Novel <i> <scp>RHCE</scp> * <scp>cE</scp> ( <scp>341A</scp> ) </i> allele

Transfusion · 2026-04-16

The Rh blood group system is highly polymorphic: 56 antigens described to-date.1 Antigen immunogenicity and prevalence, contribute to clinical relevance and especially in pregnancy. Here, we report a novel RHCE allele found in two unrelated probands: a 23-year-old pregnant woman of European descent in France (S1-A) whose red blood cells (RBCs) typed D + C-E + wc + e + serologically and a White donor in the USA (S2) whose RBCs typed C-E- serologically but predicted E-positive by genotyping. A sample from the father of S1-A, a healthy blood donor (S1-B), was also tested. For samples S1-A and S1-B, serologic typing was performed by automated column agglutination technology (CAT) with IH-1000 (Bio-Rad, Hercules, CA), Vision Max (Quidel Ortho, San Diego, CA) and Qwalys 3 Evo (Diagast, Loos, France) instruments and manual CAT with DG Gel Rh Pheno (Grifols, Barcelona, Spain). S2 was tested on automated PK7300 (Beckman Coulter, Brea, CA) with Diagast reagents and in tube with Bio-Rad reagents. Genomic DNA was extracted from whole blood. S1-A was tested by: in-house Real-Time PCR assays, RHCE BeadChip (BioArray Solutions/Werfen, Warren, NJ) and Sanger sequencing of RHCE exons 1–10 and RHD exon 3 on a 3500 Dx genetic analyzer, (Thermo Fisher Scientific, Waltham, MA). RHCE exon 3 of S1-B was Sanger sequenced. S2 was tested by: PreciseType HEA and RHCE BeadChip, Sanger sequencing of RHCE exons 1 to 10, targeted RH next-generation sequencing (NGS) (MiSeq Illumina, San Diego, CA), and RHCE*E-specific Sanger sequencing for phasing. By automation S1-A RBCs typed E + W with Anti-E on IH-1000, Vision Max, and Qwalys Evo, and E negative by manual testing. See Table 1 for anti-E testing on all probands. S1-A RBCs also typed D+, C–, c+ and e+ with no ambiguity. By real-time PCR, E (c.676C) and e (c.676G) were present (E/e). RHCE*cEIV,2 frequent weak E allele in individuals of African and European descent, was excluded. RHCE Beadchip results were consistent with these findings. By Sanger sequencing, c/c, and c.676C/G (E/e) were detected. A heterozygous c.341G>A change (rs1238030431) was found in RHCE exon 3 and no other changes in sequenced regions. S1-A RHD exon 3 was also sequenced and no changes from conventional were found. RBCs from S1-B typed E + e + with multiple anti-E; and sequencing of RHCE exon 3 found no changes from wild type. S2 RBCs typed E- negative by automation and by tube testing, but was predicted E+ by PreciseType HEA. RHCE BeadChip analysis showed cE/ce, with Sanger and NGS identifying c.341G>A in heterozygosity. c.341A was found in cis with c.676C (E) by E-specific sequencing. S2 RH NGS showed RHD*01 and RHD*01 N.01. The c.341G>A change is predicted to encode p.Arg114Gln, located in the 4th transmembrane domain of the RhCE protein, in close proximity with p.226Pro (Figure S1).3 The same variant is responsible for RHD*weak D type 25 and very different phenotypes for changes at amino acid 114 have been reported, suggesting conformational sensitivity in this region.4 RHCE*ce(341A) was described in 2009 by Hustinx et al.5 in a Caucasian patient with an e+W, JAL+ phenotype. The clinical significance of the variant was uncertain, in the absence of known immunization. RHCE*cE(341A) has been previously described, but with no associated serology.6 RBCs from S1-A and S2 were not available for JAL testing. In S1-A, the change was inferred to be on a RHCE*cE background based on the patient's E + w, e+ phenotype and also on the absence of the variant allele or a E + W RBC type in S1-B. In S2, RHCE*E-specific Sanger sequencing confirmed RHCE*cE(341A), explaining the discrepancy between phenotype and genotype. These cases highlight the value of having multiple samples to confirm serologic phenotype of novel variants. The sequence was deposited in Genbank (Accession number PX392379), and given the ISBT designation RHCE*03.37. The effect of c.341A on the expression of c could not be assessed, due to RHCE*ce in trans. Although no anti-D or anti-e have been reported associated with RHD*weak D type 25 or RHCE*ce341A, respectively, the change is predicted to be located in the transmembrane region of RhCE, in close proximity with p.226. For transfusion, E-negative RBC units should be considered if transfusion is necessary for female patients of childbearing age with RHCE*cE(341A) in the absence of a conventional RHCE*E in-trans. New York Blood Center RHCE website https://www.nybce.org/national-center-for-blood-group-genomics/rhce-table/ [accessed January 11, 2026]. RHeference https://www.rheference.org/ [accessed January 11, 2026]. ISBT Blood Group Database https://blooddatabase.isbtweb.org/ [accessed January 11, 2026]. AF, RV, LR, CH, BSS, RWV and SV collected and analyzed the data, AF and RV prepared the original draft, OC, RF, CR and performed serologic testing, GOG, AB and CT performed molecular testing; and all authors reviewed and edited the manuscript. Open access publication funding provided by COUPERIN CY26. The authors have disclosed no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. FIGURE S1: Illustration of the proximity between residue p.114 in blue and p.226 in red in 3 dimensions. Based on the cryo-electromiscroscopy structure by Vallese et al.,3 3D representation of the RhAG2RhCE trimer, shown from above. The RhAG subunits are shown in gray and RhCE in light green, with the residue p.114Gln of the novel variant in blue and p.226Pro typical of E antigen in red. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Revisiting whole blood transfusion for the massively bleeding patient: The origins of resistance to change

