High Prevalence Antigens

High-prevalence antigens, sometimes called “public” antigens, are red cell markers found on the vast majority of the population, often exceeding 99% frequency. While their presence is the norm, their significance in transfusion medicine arises dramatically when a rare individual lacks one of these common antigens and develops a corresponding antibody. This scenario poses a critical challenge: finding compatible (antigen-negative) blood becomes exceptionally difficult, often requiring extensive screening and coordination through rare donor networks

Antigens of High Prevalence: The Common Denominators

Definition: A high-prevalence antigen (sometimes called a public antigen) is a red blood cell surface antigen expressed by almost everyone in a given population (or across multiple populations)

Why are they important in Blood Bank?

Antibodies are Rare: Because most people have the antigen, they usually won’t make an antibody against it (due to self-tolerance). Therefore, antibodies to high-prevalence antigens are infrequently encountered
The Compatibility Crisis: When someone does form an antibody to a high-prevalence antigen (because they are one of the rare individuals lacking it), finding compatible (antigen-negative) blood becomes extremely difficult. Imagine needing blood negative for an antigen that 99.9% of donors have!
Clinical Significance: Many antibodies against high-prevalence antigens are clinically significant, capable of causing Hemolytic Transfusion Reactions (HTR) and/or Hemolytic Disease of the Fetus and Newborn (HDFN)
Key Biochemical Carriers: These antigens can reside on various structures: glycoproteins (like Kell, Lutheran, Gerbich), proteins (like Band 3/Diego, Aquaporin-1/Colton), or even carbohydrate structures (like I, P)

Examples of Important High-Prevalence Antigens

Note: This isn’t exhaustive, but covers many clinically relevant examples

k (Cellano) - Kell System (KEL, ISBT 006)

Biochemistry: Kell glycoprotein
Prevalence: >99% in Caucasians, >99.9% in Black populations. Antithetical to K (Kpa)
Antibody (Anti-k): IgG, clinically significant (HTR, HDFN). Finding k-negative (K+k-) blood is difficult
Antigen-Negative: K+k- individuals. Extremely rare K₀ (Kell null) individuals lack all Kell antigens

Kp^b - Kell System (KEL, ISBT 006)

Biochemistry: Kell glycoprotein
Prevalence: >99.9% in most populations. Antithetical to Kp^a
Antibody (Anti-Kp^b): IgG, clinically significant (HTR, HDFN). Finding Kp(b-) blood is very difficult
Antigen-Negative: Kp(a+b-) or Kp(a-b-) (K₀)

Js^b - Kell System (KEL, ISBT 006)

Biochemistry: Kell glycoprotein
Prevalence: >99.9% in Caucasians, ~80% in Black populations (Js^a is more common in Black populations). Antithetical to Js^a
Antibody (Anti-Js^b): IgG, clinically significant (HTR, HDFN). Finding Js(b-) blood is difficult, especially for non-Black patients
Antigen-Negative: Js(a+b-)

Lu^b - Lutheran System (LU, ISBT 005)

Biochemistry: Lutheran glycoprotein (BCAM)
Prevalence: >99% in most populations. Antithetical to Lu^a
Antibody (Anti-Lu^b): Usually IgG, sometimes IgM/mixed. Can cause mild-moderate HTR (often delayed) and mild HDFN
Antigen-Negative: Lu(a+b-) or rare Lu(a-b-) null phenotypes. Finding Lu(b-) blood is difficult

U - MNS System (MNS, ISBT 002)

Biochemistry: Associated with Glycophorin B (GPB). Present when either S or s antigen is expressed normally
Prevalence: >99.9% in Caucasians, slightly lower but still very high in Black populations (~99%)
Antibody (Anti-U): IgG, highly clinically significant (severe HTR, severe HDFN)
Antigen-Negative: U-negative individuals are almost exclusively of African descent and lack GPB (usually S-s- phenotype). Finding U-negative blood is extremely challenging and requires screening donors of African ancestry

I - I System (I, ISBT 027)

Biochemistry: Branched carbohydrate structure on precursor chains (related to ABO). ‘I’ develops from fetal ‘i’ antigen during the first ~18 months of life
Prevalence: Virtually 100% in adults. (Fetal/newborn cells are rich in i, poor in I)
Antibody (Anti-I): Usually a benign, cold-reacting IgM autoantibody. Can cause issues in cold temperatures (Cold Agglutinin Disease) or interfere with room temperature/immediate spin testing. Pathologic anti-I can be potent IgM hemolysins. Alloanti-I is extremely rare (seen in adult i phenotype individuals)
Antigen-Negative: Rare adult i phenotype individuals

Vel - Vel System (VEL, ISBT 035)

Biochemistry: Carried on protein SMIM1
Prevalence: >99.9% in most populations
Antibody (Anti-Vel): Often mixed IgG/IgM, potent complement activator. Highly clinically significant (severe immediate HTR). Known for being difficult to identify serologically (weak/variable reactions)
Antigen-Negative: Vel-negative phenotype is very rare (<0.01%). Finding Vel-negative blood is exceptionally difficult, relying heavily on rare donor registries

