Life's Blood

OTHER BLOOD GROUP SYSTEMS

MNS SYSTEM

Antigens and Their Inheritance

The antigens M and N are co-dominant alleles that are closely linked to the S and s antigens, which are also co-dominant.  Chromosome 4 contains these linked genes.  These antigens are inherited by a complex pattern similar to the Rh system.  The Ms and Ns linkage is more common than the MS and NS linkages.  All these antigens, however are fairly frequent in the population with the following overall frequencies:

• M = 78%
• N = 72%
• S = 55%
• s = 89%
• U = Greater than 99%

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. 

Biochemistry of the MNS antigens

The M and N antigens are glycoproteins containing sialic acid that cross the cell membrane.  Carboxyl terminus extends into the red cells interior, a hydrophobic segment as part cell membrane and an amino terminal segment on the external environment of the red cell.  The external components of the antigens are destroyed by the enzymes like fiacin, typsin and papain.

The antigens of the MNSU blood group system are well developed in newborns. Therefore  a mother who is negative for one of these antigens could be stimulated to make antibodies thatmay cause HDN.  The antibody would have to be an IgG immunoglobulin that reacts at 37^oC)

MNS System Antibodies

Anti-M is frequently seen as a saline agglutinin if testing is done at room temperature. 

• It is predominantly IgM and can be naturally occurring. It will show dosage and therefore M homozygous cells will react with antibody more strongly than heterozygous cells.   Therefore the predominant form of the antibody is not clinically significant.  
• There are instances where some or all of the antibody is IgG in nature.  If you have an anti-M that strongly at 37^oC and/or AHG, it should be considered to be potentially clinically significant. 
• Mild to severe cases of hemolytic disease of the new born have be reported.
• Since the M antigen can be removed by enzyme, the reactivity of anti-M can be destroyed by enzyme. 
• When performing a crossmatch on a recipient's specimen that contains anti-M, a pre-warmed crossmatch should be preformed.

Anti-N is very rare and has similar reactivity as anti-M. Most often seen in kidney dialysis patients as cross-Reacting antibody to formaldehyde.  Formaldehyde is used to sterilize Dialysis equipment.

Anti-S anti-s and anti-U usually form following red cell immunization due to transfusions and pregnancies. 

• They are usually IgG and react best after 37^oC with AGT (Coombs) technique.
• All are capable of causing Hemolytic Transfusion Reactions (HTR) (delayed) and Hemolytic Disease of the Newborn (HDN)
• S is usually destroyed by enzyme but s is variable and U is not destroyed by enzyme treatment.
• Anti-U is rare but should be considered if a previously transfused or pregnant Black patient has an antibody to a high-incident antigen.

*Room Temperature
**Hemolytic Transfusion Reaction
***Hemolytic Disease of the Newborn

KELL SYSTEM

Antigens and Their Inheritance

In Dr. Mourant's article on the discovery of antiglobulin test, he recounts that they tested the serum of a number of mothers, who were believed to have babies with hemolytic disease of the newborn.  One of the reactions was not due to Anti-D. "The non-Rh antigen involved in this case was that subsequently known as Kell. Thus at the very outset the test had detected a previously unknown blood group system which has since proved to be of some clinical importance." ("The Discovery of the Anti-Globulin Test")

There are three pairs of alleles within the Kell system.  Each pair has a high frequency and low frequency gene that are co-dominate if present.  The three pairs are:

• K (Kell), or K1, and k (Cellano), K2
• Kp^a (K3) and Kp^b (K4)(Penney)
• Js^a (K6)and Js^b (K7)(Sutter)

K, Kp^a and Js^a are low frequency antigens and k, Kp^b and Js^b are high frequency antigens.  There is a Kell phenotype, K null (K_o or K5), is very rare and K, k, Kp^a, Kp^b, Js^a, Js^b antigens are not expressed. 

The Kell Systems antigens are found in only small amounts on the red cell carried on a single protein.  K has approximately 3500 sites and k has between 2000-5000.  The function of this protein is unknown.

Kell System Antibodies

Anti-Kell is the most clinically significant antibody within this system.  The Kell antigen is considered the next most antigenic after the D antigen of the Rh system.  Individuals lacking the K antigen can make anti-Kell after only two exposures to Kell-positive blood.  Because over 90% of the population are Kell negative it is not difficult to find donor blood that is compatible with the recipient.

Antibodies to other antigens in Kell system are very rare.

Antibody Characteristics of the antibodies to the Kell System are:

• IgG
• Cause HDN and HTR (delayed)
• React best in Coombs after 37^oC incubation
• Does not show dosage (homozygous KK and heterozygous Kk cells react with the same strength)
• Enzyme has no effect

*Room Temperature
**Hemolytic Transfusion Reaction
***Hemolytic Disease of the Newborn

DUFFY SYSTEM

Antigens and Their Inheritance

The Duffy antigens Fy^a and Fy^b are a pair of co-dominant alleles found on chromosome 1.  The phenotypes Fy(a-b+), Fy(a+b+), Fy(a-b+) are very common among the US white population.  Fy(a-b-) is very rare in the white population but makes up 68% of the black population of the United States.

Biochemically the Duffy antigens are glycoproteins  that has an external loop.  This external loop can be destroyed by enzymes such as ficin, papain, and trypsin.   The Fy^a  and Fy^b antigens are receptors for the malarial parasite, Plasmodium vivax.  Therefore individuals that are phenotypically Fy(a-b-) have a resistance to malaria. This particular phenotype is found up to 100% of western Africa and of course 68% of the American Blacks.