Transfusion · 2025-11-14 · 1 citations

EMB reports personal fees and non-financial support from Terumo BCT, Grifols, Abbott Laboratories, and UptoDate, outside of the submitted work. PCS is a consultant for Cerus, on the scientific advisory board for Octapharma, Grifols, Perfusion Medical, and Haima. PCS is co-founder and CMO for Kalocyte. APC is CSO of Velico Medical. PCS has a grant from BARDA to perform a trial comparing LTOWB to components in children with traumatic bleeding. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

How do we implement a prehospital whole blood administration program for shock trauma patients on a statewide basis?

Transfusion · 2025-02-13 · 1 citations

BACKGROUND: Since bleeding is a major cause of early mortality in trauma, there is continued interest in providing transfusion support as early as possible to trauma patients. Various approaches have been taken to accomplish this, including the rapid provision of blood products upon arrival at the hospital, as well as a variety of prehospital approaches. However, implementing prehospital blood availability statewide for use in all populations has been limited. STUDY DESIGN AND METHODS: The program described for prehospital transfusion identifies a direct partnership between state EMS providers and the local blood center. Predictive modeling is compared to early outcome data of the first 100 patients who received whole blood from this program. Additional discussion contains key elements of the program, including planning, validation, and implementation. RESULTS: Between May 2023 and July 2024, an average of 11 prehospital whole blood units were transfused per month against the projected average of 10-16 units administered per month, with the median time to transfusion of 29.2 min. The leading reason for blood administration was due to blunt trauma. Of the patients who were not in prehospital cardiac arrest prior to paramedic arrival or excluded for other reasons, approximately 95% survived to hospital discharge. DISCUSSION: Implementation of prehospital whole blood across the state has demonstrated effectiveness early within the first year of the program. Continued process improvements will be implemented with statewide ground paramedic agency utilization of whole blood as well as expansion into aviation divisions for more expedient whole blood administration times.

The Red Blood Cell-Improving Transfusions for Chronically Transfused Recipients (RBC-IMPACT) study: protocol description of an international multi-site observational clinical study.

PubMed · 2025-09-15

BACKGROUND: Variability in blood donors, components, and recipients are known to affect transfusion outcomes, yet the combined effects of these factors remains unclear. MATERIALS AND METHODS: The Red Blood Cell - Improving Transfusions for Chronically Transfused Recipients (RBC-IMPACT) study was a multi-center longitudinal study conducted in the United States (US) and Brazil over two years to investigate RBC survival after transfusion (Aim 1) and acute increase in iron post transfusion (Aim 2) (see https://clinicaltrials.gov/study/NCT05255445). The US RBC-IMPACT study included patients with thalassemia and sickle cell disease (SCD) and, in Aim 2 only, children with hematology-oncology diseases with a hypoproliferative bone marrow. In Brazil, the study was conducted within an established SCD cohort. Blood samples were collected immediately before and after RBC transfusion to measure hemoglobin (Hb), hemoglobin A (HbA) in SCD, and markers of iron and hemolysis. Samples were collected two hours post transfusion in a subset of participants receiving primarily single unit transfusions for Aim 2. Transfusate samples were collected from transfused units. Single nucleotide polymorphism array typing of donors and recipients to measure genetic variants including those associated with increased in vitro hemolysis of stored RBCs was conducted. Comprehensive information regarding donors, components and some recipient data were linked to key clinical data extracted from recipients' medical records to assess factors associated with RBC transfusion effectiveness. RESULTS: The outcomes for Aim 1 were RBC survival between successive transfusions, calculated as ΔHbA per day for SCD and by ΔHb per day for thalassemia, and Δbilirubin for both patient groups. The primary outcome for Aim 2 was change in serum iron from before to 2 hours after transfusion. DISCUSSION: This study will be the most detailed and granular evaluation of the predictive variables that may optimize RBC effectiveness and safety in these chronically transfused patient populations.

