Rh Blood Group System and HDFN

KN Antibodies

• Clinically insignificant, not implicated in HDFN or HTR.
• IgG antibodies can be detected with AHG (Anti-Human Globulin test).
  • Anti-Kn^a is the most common antibody in the Knops blood group.
  • Commonly found in multiply transfused individuals and multi-specific antisera.
  • Anti-Ge4 is very rare and frequently found in the black population.

Indian System (023)/In

• The individuals first found to have the antigen are coming from India.
• The CD44 gene is located on Chromosome 11.
  • CD44 acts as an adhesion molecule

IN Antigens

• There is In^a which presents with low prevalence.
• There is In^b which presents with high prevalence.
• Carried by CD44.
• Weakly expressed on cord RBCs.
• Sensitive to Ficin, papain, and DTT.
• Resistant to acid glycine EDTA.

NULL/WEAK Phenotype

• In(a-b-) is extremely rare, has only been found in a patient with congenital dyserythropoietic anemia.
• Depressed on In(Lu) RBCs, which correlates to the Lutheran inhibitor gene.
  • Connected to the reduced amount of CD44, occurs in the case of individuals who have dominant null lu phenotype mainly because of the inheritance of inhibitor gene, In(Lu).

IN Antibodies

• Anti-In^a and Anti-Inb (IgG).
  • Enhanced by AHG
  • Causes HTR but no HDN
    • Anti-In^a has a possibility of decreased RBC survival
    • Anti-Inb reported to cause immediate hemolytic transfusion reaction
  • Highly reactive at AHG testing

OK System (024)/OK

• The OK blood group system was named after Mrs. Kobutso, a native Japanese who was the first patient to produce the antibody against the antigen.KO from kobutsu was reversed d/t confusion w/ kell, hence OK
• BSG gene is located on Chromosome 19.
  • Basigin Protein (CD147) is a member of the immunoglobulin super family that mainly functions as receptors and adhesion molecules.
  • It is the invasion molecule of the malaria parasite, Plasmodium falciparum.

OK Antigens

• Ok^a antigen.
  • The glycine molecule of Ok^a was changed to valine
• OKGV
  • Valine molecule from OKGV was replaced by methionine
• Carried by CD147 (Basigin Protein).
• These antigens are well developed in newborns.
• Resistant to Ficin, papain, DTT and Glycine acid EDTA.

OK Antibodies

• Anti-Ok^a is rare.
  • IgG
  • Highly reactive on AHG test
  • Induce reduced survival of red cells
  • Not implicated with HDFN mainly because of the rarity of the phenotype
    • However, it is reported to cause reduced survival of red cells containing Ok^a antigen.

RAPH System (025)

• The name of the blood group system was derived from the first person found to produce the anti-MER2, Raph.
  • MER2 name origin
    • M- was identified as a monoclonal antibody;
    • ER- the initial of the laboratory where it was first studied, the Eleanor Roosevelt Laboratory
• CD151 gene on Chromosome 11.
  • Tetraspanin (CD151)
    • A protein that is essential for the assembly of the basement membranes in the kidney and skin.

RAPH Antigens

• MER2 antigen
  • Abundant in platelets and erythroid precursors, and other tissues
    • The antigen will reduce if the red blood cell starts to mature
    • Even if you are negative to MER2, you will not produce the antibody, mainly because the antigen is present in other tissues, particularly in the platelets.
  • Resistant to Ficin and papain
  • Sensitive to trypsin, alpha-chymotrypsin, pronase, AET

RAPH Antibodies

• Anti-MER2 (IgG).
  • Reactive at AHG phase.
  • Only produced by individuals who are true negative for the MER2 gene.
  • Found in individuals with end-stage renal disease
    • Due to the presence of anti-MER2 attacking the tetraspanin present in kidneys
• May cause HTR, but not HDN.
  • Only one individual was found to experience HTR who was transfused with three units of packed RBCs

JMH System (026)

• From John Milton Hagen, who first produced the antibody against the JMH antigen.
• SEMA7A gene on Chromosome 15.
  • CD108 is produced and where the antigens of JMH blood group system reside

JMH Antigens

• JMH1 antigen
  • The originally known antigen.
  • Found on RBCs, placenta, thymus, testes.
  • Weak on cord RBCs.
    • The JMH antigen will be expressed further, but will start to decline at the age of 50 and above.
  • Sensitive to Ficin, papain, and DTT.
  • Resistant to glycine acid EDTA.
• Other antigens: JMH2, JMH3, JMH4, JMH5, JMH6.
  • Could also be found in the thymus, placenta, testes.

JMH Antibodies

• Anti-JMH (IgG).
  • Reactive in AHG phase.
  • Found in high titers but are weakly reactive, therefore it is considered clinically insignificant.
  • Do not cause HTR or HDN.