Duffy System Antibodies

Duffy antibodies frequently seen in multiply-transfused Blacks.  Anti-Fy^a much more common than anti-Fy^b and is more likely to cause HTR and HDN.  

3. Characteristics

• IgG
• Anti-Fy^a can cause HDN and HTR (delayed) and anti-Fy^b is milder and no HDN cases have been reported but could possibly be a cause.
• React best in Coombs after 37^oC incubation
• Reactions destroyed by enzyme of the red cells

*Room Temperature
**Hemolytic Transfusion Reaction
***Hemolytic Disease of the Newborn

KIDD SYSTEM

Antigens and Their Inheritance

Jk^a and Jk^b antigens are inherited on chromosome 18 where urea transport mechanisms are located.  Cells that are Jk(a-b-) are less likely to to lyse in the presence of high concentration of urea. These antigens are inherited by the co-dominant alleles Jk^a and Jk^b that are high frequency antigens.  The Kidd antigens are thought to be grouped very close together in clusters on the red cell membrane.  Due to the close proximity of the antigens when the antibodies are attached complement can be activated.  The activation of complement can cause intravascular transfusion reactions.

Approximate frequencies among the white  US population are the following:

• Jk^a = 75%
• Jk^b = 75%
• Approximately 50% of the white population is Jk^a and Jk^b positive

The more specific frequencies are listed in the table below for both whites and blacks.

Kidd System Antibodies

Both anti-JK^a and anti-Jk^b are hard to detect and identify since they are very weak and are detected primarily at the antiglobulin phase of testing.  These antibodies are usually low titer as well as being weak reactions.  The antibodies disappear rapidly from circulation and also in stored serum since their recognition is enhanced if complement is present. These antibodies will often show dosage.  Enzyme can enhance the reaction as well as PEG enhancement solution.

Characteristics of anti-Jk^a and anti-Jk^b are as follows:

• gG
• React best after 37^oC with Coombs technique
• Can cause HDN
• Can cause Hemolytic Transfusion reactions that are acute intravascular reactions, or they may be delayed transfusion reactions that show up after the patient's immune system is reexposed and the memory cells quickly produce antibodies to the antigens.  While most of the antibodies discussed in newsletter are more likely to cause extravascular hemolytic transfusion reactions, the Kidd antibodies can activate complement and therefore cause intravascular hemolytic transfusion reactions.

*Room Temperature
**Hemolytic Transfusion Reaction
***Hemolytic Disease of the Newborn

Bg Antibodies

The Bg antibodies were first described by Bennett and Goodspeed.  They are not considered clinically significant, but may mask clinically significant antibodies.  They are antibodies to white cell antigen remnants on red cells

• Anti-Bg^a reacts with Human Leukocyte Antigen (HLA)-B7
• Anti-Bg^b reacts with Human Leukocyte Antigen (HLA)-B17
• Anti-Bg^c reacts with Human Leukocyte Antigen (HLA)-A28

Reactions relating to these antibodies are weak, react possibly at  room temperature or more commonly in the antiglobulin (Coombs) phase.  They react with only a few cells in a cell panel.  They do not cause hemolytic disease of the newborn or hemolytic transfusion reactions.  They are seen frequently seen in multiply transfused patients or in multiparous women (multiple pregnancies)

HTLA ANTIBODIES = High Titer Low Avidity

A summary of these antibodies are as follows

• Not clinically significant, but serological reactions make them look like they are
• High Titer if the antibodies are titered.  The titers are usually at least 1:64 and often will be over 1:1000
• Reactions are very weak and will break apart very readily due to the weak attraction between the antigens and antibodies (low avidity).

These antibodies basically have a high titer but a very weak reaction.  Some institutions actually score the strength of the antigen reaction in points which will allow them to differentiate some of the differences seen in various reactions.

Score = strength of reaction given points or score

• 4+ = 12 points
• 3+ = 10 points
• 2+ = 8 points
• 1+ = 5 points
• neg = 0 points

Specific serologic characteristics of the HTLA antibodies are:

• IgG
• React best in Coombs after 37oC incubation
• W+ to 1+ reactions
• React with most cells (antibodies to high-frequency antigens)
• Not clinically significant since they are not known to cause hemolytic disease of the newborn or hemolytic transfusion reactions.  Since they are antibodies to high-frequency antigens they may mask clinically significant antibodies that are also in the serum.

OBJECTIVES - BLOOD GROUPS OTHER THAN ABO/RH

For each of the blood groups listed below:

1. Recognize and translate the symbols used to denote antigens and antibodies
   
2.  List the major alleles and the relative frequency of each in the Caucasian population. (High-incidence or low-incidence)
    
3. Describe the serological characteristics of the antibodies:

• class
• temperature of reaction
• effect of enzyme
• complement binding
• dosage effect

4. Discuss the clinical significance of each antibody regarding transfusion reactions and hemolytic disease of the newborn
    
5. Describe the relationship between the Duffy system and malaria.
   
6. Describe the typical serological characteristics common to all HTLA antibodies.
   
7. Explain the difference between an antibody's titer and an antibody's score.
    
8. Describe the typical serological characteristics of the Bg antibodies
   
9. Describe the clinical significance of HTLA and Bg antibodies.
    
10. Explain the relationship between white cells and the Bg antibodies.

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