Transfusion with blood group genotype matching: advances, limitations, and challenges: a narrative review

Introduction

Rationale

Red blood cell (RBC) transfusion remains a cornerstone of supportive care for patients with chronic anemias, hemoglobinopathies such as sickle cell disease (SCD) and thalassemia, and a variety of other hematologic conditions. However, despite its clinical benefits, RBC transfusion is not without risks. One of the most significant complications is alloimmunization, the formation of antibodies against non-self RBC antigens, which can lead to hemolytic transfusion reactions (HTRs), hyperhemolysis, and substantial delays in securing compatible blood for future transfusions (1-4). The risk of alloimmunization increases with the number of transfusions, particularly in patients with antigenic disparities between donor and recipient populations, as is often the case for individuals of African descent in predominantly Caucasian donor pools. Consequently, patients who require chronic transfusion support must be carefully managed with strategies aimed at minimizing this risk (5-9).

The American Society of Hematology (ASH) Guidelines for transfusion support in chronically transfused patients with SCD recommends obtaining a patient’s RBC antigen profile before initiating transfusion therapy. Prophylactic antigen matching for C, c, E, e, and K, in addition to standard ABO and D compatibility, is strongly advised. Furthermore, extended matching for other clinically significant antigens such as Fy^a, Fy^b, Jk^a, Jk^b, S, and s should be considered when feasible, especially in patients with a history of alloimmunization or those at higher immunologic risk (10). The International Collaboration for Transfusion Medicine Guidelines recommends selecting ABO, Rh (D, C, c, E, e), and K-matched RBCs for patients with SCD and thalassemia, even in the absence of alloantibodies (11).

While traditional serologic typing has long served as the foundation of donor-recipient compatibility assessment, it has inherent limitations. These include reduced accuracy in recently transfused patients, difficulty detecting partial or variant antigens, particularly within the RH system, and challenges in identifying weakly expressed antigens such as Fy^b (12-16).

In this context, red cell genotyping has emerged as a powerful and a complementary tool for antigen matching, offering high-resolution molecular identification of RBC antigens regardless of recent transfusions or serologic ambiguity. Genotyping enables the identification of variant RH alleles and rare antigen combinations that would otherwise go undetected by hemagglutination techniques. This molecular approach is particularly valuable in populations with high genetic diversity and in patients who have developed multiple alloantibodies. Weak D variants (types 1, 2, and 3) are relatively common among individuals of European descent, whereas the Asian-type DEL variant is predominantly found in East Asian populations. In both situations, individuals can safely receive RhD-positive transfusions once their genotype has been confirmed by molecular testing (17-28).

As molecular blood group typing continues to evolve, it is transforming transfusion medicine by enabling more precise, individualized donor-recipient matching. Despite its promise, widespread implementation faces practical challenges, including cost, access to molecular testing platforms, integration with blood bank information systems, and the need for comprehensive genotyped donor registries.

Whereas most reviews emphasize advances in molecular typing technologies, the present review additionally addresses existing limitations and discusses future directions and challenges for the application of genotype-matched transfusion It highlights the critical role of genotyping in optimizing transfusion safety and efficacy, particularly in high-risk populations such as patients with SCD, and underscores the need for continued investment in infrastructure, education, and policy to support broader adoption of molecular methods in transfusion practice. This article is presented in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-25-37/rc).

Methods

A narrative literature review was conducted to identify publications related to molecular typing and genotype-matched transfusion. The search strategy included peer-reviewed full-length articles published in English between 2002 and 2025. Searches were performed in PubMed using combinations of keywords such as “molecular blood group typing”, “genotype matching”, “NGS blood groups”, “PCR-based assays”, and “alloimmunization prevention”. Additional data sources included the RHeference, Erythrogene, and RhesusBase databases, as well as publications and terminology updates from the ISBT Working Party on Red Cell Immunogenetics and Blood Group Terminology. Studies were selected based on relevance to molecular techniques, clinical application, and implementation challenges in transfusion medicine. Reference lists of key articles were also screened to identify additional pertinent studies (see Table 1).

Advances in molecular matching

The application of molecular genetics to transfusion medicine has led to significant advances in the precision and safety of RBC transfusion, particularly for patients with complex needs such as those with SCD, thalassemia, or other forms of chronic anemia. Table 2 summarizes the main applications and impact of blood group genotyping in transfusion medicine (26,29).

