WITHDRAWN: New Generation of vaccines and convalescent plasma therapy for management of CoV-2: Perspectives from the UK and potential deployment in the current global pandemic.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.transci.2021.103051. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

WITHDRAWN: Convalescent plasma, an apheresis research project targeting and motivating the fully recovered COVID 19 patients: A rousing message of clinical benefit to both donors and recipients alike.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.transci.2020.102794. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

NEW HORIZONS ON STEM CELL CRYOPRESERVATION THROUGH THE ARTIFICIAL EYES OF CD 34+, USING MODERN FLOW CYTOMETRY TOOLS.

Hematopoietic stem cell (HSC) cryopreservation is a critical step in autologous and cord blood transplantation (CBT). In most circumstances, cryopreservation is performed in a mixture containing dimethyl sulfoxide (DMSO), since DMSO is necessary to secure cell viability. Most centers use a controlled rate (slow) freezing before the long-term storage at vapor phase liquid nitrogen (LN2) temperatures (≤ -160 °C). The primary objectives for laboratories supporting HSCT programs are to provide secure storage for leukapheresis and cord blood products, and to adequately characterize the functional properties of the grafts before their infusion. In the autologous setting, the large majority of the published results dealt with the assessment of the graft before cryopreservation. On the contrary, in CBT, before a CB unit is released, a sample obtained from a contiguous segment of that CB unit needs to be tested to verify HLA type and cell viability. The effects of graft handling, cryopreservation, storage and thawing on the recovery of CD34+ cells needs to be carefully analyzed and standardized on a global level. Some technical unresolved issues still limit the application of the ISHAGE derived single platform flow cytometry protocol for the assessment of the thawed material; based on these considerations, an adaptation of both the acquisition setting and the gating strategyis necessary for reliable measurement of CD34-expressing HSC in cryopreserved grafts. Artificial intelligence applied to "big data" may provide a new tool for improving advanced processing procedures and quality management guidelines in this area of investigation.

Implementing a patient blood management program in Norway: Where to start?

Norway has recently established a working group to implement a national patient blood management (PBM) program. Although benchmarking regarding blood usage is challenging in Norway due to legal barriers, a survey was sent to different hospitals to identify possible areas to be prioritized in the first phase of the PBM program. Among them, optimizing the patient's hemoglobin level before elective surgery and implementing electronic check-lists for the indication of transfusion when ordering blood products are two measures that may have a considerable impact on blood usage. The results of the survey also showed that patients may receive a red blood cell transfusion at hemoglobin levels that are higher than those internationally recommended. Since there are no national guidelines for the use of blood products, agreement regarding hemoglobin thresholds is essential to reduce variation in transfusion practice. To achieve these goals, the transfusion specialist plays a key role in promoting the principles behind the PBM concept at the local hospital.

Implementation of a standardised method for the production of allogeneic serum eye drops from regular blood donors in a Norwegian University Hospital: Some methodological aspects and clinical considerations.

The use of autologous serum eye drops has been shown to be effective for the treatment of many ocular diseases. For patients were repeated blood sampling is not possible, allogeneic serum eye drops have been shown to be an effective and safe alternative. In our institution, we have managed to produce allogeneic serum eye drops from regular blood donors using a standardised procedure. The effectiveness and safety of this product will be evaluated in a clinical trial.

Quality assurance of the donor questionnaire and donor interview: a three year experience with an electronic donor questionnaire.

Quality assurance of the donor questionnaire and the donor interview must ensure that all relevant questions about donor eligibility are answered and documented in a reliable format. The use of the self explanatory, electronic donor information tool [EDIT], not only provided a harmonized and standardised system of quality assurance but also saved time and can be easily modified as guidelines change. This brief report highlights the principles of this tool and some of its potential benefits, as experienced over the 3 years since its introduction in Norway.

What's happening--probing of HPA-1a antigen-antibody interaction by surface plasmon resonance technology.

