Silent saboteurs in the blood supply: Rethinking irregular antibody screening and blood group genotyping in the era of new antigen discovery

Every year, blood components that contain unexpected antibodies are transfused worldwide. Most cause no discernible harm; a few cause devastating haemolysis, particularly in neonates, obstetric patients and chronically transfused individuals. The question is not whether irregular antibodies exist in healthy donors – they do so at a measurable and reproducible rate – but whether our current systems are sufficient to detect and manage them. We believe that we have already charted the map of human blood groups. ABO and Rh dominate the headlines, and most clinicians can name a few of the other ‘usual suspects’ – Kell, Duffy and Kidd. We currently have 48 blood group systems, represented by 367 antigens,[1,2] but with current resources, we can test for only 18 antigens with cell panels, and the rules of compatibility seem stable. However, new waves of discoveries continue to expand the blood group universe. In the past year alone, transfusion headlines have included MAL – a newly defined blood group that explains the long-enigmatic AnWj antigen[3] – and ‘Gwada-negative’,[4] a one-person-on-earth phenotype recognised by the International Society of Blood Transfusion (ISBT) as a blood group 48. India introduced a new version called CRIB,[5] which is a variant of the Cromer-system antigen found in Bengaluru, in partnership with IBGRL and was announced at the ISBT regional congress in Milan in June 2025. While peer-reviewed characterisation and formal ISBT assignment are still emerging, CRIB exemplifies why our donor/recipient policies must be resilient to discovery. EACH OF THESE FINDINGS UNDERSCORE THE SAME CLINICAL TRUTH: IN BLOOD TRANSFUSION, COMPATIBILITY IS FAR GREATER THAN JUST ABO AND D MATCHING They carry a quiet warning that if a blood group can remain hidden for decades – or be so rare that only one person carries it – then antibodies to it could also be circulating silently and undetected in healthy blood donors. When such plasma is transfused into a susceptible patient, the consequences may be anything but silent. Why do donor antibodies matter? When present in donor plasma (especially in platelet and plasma components), they may haemolyse recipient red cells or cause positive DATs and delayed serologic complications. Even in red cell components, residual plasma can occasionally carry risks, and detecting these antibodies in donors also flag highly immunised individuals, who merit special handling of their plasma-rich components. Although the overall risk is low, the goal of haemovigilance is not to average risk across the population – it is to prevent rare but consequential harms, particularly in infants, obstetric patients and chronically transfused populations. Irregular antibodies: What do we know about prevalence? In transfusion medicine, the term ‘irregular antibodies’ refers to non-ABO antibodies, often IgG, formed through pregnancy, transfusion or transplants. They are ‘irregular’, not because they are rare but because we do not routinely expect them in healthy donors. Extensive screening studies across continents have shown a donor antibody prevalence rate of 0.05%–3.9%.[6] Indian studies report figures in the range of 0.05%–0.36%, with alloantibodies predominating over autoantibodies and specificities clustering in Rh, MNS, Kell and Lewis.[7] On the surface, these figures seem negligible, but in a country collecting over 12 million blood units annually, they translate to the thousands of potentially harmful donations every year. The recipient alloimmunisation rates are higher and heterogeneous: the overall prevalence in India was found to be 4.8 per 100 patients receiving transfusion. The most common antibody identified in multiply transfused patients was anti-E, followed by anti-C.[8] These numbers emphasise that small percentages translate into many affected patients. India versus the world: Where do alloimmunisation risks concentrate? India’s transfusion epidemiology is distinct. Beta-thalassaemia, HbE/-thalassaemia in the East and Northeast and SCD concentrated in tribal belts create large, chronically transfused cohorts – the very populations at greatest alloimmunisation risk. For thalassaemia and sickle cell disease patients, the alloimmunisation rate is still higher, ranging from 5.6% to 8.6%[9] (dominated by Rh and Kell). National initiatives (e.g., the sickle cell mission) have intensified haemoglobinopathy screening, revealing the scale – and therefore, transfusion vulnerability – of these communities. An extensive obstetric caseload in both rural and urban hospitals translates into a high rate of alloimmunisation, especially among RhD-negative pregnancies, with 6.9%–12.8% reported in published literature from India.