The incompatible match for transfusion medicine fellowships

Transfusion · 2025-01-01

Adopting a formal “match” process for filling Blood Banking/Transfusion Medicine (BB/TM) fellowships in the United States would replicate that which is already undertaken on a routine basis for medical residencies in the United States. Specifically, the National Resident Matching Program (NRMP), (a.k.a. the “Match”) is the major mechanism by which graduating medical students in the United States apply to residency programs. Applications are routed via a central administrator to individual programs which have been selected by the applicant. If offered an interview by the program, the applicants complete an interview process, after which both the candidate and program rank each other by order of preference. The process serves to standardize the format and timeline of applications, that is, there is uniform submission process, and all applicants are notified on a single date as to the outcome (approximately 3.5 months prior to the start date of fellowship training). The Match has imparted structure, logistical ease, and fairness through standardization of the residency applications process. Participating programs are barred from recruiting applicants from outside the Match. This “all or nothing” approach prevents programs from bypassing the Match when suited, underscoring a spirit of fairness in how the process is executed. Participants are legally bound to fulfill their commitments upon placement, that is, one cannot simply withdraw if one's preferred placement is unsuccessful. That should also motivate applicants and programs to rank only those whom they are willing to accept. The vast majority of programs in the United States participate in the NRMP and of the 38,494 positions offered, which represent a total of 5596 programs in 2024, 93.5% were filled.1 The Match has already been adopted by over 77 subspecialties (i.e., through the Specialties Matching Service® Fellowship Match). Germane to Pathology (i.e., the parent specialty for BB/TM), Forensic Pathology has already transitioned to the Match and several other subspecialties (e.g., Hematopathology, Hematopathology, Molecular Genetic Pathology, and Bone and Soft Tissue Pathology) have agreed to transition in 2025. A Match has been proposed for fellowships in BB/TM in the United States. The question is what advantages—or more significantly—what disadvantages would this confer to fellowship training in BB/TM? Proponents of the Match argue that a unified process (and timeline) would provide host institutions and candidates more time to evaluate each other.2 Given the limited number of slots at the competitive programs, applicants need to apply several years in advance of the actual fellowship.3 Not unique to BB/TM, subspecialties compete for the best applicants, thus encouraging applicants to apply very early. In some cases, this has been criticized for being coercive. Given the nonuniform rotation schedule in combined Anatomic and Clinical Pathology (AP/CP) training programs and emphasis on AP training early on before trainees may ever experience a CP rotation, some residents only become aware of the subspecialty later in their training by which time desirable programs may have already been filled. It also may contribute to withdrawals where applicants discover subspecialties later in their training which better suit their interests or aptitudes. By unifying the timeline, there is also the notion that smaller programs would have greater opportunity to compete for applicants. As of 2020, there were 84 ACGME-approved BB/TM fellowship positions representing a total of 52 fellowship programs, yet over a third of those available slots went unfilled.4 Nonetheless, the Match—at least for BB/TM—risks complicating a process for programs and candidates alike. Given that BB/TM is a niche subspecialty, currently, few applicants are interviewed for a given slot and decisions are understandably rendered quickly. While a Match would require many more applicants to be interviewed than is typical in the current process, it would offer no certainty as to who would ultimately secure a given position. This limits the ability to select candidates based on their interests (e.g., immunohematology, apheresis, etc.). It also complicates matters for internal candidates who may have selected their residency institution as an avenue to fellowship, particularly for those who may have begun research within one of their residency institution's laboratories, have begun applying for career development awards (e.g., K08, NBF, etc.), and made plans to continue on at that institution beyond their one-year BB/TM fellowship. Such candidates and their institutions would be forced to invest considerable effort to unnecessarily expand their application processes without any benefit to the applicant or the program. The Match also seems undesirable to the BB/TM applicants themselves. When first proposed over a decade ago, a survey of 428 pathology residents and fellows found that only 20.6% favored a Match.5 Even a unified timeline was only favored by 62.1% of respondents. The typical pathology residency (i.e., the major source of applicants) can extend for 4 or more years, during which time trainees are more likely to become settled geographically, which often includes finding partners and having children who may not be easily transportable to wherever the Match forces them to go. Even if able to relocate for a single year, the uncertainty surrounding location of the matched program, is far from ideal given the short period between notification and the start date of the program. Two issues are being conflated: (1) the Match and (2) unfilled positions in BB/TM. Beyond adding complexity for applicants and programs, it is unclear how a Match would remedy the dissatisfaction surrounding fill rates which disproportionately affect smaller programs (specifically those located in smaller cities).4 Positions go unfilled for a myriad of personal (e.g., health and family) and professional (e.g., change of career trajectory, interests, etc.) reasons. Even filled positions may later see applicants withdraw with insufficient time to fill ahead of an academic year. At best, the Match will add to the administrative burden and cost of oversight. At worst, it could further dissuade prospective applicants from pursuing fellowships in BB/TM. These issues should be considered carefully when considering a change in the current process for BB/TM fellowship recruitment. Perhaps a better approach to filling BB/TM fellowship positions would be to focus on us all doing a better job of exposing medical students to the opportunities provided by careers in Blood Banking and Transfusion Medicine. EMB was supported in part by the National Heart Lung and Blood Institute (1K23HL15182). EMB reports personal fees and nonfinancial support from Grifols, Abbott, UptoDate, Tegus, and Health Advances outside of the submitted work. EMB is a co-investigator on a US government funded clinical trial evaluating Mirasol Pathogen Reduction Technology.