The ability to test for multiple antigens in a single assay, including those for which no serologic reagents are available as for example U, Do^a, Do^b, Jr^a, Lan, Vel and others, along with the potential for high-resolution RH matching based on RH variant alleles, and the reduction in serologic workups, make genotype matching a promising advancement in the future of transfusion medicine. This approach holds great potential for mitigating immune complications and improving transfusion outcomes. Below are key areas where molecular matching has advanced the field.

High-resolution genotyping technologies

The genetic basis of 371 blood group antigens, classified across 48 blood group systems (30), is now known, and various genotyping techniques are currently available for red cell typing. Modern molecular platforms—such as microarrays, high-density arrays, and next-generation sequencing (NGS) have revolutionized the characterization of RBC antigen genotypes (30-39). Table 3 presents some of the high-resolution blood group genotyping technologies currently available for human erythrocyte antigens (HEAs) and RH.

These advanced technologies allow for the comprehensive identification of alleles encoding clinically significant blood group antigens across multiple systems, including Rh, Kell, Duffy, Kidd, MNS, and others, as well as detection of rare variants and null alleles. This high-resolution genotyping is especially valuable in populations with high genetic diversity or a high prevalence of blood group variants, where traditional serologic methods often fall short. RBC alloimmunization varies across human populations and ethnic groups. A study performed by Kim et al. (40) document distinct alloantibody profiles in Korean patients, underscoring the need to tailor extended phenotyping to local population genetics.

By enabling precise and large-scale genotyping of both patients and donors, these platforms offer a more efficient, accurate, and scalable approach to matching, thereby reducing the risk of alloimmunization and other transfusion-related complications. Moreover, molecular testing enhances the ability to identify compatible blood units for patients with RH variants, with complex antibody profiles or those requiring chronic transfusion support (41-45). The development of RBC antigen genotyping using NGS and high-density DNA arrays offers the potential to overcome many of the limitations of the current polymerase chain reaction (PCR)-based genotyping assay formats. NGS provides an unparalleled ability to detect genetic variations, including novel variants and complex structural variants (SVs), positioning it as the new gold standard for RBC antigen genotyping. NGS has been an effective strategy to identify ABO subgroup alleles, RH variant alleles, and rare blood group genotypes, and it has the potential to improve blood group antigen matching for transfusion (46-49). As a result, NGS is poised to replace conventional PCR-based genotyping for resolving serological discrepancies and identifying complex or novel antigen variants.

High-density DNA arrays, on the other hand, enable cost-effective screening of all known genetic variants—including SVs—across thousands of samples simultaneously. Blood types have been predicted from genome array data using known variant determinants in large cohorts and to type a wide range of blood cell antigens across diverse ancestries (37,50). Meanwhile, high-density DNA arrays may allow for routine, large-scale genotyping of all blood donors for most genetically defined antigens (51).

Although these technologies are not suitable for acute cases or in situations where time is a factor, due to delays in donor typing compared with serologic methods, integrating them into routine blood bank workflows can improve inventory management, support the creation of genotyped donor registries, and promote more equitable transfusion practices in multiethnic populations.

Detection of variant and partial antigens

One of the most significant advances in transfusion medicine is the ability to identify variant alleles such as those in the RHCE, RHD, and ACKR1 genes that may not be reliably detected through conventional serologic methods. Molecular genotyping enables the precise identification of partial D, weak D, Del, and hybrid RHD alleles, many of which may present as D-positive serologically but lack key D epitopes. When patients with such variants are transfused with RBCs expressing the full D antigen, they remain at risk of alloimmunization due to immune recognition of the missing epitopes (52-56). Additionally, DNA typing can help differentiate between weak D and partial D variants in transfused patients, providing essential information for establishing appropriate transfusion policy recommendations (57). Similarly, high-resolution RH genotyping allows for the detection of RHCE variant alleles, which have been associated with Rh alloimmunization and delayed hemolytic transfusion reactions (DHTRs), particularly in individuals with SCD, who are frequently transfused and often have RH backgrounds that differ from donor populations (14,15,47,58-60). Molecular testing also enables the detection of clinically relevant ACKR1 polymorphisms, such as the common −67T>C single nucleotide variant (SNV) in the GATA-1 binding site of the FY*B allele. This SNV, prevalent in individuals of African descent, silences ACKR1 gene expression on RBCs, resulting in the Fy(a−b−) phenotype, an important consideration for transfusion matching and malaria resistance (61-63). By uncovering these antigenic variations, many of which are undetectable by standard serology, molecular genotyping offers a more comprehensive and accurate immuno-hematologic profile for each patient. This is particularly critical in chronically transfused individuals, who are at high risk of alloantibody formation.

