Other Blood Group Systems

Renee Wilkins, PhD, MLS(ASCP)cm CLS 325/435 School of Health Related Professions University of Mississippi Medical Center

Facts
Over 200 blood antigens exist! Unfortunately, we only get to review the most relevant antigens We will discuss each of these major antigens, their antibodies, and the clinical significance of each

Major Blood Group Systems

Lewis I P MNSs Kell Kidd Duffy

Basic terms to remember

Clinical significance: antibodies that are associated with decreased RBC survival

Transfusion reactions HDN

Not clinically significant: antibodies that do not cause red cell destruction Cold reacting antibodies: agglutination best observed at or below room temp. Warm reacting antibodies: agglutination best observed at 37C

Systems that Produce Cold-Reacting Antibodies

Lewis Antigens
Soluble antigens produced by tissues and found in body fluids (plasma) Adsorbed on the RBC

Lewis substance adheres to RBC becoming an antigen

RBC
Le substance in plasma

Le genes

Lewis inheritance
Lewis system depends on Hh, Se, and Le genes le, h, and se do not produce products If the Le gene is inherited, Lea substance is produced Le, H, and Se genes must ALL be inherited to convert Lea to Leb. Examples:

Le se H Le Se H le H se le hh se

Le(a+b-) Le(a-b+) Le(a-b-) Le(a-b-)

Lewis Antibodies

Usually occur naturally in those who are Le(a-b-) Other phenotypes RARELY produce the antibody IgM (may fix complement, becoming hemolytic) Enzymes enhance activity May be detected soon after pregnancy because pregnant women may temporarily become Le(a-b-) No clinical significanceWhy?

Le antibodies in a patient can be neutralized by the Lewis antigens in the donors plasma (cancel each other out) do not cause HDN because they do not cross placenta (antigens not developed well in cord blood) Le(a-b-)

I antigens
These antigens may be I or i They form on the precursor chain of RBC Newborns have i antigen Adults have I antigen i antigen (linear) converts to I (branched) as the child matures (precursor chain is more linear at birth) at about 18 months

I antibodies
Most people have autoanti-I (RT or 4C) Alloanti-I is very rare Cold-reacting (RT or below) IgM antibody Clinically insignificant Can attach complement (no hemolysis unless it reacts at 37) Prewarming the tests can eliminate reactivity Enzymes can enhance detection

I antibodies
Anti-I often occurs as anti-IH This means it will react at different strengths with reagent cells (depending on the amount of H antigen on the RBC)

O cells would have a strong reaction A cells would have a weaker reaction

Anti-I antibodies

Anti-I:

Associated as a cause of Cold Agglutinin Disease (similar to PCH) May be secondary to Mycoplasma pneumoniae infections
rare and is sometimes associated with infectious mononucleosis

Anti-i:

P Antigen
Similar to the ABO system The most common phenotypes are P1 and P2

P1 consists of P1 and P antigens P2 consists of only P antigens

Like the A2 subgroup, P2 groups can produce anti-P1 75% of adults have P1

P1 Antigen
Strength of the antigen decreases upon storage Found in secretions like plasma and hydatid cyst fluid

Cyst of a dog tapeworm

P antibodies

Anti-P1

Naturally occurring IgM Not clinically significant Can be neutralized by hydatid cyst fluid to reveal more clinically significant antibodies
Produced in individuals with paroxysmal cold hemoglobinuria (PCH) PCH IgG auto-anti-P attaches complement when cold (fingers, toes). As the red cells circulate, they begin to lyse (releasing Hgb) This PCH antibody is also called the DonathLandsteiner antibody

Anti-P

MNSs Blood System

4 important antigens (more exist):

M N S s U (ALWAYS present when S & s are inherited)

M & N located on Glycophorin A S & s and U located on Glycophorin B Remember: Glycophorin is a protein that carries many RBC antigens

MNSs Antigens
M & N only differ in their amino acid sequence at positions 1 and 5

M Glycophorin A N

RBC
U S

Glycophorin B

S & s only differ in their amino acid sequence at position 29

COOH end ..

