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Martin L Olsson - One of the best experts on this subject based on the ideXlab platform.
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Towards Universally acceptable Blood
Nature Microbiology, 2019Co-Authors: Henrik Clausen, Martin L OlssonAbstract:Metagenomic screening of gut microbiomes led to the discovery of a new enzymatic process for the removal of group A antigens on red Blood cells, providing new hope for the development of Universal Blood.
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Will Genotyping Replace Serology in Future Routine Blood Grouping? Opinion 4
Transfusion Medicine and Hemotherapy, 2009Co-Authors: Jill R. Storry, Martin L OlssonAbstract:The core question of this forum addresses whether genotyping will replace serology in future routine Blood grouping. Our response to that question is another: will genotyping need to replace serology? The past two decades in transfusion medicine have witnessed development in two different directions: the older path is one of developing a ‘Universal’ Blood supply where all Blood is somehow converted to an inert group-O-like status. The Holy Grail is to eliminate pretransfusion testing, permit the transfusion of any unit of Blood to any person and to prevent possible post-transfusion ABO-related haemolytic events. The more recent path leads in the opposite direction, i.e. development of more comprehensive genotyping platforms so that patient and Blood donor may be matched specifically for as many antigens as possible and thus limit alloimmunisation events through antigen compatibility. This mimics our current testing practices although on a more grandiose scale and answers the primary forum question with a probable yes, since discrimination at the molecular level is much more comprehensive than that which can be achieved serologically. The bases of the high-throughput genotyping platforms are discussed in detail elsewhere in this journal; different approaches to developing Universal Blood have also been the subject of comprehensive investigation. It is not our intention to review them again but more to look objectively at the value of the new developments and see if indeed they have a role in improving the way we provide Blood to patients. Personalised medicine is a continuously expanding field based on the knowledge of the inter-individual variations in the human genome and increased understanding of the molecular basis of disease. Identification of molecular markers as risk factors for alloimmunisation would provide means to select patients who could benefit the most from more well-matched red cell transfusions and constitute a more prophylactic approach than today's. Current practice is to match patients and donors for ABO and RhD antigens at a minimum. Matching for K and c antigens in female patients of childbearing age is also common in many transfusion services. Discovery of the molecular bases behind most of the clinically important Blood group antigens has prompted the development of genotyping platforms on the premise that if Blood for transfusion is more closely matched to the genotype of the patient, then allo-immunisation events can be decreased or possibly even avoided. These events occur in an estimated 1–2% of transfusions and may delay medical care, prolong hospital stay, and result in less than optimal medical treatment. After a reasonable dose of scepticism initially, many Blood centres and transfusion services are now competing to install systems able to achieve this goal. However, cost-efficiency is still a central issue. There have been two primary pathways in the approach to Universal Blood: one has been to mask the erythrocyte surface antigens using polyethylene glycol (PEG) and its derivatives; the other has been to enzymatically cleave the A and B antigens, which are the single greatest barrier in transfusion medicine. PEG technology, which looked very promising initially, has proven to be more immunogenic than anticipated. Furthermore, masking of A and B antigens has also proven difficult to accomplish at moderate doses of PEG. These results are echoed by enzymatic removal strategies, which appear to show promise, but still transfusion of red cells against anti-A and anti-A,B following removal of A antigens remains to be proven clinically viable. However, proof of principle has been achieved for transfusion of treated group B red cells into group O or A healthy volunteer and patient recipients. A third more recent approach to the production of a Universal Blood supply is the large-scale in vitro culture of erythrocytes in bio-reactors. The exciting potential of this technology is that one could potentially knock out genes for Blood group antigens that were not required for the function of the erythrocyte. In any case, the phenotype could be selected so as to provide the most immunogenically inert form. The current major challenges in this field are production costs and the realisation of mass production. So, how do these different approaches help in answering the question posed by this forum? The single greatest Blood group-related danger to transfusion recipients remains