J MH (John Milton Hagen) - J MH System (J MH, ISBT 026)

Biochemistry: Located on Semaphorin 7A (CD108), a GPI-linked protein
Prevalence: >99.9% in most populations
Antibody (Anti-J MH): Usually IgG, often weak, refractile, and difficult to work with (“nebulous”). Generally considered clinically insignificant or only causing mild RBC destruction. Can mask other significant antibodies. Antigen expression can be weak or variable
Antigen-Negative: J MH-negative is extremely rare

Di^b - Diego System (DI, ISBT 010)

Biochemistry: Located on Band 3 protein (Anion Exchanger 1)
Prevalence: >99.9% in most non-Asian/Native American populations. Antithetical to Di^a
Antibody (Anti-Di^b): IgG, clinically significant (HTR, HDFN)
Antigen-Negative: Di(a+b-) individuals (more common in East Asian/Native American populations)

Wr^b - Diego System (DI, ISBT 010)

Biochemistry: Requires interaction between Band 3 and Glycophorin A
Prevalence: >99.9% in most populations. Antithetical to Wr^a
Antibody (Anti-Wr^b): Extremely rare (as antigen is high prevalence). Can be IgG, potentially significant. More common is autoanti-Wr^b in Warm Autoimmune Hemolytic Anemia (WAIHA)
Antigen-Negative: Wr(a+b-) individuals

Co^a - Colton System (CO, ISBT 015)

Biochemistry: Located on Aquaporin-1 (water channel)
Prevalence: >99.7% in most populations. Antithetical to Co^b
Antibody (Anti-Co^a): IgG, clinically significant (HTR, HDFN)
Antigen-Negative: Co(a-b+) or rare Co(a-b-) null phenotype

Ge3 - Gerbich System (GE, ISBT 020)

Biochemistry: Located on Glycophorin C (GPC) and Glycophorin D (GPD)
Prevalence: >99% in most populations
Antibody (Anti-Ge3): IgG, clinically significant (HTR, HDFN)
Antigen-Negative: Individuals with Gerbich null phenotypes (e.g., Ge:-2,-3,-4 or Leach phenotype). Finding Ge3-negative blood is difficult

Emm - EMM System (EMM, ISBT 044)

Biochemistry: Unknown protein carrier (as of recent knowledge, may be updated)
Prevalence: >99.99% (extremely high)
Antibody (Anti-Emm): IgG, potent complement activator. Highly clinically significant (severe HTR, HDFN)
Antigen-Negative: Emm-negative phenotype is exceedingly rare. Finding compatible blood requires extensive international collaboration

Challenges and Management

Identification: Confirming the antibody specificity often requires testing against a panel of rare antigen-negative cells, typically done in an Immunohematology Reference Laboratory (IRL)
Finding Compatible Blood: This is the major hurdle. Strategies include:
- Screening large numbers of donors (thousands)
- Utilizing national and international Rare Donor Programs
- Testing family members (siblings have a 1 in 4 chance of having the same rare phenotype)
- Autologous donation: (patient donating for themselves) if the need is anticipated and the patient is eligible
- Molecular genotyping of donors can sometimes help identify rare antigen-negative units more efficiently
Clinical Decisions: Balancing the risk of transfusion reaction vs. the risk of delaying transfusion. Sometimes, the “least incompatible” blood might be considered in emergencies if truly antigen-negative blood is unavailable, but this carries significant risk

Key Terms

High-Prevalence Antigen: An antigen found on the red blood cells of a very large percentage (typically >99%) of a given population
Null Phenotype: A rare phenotype where an individual lacks all antigens within a specific blood group system (e.g., K₀, Rh_null, Lu(a-b-)). These individuals may produce complex antibodies reacting with all cells except those of the same null type
Rare Donor Program: A system or registry (often national or international) that catalogs donors known to have rare blood types (lacking high-prevalence antigens or possessing combinations of uncommon antigens) to facilitate finding compatible blood for patients with rare antibodies
Reference Laboratory (Immunohematology Reference Laboratory - IRL): A specialized laboratory equipped with the reagents (including rare antisera and antigen-typed cells), techniques, and expertise to investigate and resolve complex immunohematology problems, including identifying antibodies to high- and low-prevalence antigens
Clinically Significant (Antibody): An antibody capable of causing adverse reactions to transfusion (Hemolytic Transfusion Reactions - HTR) or causing Hemolytic Disease of the Fetus and Newborn (HDFN). Many antibodies to high-prevalence antigens fall into this category
Antithetical Antigen: One of a pair of antigens encoded by alleles at the same gene locus (e.g., K and k, Fy^a and Fy^b). If an antigen is high prevalence (like k), its antithetical partner (K) is often low prevalence

Other Blood Groups

Low Prevalence Antigens