.5, 4, 3, 2, 1 (NH2 end)

MNSs antigens
all show dosage M & N give a stronger reaction when homozygous, (M+N-) or (M-N+) Weaker reactions occur when in the heterozygous state (M+N+) Antigens are destroyed by enzymes (i.e. ficin, papain)

U (Su) antigen
The U antigen is ALWAYS present when S & s are inherited About 85% of S-s- individuals are Unegative (RARE) U-negative cells are only found in the Black population

Frequency of MNSs antigens

Phenotypes
M+ N+ S+ s+ U+

Blacks (%) 74
75 30.5 94 99

Whites (%) 78
72 55 89 99.9

High-incidence antigen

Thought..

Can a person have NO MNSs antigens?

Yes, the Mk allele produces no M, N, S, or s antigens Frequency of 0.00064 or .064%

Anti-M and anti-N antibodies

Demonstrate dosage Anti-M and anti-N

IgM (rarely IgG) Clinically insignificant If IgG, could be implicated in HDN (RARE) Will not react with enzyme treated cells

Anti-S, Anti-s, and Anti-U

Clinically significant IgG Can cause RBC destruction and HDN Anti-U

will react with S+ or s+ red cells Usually occurs in S-s- cells Can only give U-negative blood units found in <1% of Black population Contact rare donor registry

MNSs Antibody Characteristics

Antibody Anti-M Anti-N Anti-S Clinically significant IgM (rare IgG) No IgM IgG No Yes IgG Class

Anti-s
Anti-U

IgG
IgG

Yes
Yes

Systems that Produce WarmReacting Antibodies

Kell System
Similar to the Rh system 2 major antigens (over 20 exist)

K (Kell), <9% of population k (cellano), >90% of population

The K and k genes are codominant alleles on chromosome 7 that code for the antigens Well developed at birth The K antigen is very immunogenic (2nd to the D antigen) in stimulating antibody production

Other Kell antigens

Other sets of alleles also exist in the Kell system: Analogous to the Rh system: C/c and E/e Kp antigens

Kpa is a low frequency antigen (only 2%) Kpb is a high frequency antigen (99.9%) Jsa (20% in Blacks, 0.1% in Whites) Jsb is high frequency (80-100%)

Js antigens

Kell antigens
Kell antigens have disulfide-bonded regions on the glycoproteins This makes them sensitive to sulfhydryl reagents:

2-mercaptoethanol (2-ME) Dithiothreitol (DTT) 2-aminoethylisothiouronium bromide (AET)

Kellnull or K0
No expression of Kell antigens except a related antigen called Kx As a result of transfusion, K0 individuals can develop anti-Ku (Ku is on RBCs that have Kell antigens) Rare Kell negative units should be given

Kell antibodies

IgG (react well at AHG) Produced as a result of immune stimulation (transfusion, pregnancy) Clinically significant Anti-K is most common because the K antigen is extremely immunogenic k, Kpb, and Jsb antibodies are rare (many individuals have these antigens and wont develop an antibody) The other antibodies are also rare since few donors have the antigen

Kx antigen

Not a part of the Kell system, but is related

Kx antigens are present in small amounts in individuals with normal Kell antigens Kx antigens are increased in those who are K0

McLeod Syndrome

The XK1 gene (on the X chromosome) codes for the Kx antigen When the gene is not inherited, Kx is absent (almost exclusive in White males) Causes abnormal red cell morphologies and decreased red cell survival:

Acanthocytes spur cells (defected cell membrane) Reticulocytes immature red cells

Associated with chronic granulomatous disease

WBCs engulf microorganisms, but cannot kill (normal flora)