The integration of genotyping into routine transfusion protocols enables the selection of more precisely matched donors, minimizes alloimmunization to variant and partial antigens, and enhances transfusion safety. Ultimately, this approach supports the broader goals of precision transfusion medicine, where therapy is tailored to the individual’s genetic background and immunologic history.

Personalized transfusion support

Genotype-guided donor selection enables personalized transfusion strategies, improving antigen matching and potentially reducing alloimmunization rates. Studies have shown that patients receiving genotype-matched RBCs have lower rates of alloimmunization than those matched by serology alone (15,17,64,65). Genotype matching can identify precise antigen mismatches at the DNA level before alloimmunization occurs, enable prophylactic extended matching, significantly reducing the risk of forming new antibodies, support chronically transfused patients by maintaining antigen compatibility over time, reducing the risk of HTRs and delays in care. Additionally, by enabling proactive donor-recipient matching, these technologies support a shift toward precision transfusion strategies (25,66). As the cost of genotyping continues to decline and integration with transfusion services improves, the routine application of these molecular tools is expected to play an increasingly central role in transfusion medicine (67). Their adoption represents a critical step forward in personalizing transfusion care, optimizing blood resource utilization, and addressing disparities in transfusion outcomes among underrepresented populations.

Donor registry optimization

High-throughput genotyping of blood donors supports the creation of extensive and diverse donor registries, facilitating the identification of rare donors for patients with uncommon antigen combinations. High-throughput molecular typing of large donor pools has allowed the development of national and international genotyped donor databases, which help identify rare or matched units for patients with unusual phenotypes or multiple alloantibodies (68,69). Integration of multiethnic donor recruitment strategies increases access to antigen-compatible units for minority patients (70,71). Donors can be pre-screened for rare phenotypes [e.g., U−, Js(b−), Vel−] that may be urgently needed for specific patients (37). These registries support precision matching and are particularly vital in the provision of rare blood units across borders in a globalized healthcare context.

Digital integration and databases

Advances in informatics and integration of genotype data into transfusion service databases allow for automated matching algorithms, reducing human error and enhancing operational efficiency (37,38). Advances in information technology have facilitated the integration of genotyping data into transfusion service software, electronic health records, and laboratory information systems. This allows for automated donor-recipient matching based on stored genotypes, reduction in manual errors and delays and improved inventory management by tagging donor units with genotypic profiles for rapid identification (25,62). The use of clinical decision support tools can help transfusion services manage patients with complex alloantibody histories or difficult-to-match antigen profiles, using real-time data to guide unit selection.

Limitations of molecular matching

Despite its advantages, molecular matching has limitations. These include incomplete coverage of antigen systems, turnaround time constraints, high implementation costs, challenges interpreting novel variants, and limited availability of genotyped donors (26,72-75).

Incomplete coverage of antigen systems

While many clinically relevant blood group antigens can now be accurately genotyped, certain blood group systems, rare variants, and null alleles continue to present challenges. Most current molecular assays are designed to detect common alleles and well-characterized phenotypes, which can limit their ability to identify less frequent or novel variants (25,32,39). As a result, some clinically important discrepancies may go undetected, particularly in genetically diverse populations or in individuals with complex serologic profiles (12,36). Furthermore, the correlation between genotype and phenotype is not always straightforward. Factors such as gene silencing, hybrid alleles, alternative splicing, and regulatory mutations can alter antigen expression without changing the coding sequence in a predictable way. These complexities highlight the need for continued refinement of molecular assays, expanded allele databases, and the integration of serologic, molecular, and clinical data to improve the interpretation of genotyping results. These limitations impose a further complexity on techniques such as NGS and high-density arrays where simple variant lookups no longer suffice in going from genotype to phenotype. In cases such as silencing or where several genes or variants interact in complex ways to result in phenotypes the data would have to be interpreted correctly for correct phenotype prediction, when serological methods can simply just measure presence or absence of antigen. Advanced techniques such as full gene sequencing and long-read sequencing may offer additional resolution, enabling the detection of novel or complex variants that are not covered by standard genotyping platforms (42,72-78). In clinical practice, a cautious and comprehensive approach remains essential, particularly when managing patients with unexplained antibodies or rare phenotypes.