the ABO system. Unfortunately, the complexity of the ABO genes when compared with the relative simplicity of serological typing and availability of inexpensive reagents, is such that it is unlikely that anyone would rely on genotyping only for the assignation of ABO group to a unit of Blood. However, as part of a Blood group micro-array the genotyping information obtained could add to the value of routine serology, e.g. in identification of weak A or B subgroups or low-grade chimeras missed by serological routine tests. But what about the other Blood group systems? There certainly, genotyping could replace serological testing. Typing for RhD remains imperfect serologically and is dependent on the clone(s) of anti-D used and also the number and specificity of D epitopes carried by the red cells. The molecular basis of RhD variants are readily incorporated into a genotyping approach and have been shown in one trial with BloodChip® (Progenika Biopharma, Derio, Spain) to correlate well with serological expression. What about new alleles that have the potential to result in an erroneous prediction of phenotype? As always, the discussion is completely different for patients/recipients and donors. If a patient is predicted to be RhD-positive despite really being RhD-negative, e.g. due to technical error or an unidentified pseudogene, it may lead to RhD immunisation. Thus, for patient typing the same precautionary principle discussed above for ABO genotyping may apply. But what about a mistyped unit, e.g. predicted RhD-positive due to a pseudogene when it really is RhD-negative? These will always exist but is it best use of medical testing resources to ensure that each and every one is captured? For other Blood group antigens of clinical importance, genotyping offers another dimension and an added value beyond today's standard of routine care. Therefore, rare errors, most of which will probably be false-positive predictions, could be more acceptable since the advantages outnumber the risks. The major remaining question again is cost. Should this practice be used for all donors, or with whom should we start? It is quite likely that Blood centres need a start-up phase anyway so stable group O donors are probably a cost-efficient group to start with. Subsequently, all donors but also all non-acute patients could or should be typed in order to decrease alloimmunisation, based on a priority matrix selecting the optimal unit for each patient at any given time. While the result of a donor typing can be recycled and utilised throughout the donor's life, patient typing should perhaps initially be limited to chronically transfused recipients. Again, for the full benefit of masSscale genotyping efforts also other patient categories should be considered. Perhaps a combined approach using enzymatic conversion (ECO) to remove A and B antigens together with a genotyping platform for all other clinically relevant antigens will enable us to obtain an optimised Blood supply eventually. In addition, the array could help assure that the ABO groups were correctly assigned for selection of A- or B-degrading exogly-cosidase for conversion. The advantages are clear: in addition to eliminating ABO-associated haemolytic events, the availability of ECO Blood would improve inventory management and other supply chain issues since all Blood will be available to any patient independent of ABO group, perhaps most importantly in emergency situations or massive bleeding. Computerized genotype information for all other Blood group systems will decrease the risk of clerical or serological errors and ensure that the best possible match for a patient can be made each time Blood is required.
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modifying the red cell surface towards an abo Universal Blood supply
British Journal of Haematology, 2007Co-Authors: Martin L Olsson, Henrik ClausenAbstract:Eliminating the risk for ABO-incompatible transfusion errors and simplifying logistics by creating a Universal Blood inventory is a challenging idea. Goldstein and co-workers pioneered the field of enzymatic conversion of Blood group A and B red Blood cells (RBCs) to O (ECO). Using alpha-galactosidase from coffee beans to produce B-ECO RBCs, proof of principle for this revolutionary concept was achieved in clinical trials. However, because this enzyme has poor kinetic properties and low pH optimum the process was not economically viable. Conversion of group A RBCs was only achieved with the weak A(2) subgroup with related enzymes having acidic pH optima. More recently, the identification of entirely new families of bacterial exoglycosidases with remarkably improved kinetic properties for cleaving A and B antigens has reinvigorated the field. Enzymatic conversion of groups A, B and AB RBCs with these novel enzymes resulting in ECO RBCs typing as O can now be achieved with low enzyme protein consumption, short incubation times and at neutral pH. Presently, clinical trials evaluating safety and efficacy of ECO RBCs are ongoing. Here, we review the status of the ECO technology, its impact and potential for introduction into clinical component preparation laboratories.