This brief report summarizes the use of surface plasmon resonance technology (SPRT) in probing HPA-1a antigen-antibody interactions, based on a poster presented at the 60th meeting of the American Association of Blood Banks. It was concluded that the GP purification method could affect the performance of antigen in SPRT. It also highlighted that chips immobilised with Monoclonal antibody (Mab)-purified GP-IIb/IIIa work satisfactorily with both monoclonal and recombinant Abs with the appropriate concentration and binding affinity, while determination of the avidity and concentration of maternal polyclonal antibodies in respect to clinical severity on NAIT warrants further development.

Commentary on the 5th annual course in Transfusion Medicine arranged by the Norwegian Red Cross Blood Programme.

This commentary deals briefly with various topics discussed in the recent annual course in Transfusion Medicine, organized by the Norwegian Red Cross Blood Programme.

Transfusion medicine in Norway: new problems and new opportunities.

During 2005 Norwegian Transfusion Medicine has faced some new problems, sought new solutions and gained strength. Interactions with the public and the health authorities have been important issues for consideration, which are discussed below.

Update on pathogen reduction technology for therapeutic plasma: an overview.

Human plasma for therapeutic use, besides having optimal viral safety, must contain optimal levels of all coagulation factors and protease inhibitors to be clinically effective. Several new technologies for pathogen reduction of plasma (PRT) exist and are entering the stage of clinical testing. The main objective of this overview is to provide an update on the current states of three promising photoactive technologies that target pathogen nucleic acid for pathogen inactivation, applicable to single unit fresh-frozen plasma (FFP) and to highlight the experiences gained with classical pathogen reduction of pooled plasma using solvent-detergent (SD) treatment. It should be emphasized that none of the currently applied methods inactivate all types of pathogens and all have some effect on plasma quality when compared to fresh-frozen plasma. Pooled SD-plasma is the best documented clinical product, followed by methylene blue light treated (MBLT)-plasma. Recently, Psoralen light treated (PLT)-plasma has been introduced (CE-marked product in Europe) while Riboflavin light treated (RLT)-plasma is still under development. In principal, PRT for plasma not only differs in terms of the spectrum and log of pathogen reduction potential, but also in respect to the physicochemical/biological characteristics, and profiles of the adverse reactions, particularly in vulnerable patient groups. Therefore, an additional practical step such as oil extraction followed by chromatography to remove the solvent/detergent, and filtration or the use of some special absorbing matrix is required to reduce the residual photosensitive chemicals, their metabolites and photo adducts. This is required to improve the safety margin of the final product. Moreover, while it may be convenient to think that a combined pathogen reduction technology could improve the spectrum of known pathogens to be inactivated, one needs, in practice, to balance between the degree of pathogen reduction and the loss of some plasma protein activity. From the quality point of view, SD-plasma is a pooled standardized pharmaceutical product with extensive in-process control. However, both differences in production processes and the plasma source can influence final product quality. On the other hand, single unit plasma derived from nucleic acid PRT cannot be monitored by pharmaceutical process control and demonstrates the wide range of concentrations normally observed for plasma proteins. Pooling has the disadvantage that one single plasma unit can contaminate a whole pool, but this can be offset by several advantages that pooling and the SD process offer. Among these are reduction of a possible pathogen load by dilution and by neutralizing antibodies in the plasma pool, dilution and possible neutralization of antibodies and allergens which essentially eliminates transfusion-related acute lung injury (TRALI) and reduces allergic reactions significantly, removal of residual blood cells, cell fragments and bacteria, and removal of the largest von Willebrand-factor (vWF) molecules. On the other hand, some streamlining is required for technologies using single units of plasma, such as the use of plasma from male non-transfused donors to reduce TRALI and to avoid the O blood group in order to meet current specifications for FFP [Seghatchian J. What is happening? Are the current acceptance criteria for therapeutic plasma adequate? Transfus Apheresis Sci 2004; 31:67-79], and to exploit the potential benefit to inactivate residual lymphocytes and prevent transfusion-associated graft versus host disease. The cost effectiveness of pathogen inactivation is very low (> 2 million US dollar/life year saved), if however, non-infectious complications such as TRALI are taken into account; the cost for SDP is reduced to < 50,000 British pound/life year saved for those 48 years. Finally, from the therapeutic standpoint, two important questions still remain to be answered. First, whether the various pathogen reduced plasma products are clinically interchangeable and second, whether the conventional quality requirements of FFP are still adequate for the newer plasma products. These questions can only be answered by a head to head comparison, followed by large-scale clinical trials.