Gill System (029)

• AQP3 gene on Chromosome 9.
  • AQP3 or glycerol transporter aquaporin-3 which is a member of the major intrinsic protein family of water and glycerol channels

GIL Antigens

• GIL Antigen
  • Carried by AQP3.
  • Resistant to glycine-acid EDTA and DTT.
  • Enhanced by Ficin and papain

GIL Antibodies

• Anti-GIL
  • IgG
    • Reactive at 37 degree Celsius
    • Enhanced by AHG
  • Cause HTR but not HDFN
    • Only one case reported HTR

RH-Associated Glycoprotein System (030)

• RHAG gene on Chromosome 6.
  • RHAG glycoprotein
    • Does not contain the antigens in itself but needs to be in complex with the Rh proteins to express the Rh antigens: D, C ,E
      • If not present, it will lead to a null phenotype.

RHAG Antigens

• High prevalence
  • Duclos, DSLK, RHAG 4
• Low prevalence
  • Ola

RHAG Antibodies

• Anti Duclos, Anti Ola, Anti DSLK.
  • Significance is still unknown.
  • Rarely encountered.
• Anti RHAG 4
  • Only one case that caused HDFN
  • Its significance is still unknown for transfusion.

FORS System (031)

• Named after the person who discovered it, Mr. John Frederick Forssman
• GBGT1 gene on Chromosome 9.
  • The product is a glycosyltransferase by adding a sugar molecule (N-acetylgalactosamine) to the P antigen.

FORS Antigens

• FORS1
  • Said to be another subgroup of A
    • Assigned as: Apae - Mainly because of its immunodominant sugar which is the N-acetylgalactosamine which is similar to the immunodominant sugar of A antigen.
  • Addition of GalNac to P antigen
  • Receptor for E. coli
    • A lot of FORS1 antigen can be more susceptible to E. coli infection.
  • FORS1 glycolipid is not normally expressed in the RBC but rather can be found in other tissues whether they are healthy/malignant such as the:
    • Reported to expressed the FORS1 antigen:
      • Gastric tissues
      • colonic mucosa
      • Lungs
      • kidney
  • Enhanced with Ficin and papain.
  • Resistant to DTT and glycine-acid EDTA.

FORS Antibodies

• Anti-FORS1 (IgM)
  • Reactive at 4°C (cold reacting antibodies)
  • Unknown clinical significance.

JR System (032)

• Named after the patient who was able to produce an antibody against this antigen named Rose Jacobs (RJ → JR)
• ABCG2 gene on Chromosome 4
  • Member of the adenosine triphosphate binding cassette transporters (ATP binding cassette transporter)
    • Distributed all throughout the body
    • Gives problems in chemotherapy
    • Involved in the multidrug resistance of the tumor cells

JR Antigens

• Jra
  • Fully developed at birth
  • Resistant to Ficin, papain, DTT, glycine acid EDTA

JR Antibodies

• Anti-Jra (IgG)
  • Causes HDFN and HTR
  • Reactive in body temperature.

LAN System (033)

• ABCB6 gene on Chromosome 2.
  • Member of the adenosine triphosphate binding cassette transporters (ATP binding cassette transporter)
    • Functions in heme synthesis
    • ATP dependent uptake of heme and porphyrins into the mitochondria.

LAN Antigens

• Lan (99%)
  • High incidence antigen (99% of the population)
  • Present not only in the red cell but widely expressed in the:
    • Heart, skeletal muscle, fetal liver, eye, mitochondrial membrane, and Golgi apparatus.
  • Resistant to Ficin, papain, DTT, and glycine acid EDTA.

LAN Antibodies

• Anti-Lan (IgG)
  • Causes HTR (Hemolytic transfusion Reaction)and mild HDFN
  • Binds complement
  • Clinically significant

VEL System (034)

• SMIM1 gene on Chromosome 1
  • Produces SMIM1 protein

VEL Antigens

• Vel
  • Located in a single-pass integral membrane protein (SMIM1 protein)
  • Enhanced with to Ficin and papain
  • Resistant to DTT and glycine acid EDTA

VEL Antibodies

• Anti Vel (IgG and IgM)
  • IgG form (most common)
  • Causes HTR and severe HDFN
    • Severe forms of hemolytic transfusion reaction
    • Severe hemolytic disease of fetus and newborn
  • Clinically significant
  • Has the ability to activate complement which can cause both in vivo and in vitro hemolysis
  • The reaction of the antibody with the Vel antigens is going to vary on the red cell of one individual to another
    • There could be instances that weak Vel reacting red cells could pick a side or can be detected as Vel negative
  • Weak Vel → Vel Negative (Dangerous)
    • Can bind to compliments
    • Which can result in severe cases of HTR as well as HDFN
    • Could lead to difficulties in navigating its presence (clinically significant)

CD59 System (035)

