Other Blood Group Systems

Renee Wilkins, PhD, MLS(ASCP)cm

CLS 325/435School 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 37°C

Systems that Produce Cold-

Reacting Antibodies

Lewis Antigens Soluble antigens produced by tissues and

found in body fluids (plasma) Adsorbed on the RBC

Le genes

Le substance in plasma

RBC

Lewis substance adheres to RBC

becoming an antigen

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(a+b-) Le Se H Le(a-b+) le H se Le(a-b-) le hh se 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 significance…Why?

Le antibodies in a patient can be neutralized by the Lewis antigens in the donor’s 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 4°C) 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

Anti-i: rare and is sometimes associated with

infectious mononucleosis

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 Anti-P

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 Donath-Landsteiner antibody

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

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 …..

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 U-

negative (RARE) U-negative cells are only found in the

Black population

Frequency of MNSs antigens

Phenotypes Blacks (%) Whites (%)

M+ 74 78

N+ 75 72

S+ 30.5 55

s+ 94 89

U+ 99 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 IgG Class Clinically significant

Anti-M IgM (rare IgG) No

Anti-N IgM No

Anti-S IgG Yes

Anti-s IgG Yes

Anti-U IgG Yes

Systems that Produce Warm-Reacting

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%)

Js antigens Jsa (20% in Blacks, 0.1% in Whites) Jsb is high frequency (80-100%)

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 won’t 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 Jk(a+b-) 26.3 51.1

JkaJkb Jk(a+b+ 50.3 40.8

JkbJkb Jk(a-b+) 23.4 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 Blacks Whites

Fy(a+b-) 9 17

Fy(a+b+) 1 49

Fy(a-b+) 22 34

Fy(a-b-) 68 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

Anti-Lub

Rare because Lub is high incidence antigen IgG Associated with transfusion reactions (rare HDN)

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

LIiPMABHNNaturally Occurring

Warm antibodies (IgG)

Rh antibodies Kell Duffy Kidd S,s

Remember enzyme activity:

Enhanced by enzymes

Destroyed by enzymes

KiddRh

LewisIP

Fya and Fyb M, NS, s

Papain, bromelin, ficin, and trypsin

Remembering Dosage: Kidds and Duffy the Monkey (Rh) eat lots

of M&Ns

Jka, Jkb, Fya, Fyb, C, c, E, e (no D), M, N, S, s

M&Ns

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

M&Ns

Kidd Duffy Rh MNSs