Other Blood Group Systems, Collections, and Series

Blood group systems not described in other chapters are discussed here, as well as antigens that have not yet been assigned to a blood group system. The International Society of Blood Transfusion (ISBT) classifies RBC antigens and also denotes them as low-frequency or high-frequency. Low-frequency antigens have a prevalence of less than 1% while high-frequency antigens have a prevalence of greater than 90%. Per ISBT, blood group system “ consists of one or more antigens controlled at a single gene locus, or by two or more very closely linked homologous genes with little or no observable recombination between them. ”

There are 36 blood group systems comprising more than 316 different RBC antigens. Some of the blood group systems of interest in transfusion medicine discussed in this chapter are shown diagrammatically in Fig. 30.1 . A number of antigens (currently 38) cannot yet be assigned to a system due to lack of information. These antigens are grouped into a collection or series. A collection “ consists of serologically, biochemically, or genetically related antigens ,” while antigens not able to be classified into a system or collection are grouped according to prevalence in a series: low-prevalence antigens are the 700 series and high-prevalence antigens the 901 series .

Blood group systems in this chapter are divided into three categories:

1.
Potentially clinical significant
2.
Sometimes clinically significant
3.
Not considered clinically significant

Importantly, there can always be exceptions to these classifications.

Potentially Clinically Significant Blood Group Systems

Dombrock System

Dombrock system currently consists of 10 antigens that include common polymorphic Do ^a and Do ^b , and several high-prevalence antigens including Gy ^a , Hy, and Jo ^a . Null phenotype, Gy(a−), is rare. Hy− and Jo(a−) are found in black individuals and are associated with weak expression of Do ^a and Do ^b . Dombrock antigens are carried on adenosine diphosphate ribosyltransferase (Dombrock glycoprotein), which is linked to RBC membrane by glycosylphosphatidylinositol (GPI). Antibodies to Do ^a and Do ^b are usually found in sera containing other RBC alloantibodies and are often weakly reactive, making them difficult to identify. In addition, these antibodies often drop over time to undetectable levels. Anti-Do ^a and anti-Do ^b have caused acute and delayed hemolytic transfusion reactions (HTRs); hemolytic disease of the fetus and newborn (HDFN) has not been reported. Antibodies to Gy ^a , Hy, and Jo ^a cause moderate delayed HTR and no HDFN.

Diego System

Diego antigens are carried on Band 3 (AE-1) that functions as the major chloride–bicarbonate exchanger in the RBC membrane important for CO ₂ transport and a major structural RBC membrane protein. Absence of Band 3 is thought not to be compatible with life. Diego antigens include two pairs of antithetical antigens (Di ^a /Di ^b and Wr ^a /Wr ^b ) and ∼18 other low-prevalence antigens. Di ^b is the high-prevalence antigen, and Di ^a is rare in all but some North and South American groups where it can occur in 11%–54% of individuals. Uniquely, expression of high-prevalence Wr ^b antigen is dependent on both Band 3 and glycophorin A (MN). Anti-Di ^a and anti-Di ^b have caused HTRs and HDFN. Anti-Wr ^a is relatively common antibody reported in 1%–8% of normal donors and 30% of patients with autoimmune hemolytic anemia. Antibody is IgG and/or IgM and can occur with or without RBC exposure. Anti-Wra has caused HTRs and HDFN. Anti-Wr ^b is rare but potentially causes HTR but has not caused HDFN.

Colton System

Colton antigens reside on RBC water channel protein aquaporin-1 (AQP-1). Co ^a and Co4 are high-prevalence antigens, and Co ^b is found in 8% of Caucasians and is uncommon in other ethnic groups. Co(a−b−) phenotype, which is also called Co:−3 or Co null is very rare. Antibodies have been implicated in HTR and mild to severe HDFN.

Gerbich System

Gerbich antigens are carried on glycophorin C and glycophorin D, which are products of a single gene ( GYPC ) using alternative initiation sites. System includes high-prevalence antigens Ge2, Ge3, and Ge4 and number of other high- and low-prevalence antigens. There are three Gerbich system phenotypes: the Yus type (Ge:−2, 3, 4; individuals with this phenotype can form anti-Ge2), the Gerbich type (Ge:−2, −3, 4; individuals with this phenotype can form anti-Ge2 or -Ge3) and the Leach type (Ge:−2, −3, −4; individuals with this phenotype are true nulls for glycophorin C and D and can form anti-Ge2, -Ge3, or -Ge4). Antibodies variably cause HTR, and anti-Ge3 has caused late onset HDFN. Antibodies to low-prevalence antigens rarely result in HDFN.