Turnaround time and laboratory capacity

Although genotyping is increasingly rapid, it is still not real-time. Serological methods remain the standard approach for pretransfusion testing because they are rapid and can provide results within 30 minutes to a few hours, depending on the level of testing required. Automated platforms can further reduce processing time, making serology suitable for acute transfusion situations. In contrast, molecular methods such as PCR-based assays typically require 4 to 8 hours, while microarray-based genotyping platforms have a turnaround time of 8 hours to 1 day. NGS offers the most detailed allele-level resolution but generally requires 2 to 5 days to complete, including bioinformatic analysis. Emergency transfusions usually rely on serologic matching due to the immediate need (51). Moreover, not all institutions have access to molecular testing infrastructure or expertise.

Cost and resource allocation

Genotyping technologies and infrastructure remain costly, especially in resource-limited settings. Reagents, equipment, bioinformatics support, and trained personnel all contribute to the high cost of implementation and maintenance (79).

Interpreting complex or novel variants

The interpretation of new or rare alleles requires expert knowledge, curated databases, and sometimes functional studies (80-91). Misinterpretation may lead to incorrect antigen prediction and risk of alloimmunization.

Donor genotype availability

Even with robust genotyping efforts, the number of typed donors may not match the needs of all patients, particularly for those with RH variants, uncommon or complex antigen profiles. The scarcity of genotype-matched units can limit practical utility.

Challenges and future directions

Key challenges include global inequity in access to molecular testing, the need for ethnically diverse donor registries, integration into clinical workflows, ethical concerns about genetic data, and the need for more outcome-based research.

Global inequity and standardization

While high-income countries are increasingly adopting molecular matching, low- and middle-income countries often lack access. Efforts must be made to standardize and democratize genotyping technologies and donor database sharing across regions.

Ethnic diversity and representation

Genetic diversity across populations underscores the need for ethnically diverse donor registries. Underrepresentation of minority groups remains a barrier to effective molecular matching.

Integration with clinical decision-making

Educating clinicians and transfusion specialists on the clinical implications of genotypic information is essential. Decision support tools and clear guidelines are needed to help interpret and apply molecular matching data in practice.

Ethical and regulatory considerations

Widespread genotyping raises questions about genetic data storage, patient privacy, and consent. Transparent policies and secure systems are needed to govern the use of genomic data in transfusion medicine.

Research and evidence generation

More prospective studies are needed to assess the clinical outcomes and cost-effectiveness of molecular matching, especially in high-risk populations. Long-term data will help define its role relative to conventional serologic strategies

Conclusions

The advances in genotype matching are not merely technological milestones but represent a shift toward precision transfusion medicine, where compatibility is guided by genotype, not just phenotype. Molecular matching represents a major advance in transfusion safety and precision, especially for high-risk and chronically transfused populations. By enabling more accurate donor-recipient compatibility, it offers a pathway to reduce alloimmunization, improve transfusion outcomes, and support personalized care. However, widespread implementation is hindered by logistical, economic, and technical limitations. Although remarkable advances have been achieved in molecular typing technologies, significant challenges remain for their routine implementation in transfusion medicine. Current genotyping platforms still face incomplete allele coverage and occasional genotype-phenotype discrepancies, particularly in complex systems such as RH and MNS. Refinements such as expanding allele databases, adopting high-throughput next-generation sequencing, and improving bioinformatic interpretation could enhance accuracy. Additionally, the long turnaround time and high cost limit use in acute settings, highlighting the need for rapid assays and cost-effective workflows. Addressing these limitations through standardized protocols, collaborative data sharing, and investment in automation and informatics infrastructure will be critical to realizing the full potential of molecular typing for safe and equitable transfusion support.

A key challenge for the broader acceptance of genotyping as a routine part of blood management is the construction of a standard high density array aimed at RBC determination, combined with a robust software component to support automatic genotype interpretation without the need of human oversight. If these two component were to be developed and made available the barrier to adoption would be reduced, and large scale adoption would likely lead to cost reduction in time.

Addressing these challenges will require coordinated efforts in research, infrastructure development, policy-making, and international collaboration. As genotyping technologies become more accessible and affordable, genotype matching is poised to become an integral part of modern transfusion medicine.

Acknowledgments

None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-25-37/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-25-37/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-25-37/coif). L.C. serves as an unpaid editorial board member of Annals of Blood from February 2024 to January 2026. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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