Kidd Blood Group

2 antigens

Jka and Jkb (codominant alleles) Show dosage

Genotype Phenotype Whites (%) Blacks (%) JkaJka JkaJkb JkbJkb Jk(a+b-) Jk(a+b+ Jk(a-b+) 26.3 50.3 23.4 51.1 40.8 8.1

JkJk

Jk(a-b-)

rare

rare

Kidd Antigens
Well developed at birth Enhanced by enzymes Not very acessible on the RBC membrane

Kidd antibodies

Anti-Jka and Anti-Jkb

IgG Clinically significant Implicated in HTR and HDN Common cause of delayed HTR Usually appears with other antibodies when detected

Kidd antibodies

Anti-Jk3

Found in some individuals who are Jk(a-b-) Far East and Pacific Islanders (RARE)

Duffy Blood Group

Predominant genes (codominant alleles):

Fya and Fyb code for antigens that are well developed at birth Antigens are destroyed by enzymes Show dosage
Phenotypes Fy(a+b-) Blacks 9 Whites 17

Fy(a+b+)
Fy(a-b+) Fy(a-b-)

1
22 68

49
34 RARE

Duffy antibodies
IgG Do not bind complement Clinically significant Stimulated by transfusion or pregnancy (but not a common cause of HDN) Do not react with enzyme treated RBCs

The Duffy and Malaria Connection

Most African-Americans are Fy(a-b-) Interestingly, certain malarial parasites (Plasmodium knowlesi and P. vivax) will not invade Fya and Fyb negative cells It seems either Fya or Fyb are needed for the merozoite to attach to the red cell The Fy(a-b-) phenotype is found frequently in West and Central Africans, supporting the theory of selective evolution

Other Blood Group Antigens

Lutheran Blood Group System

2 codominant alleles: Lua and Lub Weakly expressed on cord blood cells Most individuals (92%) have the Lub antigen, Lu(a-b+) The Lu(a-b-) phenotype is RARE

Lutheran antibodies

Anti-Lua

IgM and IgG Not clinically significant Reacts at room temperature Mild HDN Naturally occurring or immune stimulated
Rare because Lub is high incidence antigen IgG Associated with transfusion reactions (rare HDN)

Anti-Lub

Bg Antigens

Three (Bennett-Goodspeed) Bg antigens:

Bga Bgb Bgc

Related to human leukocyte antigens (HLA) on RBCs Antibodies are not clinically significant

Sda Antigens
High incidence antigens found in tissues and body fluids Antibodies are not clinically significant Antibodies characteristically cause mixed field agglutination with reagent cells

Xg Blood Group

Only one exists (Xga) Inheritance occurs only on the X chromosome 89% Xga in women 66% in males (carry only one X) Men could be genotype Xga or Xg Women could be XgaXga, XgaXg, or XgXg Example: Xg(a+) male with Xg(a-) woman would only pass Xg(a+) to daughters, but not sons The antigen is not a strong immunogen (not attributed to transfusion reactions); but antibodies may be of IgG class

HTLA Antigens
High Titer Low Avidity (HTLA) Occur with high frequency Antibodies are VERY weak and are not clinically significant Do not cause HDN or HTR

Review

Cold Antibodies (IgM)

Anti-Lea Anti-Leb Anti-I Anti-P1 Anti-M Anti-A, -B, -H Anti-N

LIiPMABHN
Naturally Occurring

Warm antibodies (IgG)

Rh antibodies Kell Duffy Kidd S,s

Remember enzyme activity:

Papain, bromelin, ficin, and trypsin

Enhanced by enzymes Kidd Rh Lewis I P

Destroyed by enzymes Fya and Fyb M, N S, s

Remembering Dosage:

Kidds and Duffy the Monkey (Rh) eat lots of M&Ns

M&Ns M&Ns

Jka, Jkb,
Kidd

Fya, Fyb,
Duffy

C, c, E, e (no D),
Rh

M, N, S, s
MNSs

adapted from Clinical Laboratory Science Review: A Bottom Line Approach (3rd Edition)