• CD59 gene on Chromosome 11
  • Glycosylphosphatidylinositol (GPI) linked complement regulatory protein
    • Also known as Membrane inhibitor of lysis (MIRL)
  • MIRL - key role in detecting complement regulated hemolysis by interfering with the membrane attack complex by inhibiting the binding of C8 and C9

CD59 Antigens

• CD59.1
  • Located in CD59 protein
  • Enhanced by enzymes
  • Sensitive to DTT
  • Associated with PNH (Paroxysmal Nocturnal Hemoglobinuria)
    • PNH Patients
      • Deficient in all GPI linked proteins including CD59
    • No CD59 → red cells are prone to lysis
      • Since membrane complex cannot be inhibited
      • No protein can inhibit the binding of the C8 and C9

CD59 Antibodies

• Anti-CD59.1 (IgG)
  • Patients with CD59 deficiency will show PNH-like symptoms such as:
    • Hemolysis, strokes, and Neuropathy

Augustine System (036)

• SCL29A1 gene on Chromosome 6
  • Codes for a protein equilibrative nucleoside transporter 2 (ENT2) where AUG antigens are located

AUG Antigens

• Three types:
  • AUG1
  • AUG2 (Ata)
    • High prevalence
  • AUG3
• AUG1 and AUG2 (Ata)
  • Fully developed at birth
  • Resistant to Ficin, papain, DTT, glycine-acid EDTA

AUG Antibodies

• Anti Ata (IgG)
  • Causes severe HTR and mild HDFN (one case)
• Anti AUG3
  • Causes severe HDFN
• All are considered clinically significant

ISBT Blood Group Collections

• Blood groups whose antigens tend to have a biochemical or serologic and genetic information and relationship
• However, they do not meet the standards or the criteria for it to be called a system and thus remained to be an ISBT blood group collection
  • Requires further studies for it to be considered as a blood group system
• This collection has a series of 200
• Some are unnamed however they are already having their symbols
• Has antigens that are considered to of low and high prevalence
  • Cost (COST)

Antigens Present

• Csa
  • High prevalence (95%)
• Csb
• Er (ER)

Three Antigens

• Era
• Erb
• Er³

Era and Er³

• High prevalence

• Majority tend to have this antibody

• GLOB

  • Associated with another blood group which is P1PK
  • Antigen Present

• LKE

• High prevalence with 98% of the population

• UNAMED BLOOD GROUP COLLECTION

  • Antigens Present

• Le^c

• Le^d

  • Both antigens have a very low prevalence

• MN CHO

  • Antigens Present

• Hu, M1, Tm, Can, Sext, Sj

• associated with the M or N antigens in he MnSs blood group systems which are expressed in the glycophorin A

• Frequency is unknown because it is going to vary between ethnicities or there are only few studies conducted for this blood group particularly in determining its frequency distribution among the population

• ISBT 700 SERIES

  • Blood groups whose antigens are in very low prevalence in which they could be found in less than 1% of the most random populations

  • Genes responsible for the production of such antigens are still unknown

  • Has 9 antigens

• Batty Christiansen

• Billes Box

• Torkildsen Peters

• Reid Jensen

• Livesay

  • Need further studies in order to be promoted to become a blood group system regardless of they have the number and symbols.

• ISBT 901 SERIES

  • Composed of blood groups whose antigens are found in more than 90% of the majority population in which it will be difficult to find a blood bag that is negative for such antigen
  • Although they are high frequency antigens, the genes that cause the formation of such antigens are still unknown

• Thus, still not considered as a blood group system

• Requires more genetic studies in order to identify the genes that causes its expression

• Anton (Anwj)

  • Clinically significant
  • Receptor for the invasion of Haemophilus influenza

• Sid (Sda)

  • Clinically significant
  • Found to be a component of Tamm-Horsfall Protein which is in the casts as well in the mucus threads of the urine

• HLA ANTIGENS

  • HLA class 1 Antigens are found in all nucleated cells except for red blood cells in their immature form

• RBCs tend to contain nuclei but as it is going to disappear, the amount of HLA antigens are also going to decrease to the point that they are no longer detectable

• But mature RBCs that contain HLA antigens are going to given another name so they already known as Bga, Bgb, Bgc

• Bg = Benette_Goodspeed

• ANTIGENS

• Bga -> corresponds to HLA 07

• Bgb -> corresponds to HLA 17

• Bgc -> corresponds to HLA 28

• +Bga, Bgb, Bgc

• resistant to enzymes, DTT and AET

• sensitive to chloroquine and glycine acid EDTA

• The two reagents are utilized to remove the HLA antigens found on the surface of the RBCs to prevent it from interfering in the testing

• ANTIBODIES

• Not clinically significant

• Role in Transfusion Associated acute Lung Injury (TRALI)

• An adverse reaction of a blood transfusion