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SI14 Stripped Red Cells–Efforts to Eliminate A and B Antigens from the Blood Supply
Transfusion Medicine, 2006Co-Authors: Martin L OlssonAbstract:Eliminating the risk for ABO-incompatible transfusion errors and simplifying Blood logistics by creating an ABO-Universal Blood inventory is a challenging idea but not a new one. In the early 1980s Goldstein and co-workers at the New York Blood Centre pioneered the field of enzymatic conversion of Blood group B red Blood cells (RBC) to group O. They used native or recombinant α-galactosidase from green coffee beans to remove the immunodominant galactose residues terminally located in the carbohydrate chains found on group B RBC. These enzyme-converted O (ECO) RBC survived normally in the circulation of individuals independent of the Blood group of the recipient. Small infusions were escalated to single, multiple and repeated RBC units. A successful phase II clinical trial in patients was reported in 2000 by Kruskall et al. However, economically unfavourable doses of enzyme were required to convert a unit of Blood due to the low pH optimum of the enzyme. Conversion of Blood group A cells was never achieved due to lack of A-converting enzymes working at RBC-friendly conditions. Also, the chemical nature of group A antigens is more complex due to the A1/A2 subgroups. Following screening of >2500 microorganisms we recently identified a novel family of bacterial exoglycosidases with specificities for the Blood group A or B antigens and remarkably improved kinetic properties. Enzymatically converted group A and B RBC type as group O and can now be achieved under cost-efficient and optimised conditions including neutral pH and room temperature incubation. Clinical trials to evaluate the safety and efficacy of ECO RBC are currently ongoing. Of the different strategies envisioned to create a Universal Blood component supply, the ECO concept is the only one for which clinical trials in humans have been performed. The presentation will review the current status of this exciting technology and its potential for introduction in the clinical component preparation laboratory. The speaker is a Visiting Associate Professor at Harvard Medical School, Boston, MA, USA and also a scientific consultant to the R&D biotech company ZymeQuest, Inc., Beverly, MA, USA. He gratefully acknowledges the significant and dedicated work performed by numerous members of the ECO team at Copenhagen University, Harvard Medical School, Lund University Hospital Blood Centre and the scientific staff at ZymeQuest.
Henrik Clausen - One of the best experts on this subject based on the ideXlab platform.
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Towards Universally acceptable Blood
Nature Microbiology, 2019Co-Authors: Henrik Clausen, Martin L OlssonAbstract:Metagenomic screening of gut microbiomes led to the discovery of a new enzymatic process for the removal of group A antigens on red Blood cells, providing new hope for the development of Universal Blood.
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A novel α-N-acetylgalactosaminidase family with an NAD+-dependent catalytic mechanism suitable for enzymatic removal of Blood group A antigens
Biocatalysis and Biotransformation, 2010Co-Authors: Gerlind Sulzenbacher, Henrik Clausen, Eric P. Bennett, Steven B. Levery, Yves Bourne, Guillaume Ponchel, Bernard HenrissatAbstract:AbstractEnzymatic removal of Blood group A and B antigens from the surface of red Blood cells to develop Universal Blood was a pioneering vision originally proposed more than 25 years ago. A great variety of enzymes, potentially suitable for enzymatic conversion of red Blood cells, has been described since, but the process has not been economically viable because of the poor kinetic properties and low pH optimum of enzymes. Recently, the identification of two new families of bacterial glycosidases with enhanced kinetic properties for the removal of A and B antigens at neutral pH marked a milestone in the field of transfusion medicine (). Here we present a detailed structural analysis of Elizabethkingia meningosepticum a-N-acetylgalactosaminidase (NagA) shown to efficiently cleave the A antigen. NagA, a member of glycoside hydrolase (GH) family 109, employs an unusual catalytic mechanism involving NAD+. Comparison of the active-center structure with that of members of GH family 4 reveals a striking degree ...