Role of the Physician in the Blood Center

Elsevier eBooks · 2024-11-22

Cryoprecipitate and Fibrinogen Concentrates

Elsevier eBooks · 2024-11-22

Creating a plasma coordination center to support COVID-19 outpatient trials across a national network of hospital blood banks

Journal of Clinical and Translational Science · 2024-01-01 · 1 citations

Introduction: In response to the COVID-19 pandemic, we rapidly implemented a plasma coordination center, within two months, to support transfusion for two outpatient randomized controlled trials. The center design was based on an investigational drug services model and a Food and Drug Administration-compliant database to manage blood product inventory and trial safety. Methods: A core investigational team adapted a cloud-based platform to randomize patient assignments and track inventory distribution of control plasma and high-titer COVID-19 convalescent plasma of different blood groups from 29 donor collection centers directly to blood banks serving 26 transfusion sites. Results: We performed 1,351 transfusions in 16 months. The transparency of the digital inventory at each site was critical to facilitate qualification, randomization, and overnight shipments of blood group-compatible plasma for transfusions into trial participants. While inventory challenges were heightened with COVID-19 convalescent plasma, the cloud-based system, and the flexible approach of the plasma coordination center staff across the blood bank network enabled decentralized procurement and distribution of investigational products to maintain inventory thresholds and overcome local supply chain restraints at the sites. Conclusion: The rapid creation of a plasma coordination center for outpatient transfusions is infrequent in the academic setting. Distributing more than 3,100 plasma units to blood banks charged with managing investigational inventory across the U.S. in a decentralized manner posed operational and regulatory challenges while providing opportunities for the plasma coordination center to contribute to research of global importance. This program can serve as a template in subsequent public health emergencies.

Quality of life and <scp>cost‐effectiveness</scp> of convalescent plasma compared to standard care for hospitalized <scp>COVID</scp>‐19 patients in the <scp>CONCOR</scp>‐1 trial

Transfusion · 2024-03-21 · 4 citations

BACKGROUND: The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings. METHODS: Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population. RESULTS: 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078. DISCUSSION: Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19.

Cost-Effectiveness of Convalescent Plasma for COVID-19:  A Cost-effectiveness Analysis of the CONCOR-1 Randomized Trial

Research Square · 2023-07-06 · 1 citations

Abstract Background The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. Though stopped early due to the lack of treatment benefit, the cost-effectiveness of convalescent plasma provides insight into its potential as an alternative treatment option in resource constrained settings. Methods Individual patient data on health outcomes and healthcare resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer’s perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L was measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of patients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled in the study were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses the costs from this population. Results 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 both arms (p = 0.85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms respectively (p = 0.46). The incremental cost was $4,458 and incremental quality-adjusted life day was − 0.078. Conclusion These results indicate that convalescent plasma was less effective and more costly than standard care in treating hospitalized patients with COVID-19. The sensitivity analysis yielded similar results to the base case analysis.