Global registry of rare donors of blood for emergency selection
Each erythrocyte carries on its surface dozens of antigens, forming over 45 blood group systems. In the vast majority of people, the phenotype is a combination of common antigens — but rarely do individuals exist whose erythrocytes are completely devoid of an antigen that almost every person on Earth has. Such donors can only be replaced by another human with the same rare phenotype.
Standard donor typing determines the group only by the ABO system and Rh factor D. But there are over 45 other blood group systems (Kell, Duffy, Kidd, MNS, Rh — full profile, not just D-antigen), and a rare phenotype often emerges only when:
• Donor blood unexpectedly does not react with any of the typical panel antibodies (‘silent’ result)\n• During blood type selection for the patient, anti-hapten antibodies to an antigen that is practically present in all people are detected (this indicates that the patient themselves has a rare phenotype)\n• Extended molecular genotyping (DNA chips that simultaneously check hundreds of known antigenic variants)
Molecular genotyping has dramatically accelerated the discovery of rare donors in recent years — previously, serological testing took years.
Rh-null (’golden blood’) means the complete absence of all Rh-system antigens at once — this is not a ’minus’ of the ordinary Rh-negative phenotype, but the absence of an entire set of more than 50 antigens. It is known to occur in fewer than 50 people worldwide.
The ABO system is based on a precursor molecule — H antigen. In people with the Bombay phenotype (genotype hh), the enzyme that synthesizes H antigen does not work at all. Without H-antigen, it’s impossible to synthesize either A or B antigens — so their erythrocytes appear serologically as ’O’, but are actually completely unique.
Key risk: People with the Bombay phenotype have antibodies against H-antigen — and this H-antigen is present on erythrocytes of all regular donors, including group O. So, the usual ’universal’ O-blood is toxic for them and will cause a severe hemolytic reaction. The only compatible blood is from another donor with hh-phenotype.
The phenotype was first described in Bombay (now Mumbai) in 1952 — hence its name. The frequency is much higher in South Asia due to population bottleneck effects and close consanguineous marriages.
To be included in the panel of rare donors, blood undergoes extensive typing for dozens of clinically significant antigens: Rh (C, c, E, e), Kell (K, k), Duffy (Fya, Fyb), Kidd (Jka, Jkb), MNS and others.
A donor is considered ’rare’ if their phenotype is absent in fewer than 1 in 1,000 people in the population — and for ultra-rare phenotypes (Rh-null, Bombay, some Kell-null combinations), the frequency drops to 1 in a million or less. These individuals become lifelong ’living blood banks’, whose phenotypes are monitored and protected over decades.
No single country has enough rare donors to independently cover all possible emergencies. That’s why national blood services join international panels — coordinated networks that allow finding the needed donor regardless of which country they live in.
The largest such network is the International Rare Donor Panel, which historically has been coordinated by the International Society for Blood Transfusion (ISBT) jointly with national reference laboratories (e.g., IBGRL in the UK, ARDP in the USA). Each country maintains its own registry of rare donors and submits aggregated (anonymized) data to the international database.
When a national blood bank cannot fulfill a request on its own, it formally submits a request to the international network, specifying the exact phenotype, required quantity, and urgency. Network coordinators search for the nearest geographically and legally accessible donor or frozen unit.
For some ultrarare phenotypes, there are only one or two active donors in the world known. Losing contact with such a donor (moving away, refusal, health issues) can mean that for a specific patient in an emergency situation, compatible blood simply does not exist anywhere on the planet — except for frozen reserves.
International blood donation transfer is not only a medical but also a regulatory task:
• Each country has its own requirements for screening for infections (HIV, hepatitis, etc.) and documentation\n• Export/import of biological materials requires customs clearance, temperature control (2–6°C for liquid blood, −80°C for frozen), and accompanying permits\n• The shelf life of erythroid mass (35–42 days at refrigeration) makes international delivery of liquid blood practically impossible over long distances — hence the critical role of frozen reserves\n• A donor can be ’legally unavailable’ temporarily (pregnancy, recent travel to an endemic area, illness)
The registry of rare donors is constantly updated: new donors are added after extended genotyping, current ones are regularly invited to donate to replenish frozen reserves, and inactive (for any reason) ones are removed from active searches, leaving only historical records in the database.
Coordination centers also maintain a ’hotline’ for round-the-clock communication — an emergency request for rare blood can come at any hour, and the network should respond within counted hours.
When a patient with a rare phenotype requires urgent transfusion, a structured search is initiated: starting with the local blood bank, then the national registry, and only as a last resort — international panels. Each level expands the pool of potential donors but also increases the time and distance to the patient.
In this simulation, the request spreads through the network in concentric waves — similar to a breadth-first search (BFS) algorithm on a graph. Each wave corresponds to a level of the network: local blood bank → regional centers → national registry → international panel.
Two parameters define the search result:
• Phenotype rarity (1 in N individuals) — determines how many compatible donors theoretically exist within any given population pool\n• Search radius — defines the size of the population pool that the network manages to cover (locally, nationally, or internationally)
The expected number of donors in the pool ≈ (pool size) / N. The rarer the phenotype and the smaller the search radius — the lower the probability of quickly finding a match.