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modifying the red cell surface towards an abo Universal Blood supply
British Journal of Haematology, 2007Co-Authors: Martin L Olsson, Henrik ClausenAbstract:Eliminating the risk for ABO-incompatible transfusion errors and simplifying logistics by creating a Universal Blood inventory is a challenging idea. Goldstein and co-workers pioneered the field of enzymatic conversion of Blood group A and B red Blood cells (RBCs) to O (ECO). Using alpha-galactosidase from coffee beans to produce B-ECO RBCs, proof of principle for this revolutionary concept was achieved in clinical trials. However, because this enzyme has poor kinetic properties and low pH optimum the process was not economically viable. Conversion of group A RBCs was only achieved with the weak A(2) subgroup with related enzymes having acidic pH optima. More recently, the identification of entirely new families of bacterial exoglycosidases with remarkably improved kinetic properties for cleaving A and B antigens has reinvigorated the field. Enzymatic conversion of groups A, B and AB RBCs with these novel enzymes resulting in ECO RBCs typing as O can now be achieved with low enzyme protein consumption, short incubation times and at neutral pH. Presently, clinical trials evaluating safety and efficacy of ECO RBCs are ongoing. Here, we review the status of the ECO technology, its impact and potential for introduction into clinical component preparation laboratories.
Joseph T. Flynn - One of the best experts on this subject based on the ideXlab platform.
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To Screen or Not to Screen? The Value of Routine Blood Pressure Measurement in Children and Adolescents
Current Pediatrics Reports, 2016Co-Authors: Michael G. Semanik, Joseph T. FlynnAbstract:Most pediatric primary care providers will take care of patients with elevated Blood pressure; however, identification of these patients can be problematic. Contradictory recommendations from consensus organizations regarding the utility of pediatric Blood pressure screening make this task more difficult. Choosing which recommendation to follow requires a careful analysis of each recommendation’s background and the evidence supporting it. In this review, we examine the association between elevated Blood pressure in childhood and adverse cardiovascular outcomes in adults, as well as the evidence linking Blood pressure treatment to the regression of target-organ damage. Although there is clearly a need for ongoing research to address gaps in the evidence, we believe that the current body of literature argues for Universal Blood pressure screening in children and adolescents.
Sarah E Messiah - One of the best experts on this subject based on the ideXlab platform.
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evidence to support Universal Blood pressure screening in school based clinical settings
Journal of School Health, 2020Co-Authors: Juliet Silberstein, Lisa Gwynn, Sunil M Mathew, Kristopher L Arheart, Sarah E MessiahAbstract:BACKGROUND: Most pediatric elevated Blood pressure (BP) remains undiagnosed. The American Academy of Pediatrics states "there is limited evidence to support school-based measurement of children's BP." We explored the utility school-based BP screening. METHODS: A cross-sectional sample of 4096 students ages 6 to 17 from Title 1 Miami-Dade Public Schools (50% female, 71% non-Hispanic black, 26% Hispanic) had their systolic/diastolic BP (SBP/DBP) and body mass index (BMI) collected over the 2016 to 2017 or 2017 to 2018 school years. Relative risks (RRs) ratios were calculated to estimate normal/elevated SBP/DBP by BMI percentile, ethnicity, and sex. RESULTS: Overall, 26.4% had at least one elevated BP measurement, of which 59% were not obese. RR for obese status was significant for all categories of elevated BP (RRs > 1.88, p < .0001). Being either female (RR = 1.34, p = .009) or Hispanic (RR = 1.31, p = .014) was significantly associated with elevated DBP. BMI accounted for <10% of the variation in BP (SBP: F(1, 4095) = 367.6, adjusted R(2) = .08, p < .0001; DBP: F(1, 4095) = 93.3, adjusted R(2) = .02, p < .0001). CONCLUSION: These findings support providing BP screenings in school settings. Low-income and minority students often have limited access to health care, higher obesity rates, and unhealthy behaviors. Our findings support Universal school-based BP screening regardless of weight status, particularly among ethnically diverse populations.