Augustine System

High-prevalence antigens AUG2 (a.k.a., At ^a ) and AUG1 belong to Augustine System as of 2015. Antigens are carried on RBC equilibrative nucleoside transporter 1 (ENT1) protein, which is responsible for adenosine transport across the plasma membrane. Anti-AUG2 is made by rare individuals of African ancestry whose RBCs lack the AUG2 (At ^a ) antigen. One individual of European ancestry whose RBCs typed AUG:−2 but plasma antibody reacted with all RBCs tested including those that were AUG2—was found to be deficient in ENT1. Total lack of ENT1 defines AUG-null or AUG:−1,−2 phenotype and antibody produced by these individuals is anti-AUG1. Anti-AUG2 has been implicated in HTRs and increased RBC clearance. Both anti-AUG1 and anti-AUG2 have caused mild or no HDFN.

Vel System

High-prevalence Vel antigen was assigned to its own blood group system in 2015. A protein called small integral membrane protein 1 (SMIM1) is lacking in individuals with Vel− phenotype. SMIM1 function is unknown. It is well documented that anti-Vel can be IgG and/or IgM and activate complement and can cause mild to severe HTRs. HDFN due to anti-Vel is not common.

Blood Group Systems Sometimes Clinically Significant

Cromer System

Cromer antigens are carried on decay accelerating factor (DAF), a complement regulatory protein that is anchored to RBC membrane by GPI and serves to regulate complement activation. DAF is missing from RBCs of patients with paroxysmal nocturnal hemoglobinuria (PNH) because they are deficient in all GPI-linked proteins. Cromer antigens are present on leukocytes, platelets, and placental trophoblasts and, in a soluble form, in plasma and urine. There are 16 high- and 3 low-prevalence antigens in the system. Individuals lacking all Cromer antigens have the Inab (Cr null) phenotype and are lacking DAF protein but have normal GPI expression in contrast to individuals with PNH. Reports of Cromer antibodies indicate variable potential clinical significance as determined by monocyte monolayer assays (MMAs), ⁵¹ Cr survival studies, or clinical data after transfusion of antigen-positive RBCs. They do not cause HDFN as placenta is a rich source of DAF, offering an alternative target to the RBCs for binding antibodies.

Lutheran System

Lutheran antigens are carried on glycoproteins that belong to a family of adhesion molecules known as B-CAM. The system consists of 24 antigens, but the major antigens are Lu ^a (low prevalence) and Lu ^b (high prevalence). The rare Lu _null phenotype is a result of homozygous inheritance of inactive Lutheran gene ( LU ), while severe reduction in expression of Lutheran antigens, often detectable only by adsorption/elution, is associated with heterozygous mutation in erythroid transcription factor gene EKLF . This “inhibitor phenotype” is termed In(Lu), and mutation in EKLF prevents normal expression of Lutheran and other blood group antigens (P1, AnWj, In ^a , and In ^b ). Mutation in erythroid transcription factor GATA-1 also results in X-linked depression of Lutheran antigen expression. Lutheran antigens are poorly developed at birth. Anti-Lu ^a has not been associated with HTRs and has rarely been associated with mild HDFN. Anti-Lu ^b has been reported to cause mild HTRs and mild HDFN. Anti-Lu3 is found in immunized individuals with the Lu(a−b−), i.e., Lu _null phenotype, and may cause delayed HTRs or HDFN.

Indian System

Indian antigens, In ^a (low prevalence) and In ^b INFI, INJA, and INRA (high prevalence), are located on CD44, a widely distributed cell adhesion molecule. Antibodies are not generally clinically significant, but there is one report of anti-In ^b associated with HTR. The high-prevalence antigen AnWj is currently assigned to 901 series of antigens and not Indian System; however, it also appears to be carried on or associated in some way with CD44. Antibodies to AnWj have caused serious HTRs, and In(Lu) RBCs (see above) are recommended for transfusion.

Scianna System

Seven Scianna antigens are carried on ERMAP (erythrocyte membrane-associated protein). Sc1 (high prevalence) and Sc2 (low prevalence) are antithetical, while Sc3, STAR, SCER, and SCAN are of high prevalence and Rd is of low prevalence. Very rare Scianna-null individuals make anti-Sc3. Antibodies to all Scianna antigens are rare. Antibodies to Scianna high-prevalence antigens have not been reported to cause HTRs or HDFN, while anti-Sc2 has resulted in mild HDFN.

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