FROM SCIENCE TO CLINICAL PRACTICE: THE EFFECT OF PROPHYLACTIC GENOTYPIC MATCHING ON ALLOIMMUNIZATION, AUTOIMMUNIZATION AND RED CELL SURVIVAL IN PATIENTS WITH SICKLE CELL DISEASE
- 1Centro de Hematologia e Hemoterapia (Hemocentro), Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil
Abstract
Background: Despite prophylactic serologic matching for Rh and K antigens, alloimmunization and transfusion-related complications remain major challenges in chronically transfused patients, particularly those with sickle cell disease (SCD). These complications are largely due to RH variant alleles and other blood group polymorphisms that are not detected by routine serologic methods. Molecular blood group genotyping has emerged as a precision medicine approach to improve donor–recipient compatibility. Objective: To evaluate prospectively the clinical impact of prophylactic genotypic matching on alloimmunization, transfusion reactions, and transfusion efficacy. Methods: We followed 108 chronically transfused patients who underwent extended RBC phenotyping and molecular genotyping for clinically relevant blood group antigens. Patients received either extended serologically matched RBC units (n = 55) or extended molecularly matched RBC units (n = 53). Clinical outcomes included alloimmunization, autoimmunization, delayed hemolytic transfusion reactions (DHTRs), and transfusion efficacy. Results: Molecular testing identified clinically significant antigen mismatches in 42% of patients, while RH variant alleles encoding partial Rh antigens were detected in 17%. Genotype–phenotype discrepancies occurred in 21.3% of patients, mainly involving RHD and RHCE variant alleles that alter antigen expression and lead to inaccurate serologic classification, as well as antigens lacking reliable serologic reagents. Alloimmunized patients were significantly more likely to have undetected serologic–genotypic mismatches. In all cases, alloantibody formation could likely have been prevented if genotype-informed donor selection had been used. Patients carrying RH variants showed an increased risk of Rh alloimmunization, with, approximately 40% developing anti-Rh antibodies after transfusion with conventionally Rh-matched RBC units. Assessment using post-transfusion HbA measurements, direct RBC survival studies, and clinical evaluation demonstrated accelerated clearance of transfused RBCs in patients with RH variants who developed antibodies. However, reduced RBC survival was also observed in some patients without detectable alloantibodies, that is, with antibody levels below the limit of routine laboratory detection, where activated macrophages contributed to accelerated RBC removal, suggesting that unrecognized antigenic disparities and other immune-mediated mechanisms may contribute to premature clearance of transfused RBCs. Compared with serologic matching, molecular matching was associated with reduced autoantibody formation, improved post-transfusion RBC survival, and enhanced transfusion efficacy. Conclusions: Our results demonstrate for the first time in a prospective study that molecular matching, by identifying clinically significant antigen mismatches and RH variants that are undetectable by conventional serologic methods, improves donor–recipient compatibility, reduces alloimmunization and transfusion-related complications, and enhances transfusion outcomes in patients with SCD. Moreover, our findings provide evidence that RH variants contribute to reduced survival of transfused RBCs through mechanisms involving antigenic mismatch, Rh alloimmunization, and immune-mediated RBC clearance.
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BibTeX
@article{santos2026from,
title = {{FROM SCIENCE TO CLINICAL PRACTICE: THE EFFECT OF PROPHYLACTIC GENOTYPIC MATCHING ON ALLOIMMUNIZATION, AUTOIMMUNIZATION AND RED CELL SURVIVAL IN PATIENTS WITH SICKLE CELL DISEASE}},
author = {Tamires Delfino SANTOS and Lilian CASTILHO},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.106988},
url = {https://doi.org/10.1016/j.htct.2026.106988},
note = {CC BY},
}
RIS
TY - JOUR
TI - FROM SCIENCE TO CLINICAL PRACTICE: THE EFFECT OF PROPHYLACTIC GENOTYPIC MATCHING ON ALLOIMMUNIZATION, AUTOIMMUNIZATION AND RED CELL SURVIVAL IN PATIENTS WITH SICKLE CELL DISEASE
AU - Tamires Delfino SANTOS
AU - Lilian CASTILHO
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.106988
UR - https://doi.org/10.1016/j.htct.2026.106988
AB - Background: Despite prophylactic serologic matching for Rh and K antigens, alloimmunization and transfusion-related complications remain major challenges in chronically transfused patients, particularly those with sickle cell disease (SCD). These complications are largely due to RH variant alleles and other blood group polymorphisms that are not detected by routine serologic methods. Molecular blood group genotyping has emerged as a precision medicine approach to improve donor–recipient compatibility. Objective: To evaluate prospectively the clinical impact of prophylactic genotypic matching on alloimmunization, transfusion reactions, and transfusion efficacy. Methods: We followed 108 chronically transfused patients who underwent extended RBC phenotyping and molecular genotyping for clinically relevant blood group antigens. Patients received either extended serologically matched RBC units (n = 55) or extended molecularly matched RBC units (n = 53). Clinical outcomes included alloimmunization, autoimmunization, delayed hemolytic transfusion reactions (DHTRs), and transfusion efficacy. Results: Molecular testing identified clinically significant antigen mismatches in 42% of patients, while RH variant alleles encoding partial Rh antigens were detected in 17%. Genotype–phenotype discrepancies occurred in 21.3% of patients, mainly involving RHD and RHCE variant alleles that alter antigen expression and lead to inaccurate serologic classification, as well as antigens lacking reliable serologic reagents. Alloimmunized patients were significantly more likely to have undetected serologic–genotypic mismatches. In all cases, alloantibody formation could likely have been prevented if genotype-informed donor selection had been used. Patients carrying RH variants showed an increased risk of Rh alloimmunization, with, approximately 40% developing anti-Rh antibodies after transfusion with conventionally Rh-matched RBC units. Assessment using post-transfusion HbA measurements, direct RBC survival studies, and clinical evaluation demonstrated accelerated clearance of transfused RBCs in patients with RH variants who developed antibodies. However, reduced RBC survival was also observed in some patients without detectable alloantibodies, that is, with antibody levels below the limit of routine laboratory detection, where activated macrophages contributed to accelerated RBC removal, suggesting that unrecognized antigenic disparities and other immune-mediated mechanisms may contribute to premature clearance of transfused RBCs. Compared with serologic matching, molecular matching was associated with reduced autoantibody formation, improved post-transfusion RBC survival, and enhanced transfusion efficacy. Conclusions: Our results demonstrate for the first time in a prospective study that molecular matching, by identifying clinically significant antigen mismatches and RH variants that are undetectable by conventional serologic methods, improves donor–recipient compatibility, reduces alloimmunization and transfusion-related complications, and enhances transfusion outcomes in patients with SCD. Moreover, our findings provide evidence that RH variants contribute to reduced survival of transfused RBCs through mechanisms involving antigenic mismatch, Rh alloimmunization, and immune-mediated RBC clearance.
SN - 2531-1379
SN - 2531-1387
ER -