
Ss Genetics
Ss genes code for the production of Glycophorin B(GPB)
S glycophorin B has Methionine at aa position 29
s glycophorin B has Threonine at aa position 29
Glycophorin B (GPB) is a glycoprotein also known as Ss-sialoglyprotein
Ss Genotypes & Phenotypes
Phenotype GenotypeFrequency %
Caucasians Blacks
S+s- SS 11 6
S+s+ Ss 44 24
S-s+ ss 45 68
S-s- Susu 0 2
• U antigen is a high incident antigen NOT seen in individuals who lack both S and s antigens.
• Individuals who lack this antigen (<1%) have a high likelihood of forming anti-U as well as anti-S and anti-s.
Rare Alleles Rare low incidence alleles found on MN
locus
Some may result from crossing over of genes of glycophorin A & B
Such crossing over results in hybrid sialoglycoproteins
Anti-M Antibodies
Variability of reactivity (Dosage) Strong reactions with
RBCs homozygous for MM
Weak reactions with RBCs heterozygous MN
Anti-M AbsClinically
Significant
Seldom
Abs class
IgG & IgM
Thermal range
4 – 22
Rare 22-37
HDNB
rare
Transfusion Reactions
Extravascular Intravascular
Rare No
Anti-N antibodiesAnti-N Abs
Clinically Significant
No
Abs class
IgM
Thermal range
4 - 22
HDNB
No
Transfusion Reactions
Extravascular Intravascular
No No
• Naturally occurring cold agglutinin
• Can form in patients with renal Failure
• During dialysis with formaldehyde sterilized equipment
• Formaldehyde may alter the N Ag structure making it appear foreign
Anti-S and Anti-s antibodiesAnti-S Abs
Clinically Significant
Sometimes
Abs class
IgG & IgM
Thermal range
4 - 37
HDNB
Yes
Transfusion Reactions
Extravascular
Intravascular
Yes No
Anti-s AbsClinically
Significant
Yes
Abs class
IgG
Thermal range
4 - 37
HDNB
Yes
Transfusion Reactions
Extravascular
Intravascular
Yes No
P Blood Group System
Genetics: These genes code for enzymes that sequentially add sugars to precursor substance.
This system is related to the ABO, Le and Ii systems.
Genes: P1, Pk, P and lower case p (silent allele)
All antigens are expressed on glycolipids on red cells
PhenotypeDetectable Antigens
Frequencies
Whites %
P1 P1, P 79%
P2 P 21%
Pk1 P, Pk Rare
Pk2 Pk Rare
p N/A Rare
•Pk is the precursor of P.
•Rare individuals do not convert Pk into P.
•Those will have Pk on RBCs.
Phenotypes, Detectable Antigens & Frequencies
Anti-P1 Antibodies
Anti-P1 Abs
Clinically Significant
occasionally
Abs class
IgM
Thermal range
4 – 22
Rare 22-37
HDNB
NO
Transfusion Reactions
Extravascular Intravascular
No Rare
Naturally occcurring Abs found in the serum of P
2
Individuals
Anti-P1 Antibodies
Allo Anti-P Antibodies
Allo Anti-P AbsClinically
Significant
Yes
Abs class
IgM
Rare IgG
Thermal range
4 – 37S
HDNB
Rare
Transfusion Reactions
Extravascular Intravascular
No Yes
Naturally occcurring Abs found in the serum of Pk and p
Individuals
Auto anti-P Antibodies It is an IgG biphasic Ab
associated with Paroxysmal Cold Hemoglobinuria (PCH)
Binds complement at cold temperatures and activates that complement in warm temperatures lysing the red blood cells.
Auto Anti-P AbsClinically
Significant
Yes
Abs class
IgG
Biphasic
Binds at 0
Hemolysis 37
HDNB
Rare
Transfusion Reactions
Extravascular Intravascular
Rare Yes
Anti Tja Antibodies
Combination of anti-P, anti-P1 & anti-Pk
Found in serum of individuals who have no P, P1 & Pk Ags on red cells
RARE BLOOD GROUPS
REMEMBER THAT !!!!!