For a phenotype frequency of 1 in 5,000,000, even a medium-sized population (~44 million) statistically includes only 8-9 potential donors — and not all of them are active, available, or living close to each other. This is when the decision shifts from ’searching for a live donor’ to ’using frozen reserves’.
Expanding the search to a wider geographical radius increases the likelihood of finding a compatible donor, but increases the average distance (and thus time) to actual blood delivery. A local bank may respond within minutes, but not have the required phenotype; an international panel is almost certainly to have a donor or frozen unit — but cross-border delivery takes hours-days.
Clinical coordinators always balance these two factors: they start the search simultaneously at all levels in parallel (not sequentially) to not lose time waiting for a response from the nearest level.
Even theoretically ’sufficient’ donor numbers in the pool do not guarantee actual matches: some donors are inactive, unavailable due to health status, traveling, pregnant (for women), or simply do not respond to an emergency call. This model accounts for this through a saturation function — the probability of matching increases more slowly with increasing theoretical number of donors, never reaching absolute 100%.
Relying solely on living donors for ultra-rare phenotypes is an extremely risky strategy: a person could get sick, move away, or become unavailable. That’s why key rare units are frozen and stored for decades in specialized cryobanks — a ’insurance policy’ that doesn’t depend on any specific individual being willing to donate blood today.
Freezing erythrocytes — a delicate process, as the formation of ice crystals damages cell membranes:
1. Fresh erythrocyte mass is slowly mixed with a glycerol solution (final concentration ~40%) — glycerol penetrates into the cell and displaces water, preventing the formation of damaging ice crystals\n2. The mixture is frozen to −80°C (the method with high glycerol concentration, most common) or to −196°C in liquid nitrogen (the method with low concentration, longer storage time)\n3. Units are marked and cataloged in the cryobank with a precise phenotype, date of preparation, and expiration date
Properly frozen erythrocytes preserve viability and functionality (ability to transport oxygen) nearly intact throughout the entire storage period.
Unlike liquid erythrocyte mass, which has a term of viability only 35–42 days, a frozen unit of rare blood can wait for its patient up to ten years. This transforms one donation into a long-term insurance policy for dozens of potential recipients.
Before transfusion, the frozen unit must be thawed and all glycerol completely removed — otherwise, it will cause osmotic hemolysis (rupture of red blood cells) directly in the patient’s circulation.
Process of deglycerolysis:
1. They are gradually thawed in a water bath at 37°C\n2. The cells are washed progressively with decreasing concentrations of saline solution (with glucose addition) to allow glycerol to exit the cell progressively, avoiding osmotic shock\n3. A specialized apparatus-cellular washer (e.g., closed-loop systems) automates several washing cycles\n4. The thawed unit has a limited storage period of only 24 hours (in an open system)—thus, the process is initiated only after confirming the patient’s actual request
Large reference laboratories and national blood services support specialized freezer banks specifically for rare phenotypes — separate from regular blood supplies. Each unit in such a bank can be the sole available resource for a specific genotype in a region or even a country.
These reserves are periodically replenished: active rare donors are invited to give blood over clinical demand at a specific moment, specifically for filling frozen stocks — alongside supporting the ’live’ registry in case fresh collection is required for an emergency.
Finding a compatible donor or a frozen unit is only half the task. The final step is the physical delivery of blood to the patient’s bed, often across borders by air, couriers, and with police escort — with timekeepers and biological limitations of the product itself.
The history of transfusion medicine knows dramatic examples. One of the most famous rare donors is James Harrison (Australia), who donated plasma with rare anti-bodies over 1,000 times during his life, saving millions of infants from hemolytic disease. For extremely rare red blood cell phenotypes (Rh-null, Bombay) there are cases where an international network organized emergency delivery of a frozen unit by air across several countries within a day for a patient needing heart surgery or trauma care.
In such cases, coordination involves national blood services, airlines (sometimes military transport aviation), customs authorities with expedited processing of biological cargoes, and local rapid response teams for the ’last mile’ from the airport to the hospital.
In 2011, a Swiss patient with the Bombay phenotype urgently needed blood during surgery — compatible units had to be sought internationally and delivered from abroad, as no live donor with that genotype was available in Switzerland at the time.
The main vulnerability of the entire rare donor system is its dependence on an extremely small number of specific living individuals. If for a phenotype, only 5–10 active donors are known worldwide:
• A disease, pregnancy, or temporary unavailability of one donor significantly reduces the global reserve\n• Natural aging of the donor population without constant search for new carriers of rare phenotypes gradually depletes the registry\n• Political instability, border closures, or pandemic travel restrictions (as during COVID-19) can block international delivery precisely when it is most needed
That is why a dual strategy — an active live registry plus a deep frozen reserve — is the only reliable approach: a live network provides flexibility and replenishment, while the frozen bank serves as a buffer, independent of any single person’s readiness to act immediately.
Modern directions of development of the rare donors system include:
• Expanded neonatal and donor population DNA genotyping for timely identification of rare phenotypes before there arises an urgent need\n• Centralized international databases in real-time instead of email or phone inquiries\n• Research on cultured laboratory erythrocytes (culture-derived RBCs) with rare phenotypes as a potentially unlimited source in the future\n• Expansion of cryobank networks in regions historically lacking access to international panels
Each of these solutions reduces the dependence of the system on a fragile resource — the limited number of living individuals whose blood is practically irreplaceable.