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Low Prevalence Antigens

Low-prevalence antigens (LPA) are the rare counterparts to common blood group markers. While finding compatible blood for patients with antibodies to LPAs is generally straightforward, the primary challenge lies in the initial detection and identification of these often-elusive antibodies, frequently revealed only by an incompatible crossmatch. Their clinical significance varies and must be evaluated individually

While antibodies to high-prevalence antigens create a finding compatible blood crisis, antibodies to low-prevalence antigens present a different set of challenges, primarily around their initial detection and confirmation

Antigens of Low Prevalence: The Rarities

  • Definition: A low-prevalence antigen (LPA), sometimes called a “private” antigen, is a red blood cell surface antigen expressed by only a small percentage of a given population, typically ranging from <0.1% up to maybe 10%, depending on the specific antigen and population
  • Biochemical Basis: Like all blood group antigens, LPAs arise from genetic variations (often SNPs) that alter the structure of proteins or glycoproteins on the red cell surface, or modify carbohydrate structures. Many LPAs are the antithetical partners to high-prevalence antigens (e.g., K is the LPA partner to the high-prevalence k antigen)

Key Characteristics and Implications

  • Antibody Frequency: Because the antigen is rare, exposure through transfusion or pregnancy is uncommon. Therefore, antibodies to LPAs are also relatively infrequently encountered in routine testing
  • Antibody Detection Challenge: This is the main issue. When a patient does form an antibody to an LPA:
    • It will likely be non-reactive with standard antibody screening cells, as these cells are usually chosen to represent common antigen profiles and will likely lack the specific LPA
    • It may react with only one cell on a larger identification panel, if that panel happens to include a cell positive for the rare antigen. This single reaction can sometimes be dismissed as insignificant or difficult to interpret
    • The antibody might only be detected during the crossmatch phase if the selected donor unit happens to be positive for the specific LPA the patient has an antibody against. This is a classic cause of an “unexpected incompatible crossmatch” with a negative antibody screen
  • Finding Compatible Blood: This is generally EASY. Since the antigen is rare, the vast majority of random donors will be antigen-negative and therefore compatible (assuming the antibody has been correctly identified)
  • Clinical Significance: Varies widely! Some antibodies to LPAs are clinically significant and capable of causing HTR and HDFN (e.g., anti-K, anti-Jsa, anti-Wra), while others are considered insignificant or have low clinical relevance. Significance must be assessed for each specific antibody

Examples of Important Low-Prevalence Antigens

Many LPAs are the less common partner in an antithetical pair within major blood group systems

K (Kell) - Kell System (KEL, ISBT 006)

  • Biochemistry: Kell glycoprotein
  • Prevalence: ~9% in Caucasians, ~2% in Black populations. Antithetical to k (high prevalence)
  • Antibody (Anti-K): IgG, highly clinically significant (can cause severe HTR and HDFN). One of the most common clinically significant antibodies outside of ABO/Rh
  • Antigen-Positive: K+k+ or K+k- individuals

Kpa (Penney) - Kell System (KEL, ISBT 006)

  • Biochemistry: Kell glycoprotein
  • Prevalence: ~2% in Caucasians, very rare in Black populations. Antithetical to Kpb (high prevalence)
  • Antibody (Anti-Kpa): IgG, clinically significant (HTR, HDFN)
  • Antigen-Positive: Kp(a+b+) or Kp(a+b-) individuals

Jsa (Sutter) - Kell System (KEL, ISBT 006)

  • Biochemistry: Kell glycoprotein
  • Prevalence: ~20% in Black populations, very rare (<0.1%) in Caucasians. Antithetical to Jsb (high prevalence in Caucasians)
  • Antibody (Anti-Jsa): IgG, clinically significant (HTR, HDFN)
  • Antigen-Positive: Js(a+b+) or Js(a+b-) individuals

Lua - Lutheran System (LU, ISBT 005)