Current issues in transfusion medicine in Norway.

Important current issues in transfusion medicine in Norway are discussed. Current patient legislation specifically defines blood donors as patients, and blood and blood products are defined as drugs. Donor selection is controversial, especially deferral of all persons born in, or having lived for more than one year in areas with high prevalence of infections that are transmitted by blood. The threshold for becoming a blood donor is high, but registered donors donate frequently, e.g. 2,4 whole blood donations per year on average. Some blood banks have specialized in multicomponent aphereis technology, in particular collection of two units of red cells.

The content of the LRS chamber provides a new quality tool for the characterization of the donor platelet profile.

Cobe Trima version 4 is an apheresis system designed for the collection of combinations of Red Blood Cells (RBC), Platelets (PLT) and plasma components from a single donor. The validation of this apheresis system for PLT components in our institution evidenced the LRS efficacy, as leucoreduction was attained on a 100% basis. However, there were some unexpected occurrences regarding the PLT content. Certain donations showed large disagreements between programmed and obtained yields, not being found clear reasons for those outcomes. Furthermore, the mean platelet volume (MPV) was relatively low when compared with other platelets components produced by other methodologies. An investigation was initiated in order to know whether these shortcomings were donor or process/instrument related. A link was established between the raw material (donor), the process/instrument and the final product, and a new tool was introduced by the study of the LRS chamber. The LRS chamber content was assessed and the PLT cellular indices and PLT aggregation states compared with those obtained from the respective donor and the final product from the same origin. The storage stability of the final products was also analyzed based on these same tests to investigate if the initial low MPV had any deleterious effect during the shelf life of the components. Twenty five plateletpheresis donors, three of them new ones, were randomly selected for this study. For the first time, the content of the LRS chamber was used as a quality tool for identification of the cause of unexpected yields. Large aggregates remained in the LRS chamber in certain donors who were prone to undergo spontaneous aggregation, making the platelet yields low and platelet MPV very small. Based on repeated failures and on this new quality parameter showing LRS chamber abnormality, two donors were temporarily deferred from the panel. While it was not possible to identify the causes, it is appropriate to raise the question whether these profiles were Trima version 4 specific or not. Hence, further investigation is needed for a better clarification. In short, the simultaneous analysis of products and LRS content provided useful information not only for the characterization of donor-related phenomena but also helped in the identification of potential shortcomings in the machine performance allowing for remedial action to be taken on evidence based data.

In vitro studies of the interaction of heparin, low molecular weight heparin and heparinoids with platelets.

Heparin, low molecular weight heparins, and heparinoids were studied for their ability to inhibit the aggregation of platelets by various agonists and for their ability to adhere to collagen. Heparin was a very effective inhibitor of aggregation with collagen and with ristocetin as it was with adhesion to collagen. The heparinoids showed little effect on aggregation or adhesion. Heparan sulfate and pentosan polysulfate did show slight inhibitory activity against collagen aggregation and adhesion and both interacted with the antibody induced by heparin therapy. It is of interest that dermatan sulfate and the pentasaccharide were almost inert in these experiments, and are unlikely to induce bleeding by inhibition of platelet function. It is highly probable that interference with the interaction of von Willebrand factor with platelets and collagen is a major mechanism for bleeding in the heparinized patient.

Bacterial contamination of blood components.

Despite considerable advances in the safety of blood components, transfusion associated bacterial infection (TABI) remains an unresolved problem. As yet there are no perfect preventative, screening and/or detection methodologies for eliminating contaminated units. Until a practical, rapid, cost-effective and logistically acceptable test becomes available, we should be satisfied with the choice of various limited solutions that at least partially improve the bacterial safety of blood components. It is also necessary to establish standardised guidelines and agreed upon systematic procedures for the recognition and reporting of the laboratory and clinical evaluation of adverse reactions in recipients of contaminated blood components.