[10] The rate of alloimmunisation in D-antigen-negative women is high, with multiple antibodies in those with a bad obstetric history.[11] Compared to some high-income settings, the burden of at-risk patients per donor unit is arguably higher in India, making preventive strategies more impactful per test performed. Present screening systems: International recommendations and guidelines on donor antibody screening While the UK, Australia, Canada and parts of Europe implement universal screening, others, such as the USA, rely on more targeted approaches [Table 1].Table 1: International recommendations for donor antibody screeningShould we screen all donors at all times? Although universal donor screening has been cited as unnecessary due to its low prevalence and high cost, these conclusions often predate the current era of automation and the new realities of expanded antigen complexity. A blanket ‘yes’ is easy to say but challenging to fund; a blanket ‘no’ ignores foreseeable harm. A tiered policy – anchored in component risk, recipient risk and laboratory capability – best matches today’s evidence. Expanding donor antibody screening has direct and tangible effects for clinicians. For transfusion medicine specialists: Enhanced screening may reduce serologic workups for delayed haemolytic transfusion reactions but increase upfront workload in antibody identification and donor notification For treating physicians (e.g. haematologists and obstetricians): Knowledge that transfused units come from antibody-screened donors or genotyped inventories offers reassurance. As per the National Blood Policy, India, 2007,[17]in addition to infectious marker screening, blood donors should be screened for unexpected antibodies to avoid any adverse transfusion reaction, especially in case of the transfusion of plasma-containing components. THE INDIAN SCENARIO IS OFTEN DICTATED BY RESOURCE CONSTRAINTS RATHER THAN BY RISK ANALYSIS Diving deeper: The promise of blood group genotyping Serology identifies the current antibody presence but misses silent or variant antigens. Genotyping helps in Permanent donor profiles unaffected by recent transfusions Extended antigen matching, for example, for Rh variants, Duffy, Kidd, MNS and Diego Rare donor identification is critical for multitransfused or obstetric patients Pre-emptive care enables the allocation of antigen-negative units as the first-line therapy. The NHS in England will soon introduce a new genetic blood matching test for people with sickle cell disease or thalassaemia to match transfusions better, which will reduce the donor blood reaction in the patient’s body.[18] In India, genotyping remains in nascent stages, but with sequencing costs falling and multiplex platforms emerging, even moderate-scale regional centres could build high-value genotype databases to support chronic transfusion programmes. From policy to practice: What should India do? Tiered screening policy for India Initiate a national surveillance programme to monitor the prevalence of irregular antibodies in donors at selected blood centres across various regions, which will inform policy thresholds. Phase 1: Introduce universal anti-A/B titre screening for Group O donors and platelet donors Launch antibody screens for donors whose products serve neonates and obstetric or chronically transfused patients. Phase 2: Deploy modular genotyping in regional centres servicing high-need populations (e.g. thalassaemia hubs and SCD belts) Link donor antibody and genotype data into centralised blood information systems. Phase 3: Establish a National Rare Donor Registry incorporating genotyped donors Mandate universal antibody screening over time, leveraging economies of scale and automation. Engage clinicians Provide clear transfusion guidelines: for example, always request antibody-screened units for high-risk patients and label phenotyped or genotyped units in the electronic medical records Adaptive Review Conduct biennial audits on transfusion outcomes: alloimmunisation rates, haemolytic reactions and turnaround time for matched units. CONCLUSION The ‘mystery blood groups’ discovered in recent years underscore the gap between scientific capability and policy practice. India stands at a unique crossroads: a large transfusion-dependent population with immense need and now the capacity to leap forward using targeted antibody screening and emerging genotyping tools. By strategically integrating global best practices and building national infrastructure, India can move towards proactive transfusion safety. It is time to chart a new map – one in which no antibody puts lives at risk simply because we did not look for it. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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