  • Biochemistry: Lutheran glycoprotein (BCAM)
  • Prevalence: ~8% in Caucasians, less common in other populations. Antithetical to Lub (high prevalence)
  • Antibody (Anti-Lua): Often IgM or mixed IgM/IgG, often naturally occurring. Can cause mild HTR, HDFN usually mild or absent. Known for characteristic loose/mixed-field agglutination
  • Antigen-Positive: Lu(a+b+) or Lu(a+b-) individuals

Dia - Diego System (DI, ISBT 010)

  • Biochemistry: Located on Band 3 protein (Anion Exchanger 1)
  • Prevalence: Low prevalence in Caucasians and Black populations (<0.1%), but significantly higher (up to 36% or more) in Native American and East Asian populations. Antithetical to Dib (high prevalence)
  • Antibody (Anti-Dia): IgG, clinically significant (HTR, HDFN). Importance varies geographically
  • Antigen-Positive: Di(a+b+) or Di(a+b-) individuals

Wra (Wright) - Diego System (DI, ISBT 010)

  • Biochemistry: Requires Band 3 protein
  • Prevalence: ~0.1% in Caucasians. Antithetical to Wrb (high prevalence)
  • Antibody (Anti-Wra): Can be IgM or IgG, naturally occurring or immune stimulated. Clinically significant (can cause severe HTR, HDFN). Sometimes seen as an autoantibody
  • Antigen-Positive: Wr(a+b+) or Wr(a+b-) individuals

Cob - Colton System (CO, ISBT 015)

  • Biochemistry: Located on Aquaporin-1 (water channel)
  • Prevalence: ~10% in Caucasians. Antithetical to Coa (high prevalence)
  • Antibody (Anti-Cob): IgG, clinically significant (HTR, HDFN)
  • Antigen-Positive: Co(a+b+) or Co(a-b+) individuals

Other Examples

  • V (MNS System): Low prevalence overall, but higher in Black populations (~30%)
  • Mg (MNS System): Low prevalence antigen associated with specific GPA variants. Anti-Mg can be significant
  • Various antigens within the Miltenberger subsystem (MNS System): A complex group of LPAs resulting from rearrangements of GYPA, GYPB, and GYPE genes
  • Sc2 (Scianna System): Low prevalence (~1%), antithetical to Sc1 (high prevalence). Anti-Sc2 can cause HTR/HDFN

Challenges and Management

  • Identification: Requires testing patient plasma/serum against panel cells known to be positive for various LPAs. This is often done in a reference laboratory setting. Testing family members can sometimes help if the antibody specificity is suspected but unconfirmed
  • Crossmatching: A serological crossmatch remains crucial. It’s the final check and the most likely place to detect an antibody to an LPA if the antibody screen was negative
  • Transfusion: If an antibody to an LPA is identified and considered clinically significant, antigen-negative blood should be provided. As noted, this is usually readily available
  • HDFN: If a pregnant person has an antibody to an LPA, the father of the baby should be phenotyped (or genotyped) for the antigen. If he is positive, the fetus is at risk of inheriting the antigen and developing HDFN

Key Terms

  • Low-Prevalence Antigen (LPA): An antigen found on the red blood cells of only a small percentage (typically <10%, often much lower) of a given population. Also sometimes called a “private” antigen
  • Antithetical Antigen: One of a pair of antigens encoded by alleles at the same gene locus (e.g., K and k, Lua and Lub). Often, if one is high prevalence, the other is low prevalence
  • Crossmatch: A laboratory test performed before transfusion to determine serological compatibility between donor red blood cells and patient plasma/serum. It serves as a final check for unexpected antibodies, including those against low-prevalence antigens potentially missed by antibody screening
  • Antibody Screen (Antibody Detection Test): A test using reagent red blood cells with known, common antigen profiles to detect the presence of unexpected antibodies in patient plasma/serum. May miss antibodies to low-prevalence antigens if the screening cells lack the specific antigen
  • Reference Laboratory (Immunohematology Reference Laboratory - IRL): A specialized laboratory with the resources (rare reagents, extensive panels, molecular capabilities) and expertise to identify complex antibodies, including those directed against 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). Antibodies to some low-prevalence antigens (like K, Wra) are significant, while others may not be