A novel method for the assessment of pro- and anti-coagulant properties of platelet-derived microvesicles and its usefulness for quality monitoring of platelet haemostatic function.

To investigate the pro- and anti-coagulant properties of platelet-derived microvesicle (MV), a novel procedure for the removal of plasma proteins was designed, which allows determination of these activities in a purified system in the same reaction vessel. While the pro-coagulant activity of the isolated MV increased on day 5 as compared to day 1, the anti-coagulant activity was significantly reduced.

Monitoring universal leucodepletion performance: the current issues within components production and testing.

The UK NBS completed the introduction of universal leucodepletion in November 1999. This involved the implementation of new methods of production, testing and monitoring, the development of which is still ongoing. Whilst important lessons have been learnt, much remains to be achieved in respect of quality improvement through standardisation of procedures, processes and product modifications to improve safety/efficacy of therapeutic blood components. Since the introduction of universal leucodepletion, many changes in component production and testing have occurred. The primary goal of this report is to review the level of standardisation and harmonisation currently achieved for low leucocyte counting within the NBS and discuss remedial actions undertaken to improve the standard of blood component production and quality monitoring and to highlight some of the related issues which are currently being worked on. The following issues are discussed.

Residual red cell and platelet content in WBC-reduced plasma measured by a novel flow cytometric method.

BACKGROUND: The levels of residual red blood cells (RBC) and platelets (PLT) in WBC-reduced plasma are often below the lower detection limit of automated blood cell counters. This study established a novel flow cytometric method for the enumeration of residual RBC and PLT in plasma. Furthermore, their levels in WBC-reduced plasma prepared by using various filters were investigated. MATERIALS AND METHODS: WBC-reduced plasma was prepared from two sources: (i) filtration of buffy-coat reduced plasma using dock-on Baxter, Pall and Maco Pharma plasma filters; (ii) filtered whole blood using integral Asahi RZ2000, Maco Pharma LST1, NPBI, and Pall WBF2 whole blood filters. Residual RBC and PLT counts were assessed by using a TruCount tube (Becton Dickinson) containing a known number of lyophilized fluorescent beads. RBC and PLT were labelled with dual monoclonal antibodies, anti-CD41-R-phycoerythrin and anti-glycophorin A-fluorescein isothiocyanide, and analyzed by flow cytometer. RESULTS: The flow cytometric method used in this method can detect residual RBC, PLT as well as RBC-MV simultaneously. The sensitivity of the assay was 50 x 10(6) cells/l with the coefficient of variations < or = 10%. Baxter and Maco Pharma plasma filters consistently reduced both RBC, RBC-MV and PLT to below 50 x 10(6/)l. Plasma derived from day 1 RZ2000 filtered whole blood contained PLT below 50 x 10(6) cells/l, whereas day 0 NPBI filtered whole blood showed the highest level of residual PLT. CONCLUSION: A sensitive and accurate method for the detection of low levels RBC, RBC-MV, and PLT was established to measure their levels in WBC-reduced plasma. The procedure is simple and practical for routine quality monitoring of plasma, as well as for setting a new specification for WBC-reduced plasma.

What's happening? The quality of methylene blue treated FFP and cryo.

It is currently unclear to what degree methylene blue in combination with removal, of cells from plasma, by filter, can directly influence the loss of active components of plasma and whether the co-precipitation of FVIII/vWf with fibrinogen/fibronectin is affected by combined methylene blue and light treatment (MBLT). These questions are investigated using the Fenwal system. Our results indicate that up to 15% of the FVIII and IX are lost due to exposure of plasma to filters and methylene blue (MB). The illumination leads to a further 10-15% loss of all other major clotting factors. Factor XI appears to be highly sensitive to the MBLT-process, while inhibitors of the coagulation system are less affected. MBLT did not grossly influence the distribution of fVIII/vWf:Ag between cryoprecipitate and cryosupernatant using a paired control/test protocol, although the fVIII/vWf recovery is reduced in MBLT samples. The three commercially available MBLT processes differ in terms of operational aspects. These may have some impact on overall quality/safety and bioequivalency.