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PA21.1 | ABO & Rh Blood Group Systems — SDL Guide (Part 2)

ABO Inheritance and the Bombay Phenotype

Infographic explaining ABO codominant inheritance, H substance dependence, Bombay phenotype testing pitfalls, and why Bombay patients can receive only Bombay blood. — **Panel A:** Precursor RBC membrane, functional H gene/FUT1 enzyme, H substance, A allele enzyme, B allele enzyme, A antigen, B antigen, hh genotype, absent H substance, absent A/B antigens despite ABO genotype. **Panel B:** AA, AO, BB, BO, AB, OO genotypes; Group A, Group B, Group AB, Group O phenotypes; codominant A and B alleles; functionally recessive O allele. **Panel C:** Routine forward grouping as apparent Group O, anti-H testing, Bombay RBC lacking H antigen, normal Group O RBC carrying H antigen, anti-A, anti-B, anti-H antibodies. **Panel D:** Bombay recipient, Bombay donor blood, routine Group O blood, H antigen on Group O RBCs, haemolytic transfusion reaction warning, O Rh-negative emergency donor limitation.

Inheritance pattern:
• A and B alleles are codominant (both expressed when present together → AB phenotype)
• O allele is functionally recessive (the enzyme is non-functional, so group O is expressed only when homozygous OO or when no A/B allele is present)
• Possible genotypes: AA, AO (both express Group A phenotype), BB, BO (Group B), AB (Group AB), OO (Group O)

Bombay phenotype (Oh):
Rarely (~1 in 10,000 in India, higher in South India), the H gene itself is homozygous non-functional. No H substance is produced → no A or B antigens can be made regardless of the ABO genotype.
• Bombay individuals type as Group O on routine testing, but their plasma contains anti-A + anti-B + anti-H — the most potent combination.
• They can only receive blood from other Bombay donors.
• Clinical trap: a Bombay patient who receives routine Group O blood will have a life-threatening haemolytic transfusion reaction (because Group O cells still carry abundant H antigen).
• Bombay phenotype is more prevalent in India than in Europe — clinically relevant for the Indian physician.

CLINICAL PEARL

Universal donor and its limits: Group O Rh-negative blood is called the 'universal donor' because it lacks A, B, and D antigens. In life-threatening emergencies when blood group is unknown, O-negative packed red cells are given. However, this is NOT truly universal: (1) The plasma of O whole blood contains anti-A and anti-B which can haemolyse recipient cells if given in large volumes — use packed cells, not whole blood. (2) O-negative is only ~7% of donors, so stocks are limited and should be reserved for true emergencies. (3) Bombay patients cannot receive even O-negative blood safely.

ABO Incompatibility: Mechanism of Intravascular Haemolysis

Diagram showing ABO-incompatible transfusion causing IgM binding, classical complement activation, MAC-mediated intravascular haemolysis, haemoglobinuria, shock, and DIC risk within minutes. — **Panel A:** ABO-incompatible donor RBCs, A or B antigens, recipient plasma, pre-formed IgM anti-A or anti-B, IgM pentamer binding, high antigen density callout.. **Panel B:** Donor RBC membrane, A/B antigen, bound IgM pentamer, Fc regions, C1q, classical complement pathway, C3 convertase, C5 convertase, C5b-C9 membrane attack complex, haemoglobin release into plasma.. **Panel C:** Haemoglobinaemia, haemoglobinuria, kidney tubule injury, dark urine, acute tubular necrosis, C3a, C5a, mast cell degranulation, fever, hypotension, shock, tissue factor release, DIC risk, first 15 minutes observation warning..

When ABO-incompatible blood enters the circulation:
1. Pre-formed IgM anti-A or anti-B binds immediately to antigens on donor RBCs (antigen density is high — ~1 million A or B sites per RBC).
2. IgM pentamers are highly efficient at activating the classical complement pathway (two Fc regions needed to bind C1q — one IgM molecule provides both).
3. Complement cascade proceeds to completion → membrane attack complex (MAC) inserts into the RBC membrane → intravascular haemolysis (haemoglobin released directly into plasma).
4. Released haemoglobin → haemoglobinaemia → haemoglobinuria (dark urine) → acute tubular necrosis if severe.
5. Complement fragments (C3a, C5a) → mast cell degranulation → fever, hypotension, shock.
6. Tissue factor release → DIC risk in severe reactions.

This entire sequence can begin within minutes of starting a transfusion — hence the rule to observe the patient for the first 15 minutes of every transfusion.

The Rh System: D Antigen and Rh Status

Diagram comparing Rh-positive and Rh-negative red blood cells, showing RHD/RHCE genes and immune anti-D IgG formation after RhD exposure. — **Panel A:** Rh-positive RBC, Rh-negative RBC, RBC membrane, cytoplasm, RhD transmembrane protein, D antigen present, D antigen absent, approximate population frequency Rh+ about 85 percent and Rh-negative about 15 percent.. **Panel B:** Chromosome 1, RHD gene, RHCE gene, Rh blood group antigens, clinical focus on D antigen.. **Panel C:** Rh-negative individual, no natural anti-D antibodies, Rh-positive blood exposure, transfusion, fetomaternal hemorrhage, sensitisation, anti-D IgG antibody, placental transfer..

The Rh system is the second most clinically important blood group system. It comprises over 50 antigens encoded by two closely linked genes on chromosome 1 (RHD and RHCE), but clinical practice focuses almost entirely on the D antigen (also called RhD).

Rh-positive (Rh+): D antigen present on RBCs (~85% of the Indian population)
Rh-negative (Rh−): D antigen absent (~15% — varies by ethnicity)

The D antigen is a transmembrane protein (not an oligosaccharide like ABO antigens). It is the most immunogenic of all blood group antigens apart from ABO — a single exposure to as little as 0.1 mL of Rh+ blood in an Rh-negative individual can trigger sensitisation.

Critical difference from ABO:
• There are no natural anti-D antibodies. Rh-negative individuals do NOT have anti-D in their plasma unless previously sensitised.
• Anti-D is an immune antibody — it forms only after exposure to D antigen (via transfusion or fetomaternal haemorrhage).
• Class: IgG (monomeric, crosses the placenta).

Side-by-side comparison of Rh-positive and Rh-negative red blood cells showing presence and absence of RhD transmembrane protein respectively. — **Panel A:** Rh-positive RBC with RhD transmembrane protein, cell membrane, cytoplasm, 85% population prevalence. **Panel B:** Rh-negative RBC with smooth membrane lacking RhD protein, cell membrane, cytoplasm, 15% population prevalence.