A blood type like no other

On June 14 we celebrate World Blood Donor Day, recognising the birthday of Dr Karl Landsteiner who discovered the ABO blood group system.

Of the 44 currently known blood group systems, ABO remains by far the most important as regards transfusion. Although group O blood lacks A and B antigens and is considered the “universal” blood group, there is one blood type for which even group O blood is incompatible.

First discovered in Bombay (now Mumbai) the Bombay (or Oh) phenotype is a rare blood type with an overall worldwide frequency of less than 1:1,000, although the frequency does vary in different populations, for example 1:10,000 in Mumbai versus 1:1,000,000 in Europe. With the worldwide Indian diaspora more examples will inevitably be seen in countries such as Australia.

The unique feature of the Bombay phenotype is an absence of H, A or B antigens. Although appearing to be group O in ABO typing, individuals with the Bombay phenotype are distinguished by the presence of a naturally occurring IgM anti-H antibody in their plasma. This antibody reacts with all normal A, B, AB, and O red cells and if transfused with non-Bombay blood the recipient may experience a severe haemolytic reaction and intravascular haemolysis. Consequently, people with the Bombay phenotype can only receive red cells from a donor with this same rare blood type.

Finding blood donors for someone with the Bombay phenotype can present logistical challenges. However, a recent article, ‘Turning universal O into rare Bombay type blood’ in the journal Nature Communications [1], describes Spanish research offering a potential solution.

In their article Anso and colleagues describe how they created Oh red cells by using an enzyme to remove the H antigen from group O red cells. The enzyme, which they called FucOB (for the α-1,2-L-fucosidase conversion of group O cells to Bombay), was extracted from the bacterium Akkermansia muciniphila commonly found in the human gut.

Although the authors go into great detail regarding their biochemical and structural analyses of FucOB and how it works its magic, their premise is simple. Taking blood samples from healthy group O blood donors they incubated the red cells with FucOB to strip fucose, the immunodominant sugar which defines the H antigen, from the glycan precursor backbone resulting in the Oh phenotype.

The FucOB treated red cells appear to maintain normal morphology, show expected glucose-6-phosphate dehydrogenase (G6PD) activity which indicates no obvious changes in the viability and integrity of the red cell membrane and were unambiguously shown to be negative for the H antigen by haemagglutination tests using Bombay (anti-H) serum and the anti-H lectin Ulex europaeus and flow cytometry using monoclonal anti-H antibodies. The authors concluded that FucOB is a promising tool for creating red cells which mimic the rare Bombay phenotype. However, it is not reported whether treated red cells are able to function or are tolerated in vivo so it is difficult to know where this work will lead.

Research efforts to improve availability of “universal” group O blood are not new [2, 3] for example conversion of group O red cells from A or B donors using enzymes extracted from coffee beans (B to O) and the bacterium Elizabethkingia meningosepticum (A to O). Another method is to create “stealth” red cells encased within a chemical jacket, for example using polyethylene glycol (PEG), which hides the ABO antigens on the red cell surface and fools the immune system. You may have also recently seen reports from the UK of the first clinical trial of blood grown in the laboratory from stems cells. Beyond the transfusion setting, gut-derived enzymes have been used to convert group A lungs to group O which may facilitate broader availability of solid organs for transplant [4].

Our ability to overcome blood supply challenges with laboratory-derived products is an exciting prospect, but scaling up to produce usable quantities remains a significant challenge. It feels that there is still some way to go before we can say farewell to our human blood donors. 

References

1.   Anso, I., Naegeli, A., Cifuente, J.O. et al. Turning universal O into rare Bombay type blood. Nat Commun 14, 1765 (2023). https://doi.org/10.1038/s41467-023-37324-z

2.   Garratty, G. Modulating the red cell membrane to produce universal/stealth donor red cells suitable for transfusion. Vox Sang, 94: 87-95 (2008). https://doi.org/10.1111/j.1423-0410.2007.01003.x

3.   Rahfeld P, Withers SG. Toward universal donor blood: Enzymatic conversion of A and B to O type. J Biol Chem. Jan 10;295(2):325-334 (2020). https://doi.org/10.1074/jbc.REV119.008164  

4.   Wang A, Ribeiro RP, Aadil A et al. Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs. Sci Transl Med, 14, eabm7190 (2022).  https://doi.org/10.1126/scitranslmed.abm7190