Minor Antigens

While at least 30 minor antigens are known, this review will focus on those of clinical significance, i.e., those known to cause hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. One of the most immunogenic minor antigen groups is the Rh group system, which is composed of over 45 different antigens, with the most common being the D and CcEe antigens. 6-8 Most Rh antibodies to Rh antigens arise secondary to exposure to blood, typically via transfusion, though pregnancy is another common source of exposure. Anti-RhD is of critical importance in prenatal and obstetric care, as its presence can cause a severe form of hemolytic disease of the fetus and newborn, with resulting hydrops fetalis and possible fetal demise. This can also be seen with anti-c and anti-E, but is often less severe. 6 Importantly, anti-RhD effects can be prevented in pregnancy through administration of RhO (D) immunoglobin to the parturient.

The Kell blood group system, most commonly K and k, are RBC transmembrane proteins. While many phenotypes exist, k negative is the most common, resulting in anti-k antibody being found in much of the population. Anti-k antibody is known to cause severe hemolytic transfusion reactions. While extremely rare, another phenotype of clinical significance is Kell-null, or the absence of any Kell antigens. Kell-null individuals produce antibodies to all Kell antigens, and so require Kell-null blood, which often requires a lengthy search through rare donor registries.

The Duffy blood group system antigens, most commonly Fya and Fyb (though multiple other antigens exist), are also RBC membrane proteins and are thought to act as a chemokine receptor for proinflammatory cytokines. 8 Antibodies to Duffy antigens can lead to hemolytic reactions of varying severity. Donors negative for all Duffy antigens are rare but are more common in individuals of African descent.

The Kidd blood group system (Jka, Jkb), are also membrane proteins, thought to play a role in reducing osmotic stress to the RBC. While absence of this protein is rare, individuals of Filipino descent are more likely to be Kidd antigen negative. This is of note because Kidd antigen antibodies have a short half-life, and levels will rapidly decline in plasma, making them difficult to detect. Cases of delayed hemolytic transfusion reaction due to presence of anti-Kidd antibody have been reported, despite negative antibody screen.

Lastly, the MNSs blood group system is based upon a large group of glycoproteins, with many possible phenotypes. While most antigens are clinically insignificant, the absence of the antigens S, s, and/or U result in antibodies that cause severe immediate and delayed hemolytic transfusion reaction.

Blood Typing

In patients for whom the need for a transfusion is possible, but unlikely, a type and screen is often ordered. A common example would be ordering a type and screen for an otherwise healthy woman expected to have an uncomplicated spontaneous vaginal delivery. A type and screen is a series of laboratory tests that analyze both a patient’s RBCs and serum for the presence of RBC antigens and antibodies that could lead to a potentially harmful hemolytic reaction if not screened for prior to administration of blood. Determining a patient’s blood type, i.e. which ABO and RhD antigens are expressed on the patient’s RBCs, is completed in two steps – forward and reverse typing. Forward type, or cell grouping, involves exposure of a patient’s RBCs to anti-A, B, AB, and D reagents that will bind to A, B, and D antigens if present on the RBC cell membrane. If the sample agglutinates on exposure to the reagents, then the antigen is present. Reverse type, or serum grouping, involves exposure of a patient’s serum to standard RBCs of known blood type (A, B, and occasionally O). If the sample agglutinates or hemolysis is present, then antibodies against specific ABO blood group antigens are present. For example, a patient with A+ blood type would agglutinate on forward typing to anti-A, anti-AB, and anti-D reagents, while on reverse typing, agglutination or hemolysis will be present once B type cells are exposed to the A type serum, indicating the presence of antibodies
against B antigens.

It is possible for forward and reverse typing incongruence and inconclusive results to occur, referred to as ABO-type discrepancy. While rare under typical circumstances, there are recognized causes of ABO-type discrepancy that can be obtained from a patient’s medical history. These include recent massive transfusion, out of group platelet transfusion, and a dysfunctional immune system, such as patient with a hematologic malignancy. If ABO-type discrepancy occurs on type and screen for these select patients, use of universal donor products should be considered.