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Evidence to Support Universal Blood Pressure Screening in School‐Based Clinical Settings
Journal of School Health, 2020Co-Authors: Juliet Silberstein, Lisa Gwynn, Kristopher L Arheart, M. Sunil Mathew, Sarah E MessiahAbstract:BACKGROUND: Most pediatric elevated Blood pressure (BP) remains undiagnosed. The American Academy of Pediatrics states "there is limited evidence to support school-based measurement of children's BP." We explored the utility school-based BP screening. METHODS: A cross-sectional sample of 4096 students ages 6 to 17 from Title 1 Miami-Dade Public Schools (50% female, 71% non-Hispanic black, 26% Hispanic) had their systolic/diastolic BP (SBP/DBP) and body mass index (BMI) collected over the 2016 to 2017 or 2017 to 2018 school years. Relative risks (RRs) ratios were calculated to estimate normal/elevated SBP/DBP by BMI percentile, ethnicity, and sex. RESULTS: Overall, 26.4% had at least one elevated BP measurement, of which 59% were not obese. RR for obese status was significant for all categories of elevated BP (RRs > 1.88, p < .0001). Being either female (RR = 1.34, p = .009) or Hispanic (RR = 1.31, p = .014) was significantly associated with elevated DBP. BMI accounted for
Margaret Grant - One of the best experts on this subject based on the ideXlab platform.
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rephill protocol for a randomised controlled trial of pre hospital Blood product resuscitation for trauma
Transfusion Medicine, 2018Co-Authors: I. M. Smith, Nick Crombie, Jon Bishop, Aisling Mclaughlin, David N Naumann, M Herbert, James M Hancox, Gemma Slinn, Natalie Ives, Margaret GrantAbstract:OBJECTIVES To describe the 'Resuscitation with Pre-HospItaL Blood products' trial (RePHILL) - a multi-centre randomised controlled trial of pre-hospital Blood product (PHBP) administration vs standard care for traumatic haemorrhage. BACKGROUND PHBP are increasingly used for pre-hospital trauma resuscitation despite a lack of robust evidence demonstrating superiority over crystalloids. Provision of PHBP carries additional logistical and regulatory implications, and requires a sustainable supply of Universal Blood components. METHODS RePHILL is a multi-centre, two-arm, parallel group, open-label, phase III randomised controlled trial currently underway in the UK. Patients attended by a pre-hospital emergency medical team, with traumatic injury and hypotension (systolic Blood pressure <90 mmHg or absent radial pulse) believed to be due to traumatic haemorrhage are eligible. Exclusion criteria include age <16 years, Blood product receipt on scene prior to randomisation, Advanced Medical Directive forbidding Blood product administration, pregnancy, isolated head injury and prisoners. A total of 490 patients will be recruited in a 1 : 1 ratio to receive either the intervention (up to two units of red Blood cells and two units of lyophilised plasma) or the control (up to four boluses of 250 mL 0.9% saline). The primary outcome measure is a composite of failure to achieve lactate clearance of ≥20%/h over the first 2 hours after randomisation and all-cause mortality between recruitment and discharge from the primary receiving facility to non-acute care. Secondary outcomes include pre-hospital time, coagulation indices, in-hospital transfusion requirements and morbidity. RESULTS Pilot study recruitment began in December 2016. Approval to proceed to the main trial was received in June 2017. Recruitment is expected to continue until 2020. CONCLUSIONS RePHILL will provide high-quality evidence regarding the efficacy and safety of PHBP resuscitation for trauma.
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RePHILL: protocol for a randomised controlled trial of pre-hospital Blood product resuscitation for trauma.
Transfusion Medicine, 2017Co-Authors: I. M. Smith, Nick Crombie, Jon Bishop, Aisling Mclaughlin, David N Naumann, M Herbert, James M Hancox, Gemma Slinn, Natalie Ives, Margaret GrantAbstract:OBJECTIVES To describe the 'Resuscitation with Pre-HospItaL Blood products' trial (RePHILL) - a multi-centre randomised controlled trial of pre-hospital Blood product (PHBP) administration vs standard care for traumatic haemorrhage. BACKGROUND PHBP are increasingly used for pre-hospital trauma resuscitation despite a lack of robust evidence demonstrating superiority over crystalloids. Provision of PHBP carries additional logistical and regulatory implications, and requires a sustainable supply of Universal Blood components. METHODS RePHILL is a multi-centre, two-arm, parallel group, open-label, phase III randomised controlled trial currently underway in the UK. Patients attended by a pre-hospital emergency medical team, with traumatic injury and hypotension (systolic Blood pressure
