Benchmarking of survival outcomes following Haematopoietic Stem Cell Transplantation (HSCT): an update of the ongoing project of the European Society for Blood and Marrow Transplantation (EBMT) and Joint Accreditation Committee of ISCT and EBMT (JACIE).

From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems.

Effect on haemostasis of different replacement fluids during therapeutic plasma exchange-A comparative multicentre observational study.

INTRODUCTION: Therapeutic plasma exchange (TPE) is used for several chronic conditions with little evidence on the efficacy and safety of different choice of replacement fluid. Measurement of haemostasis, particularly in vitro thrombin generation, could play a role in determining the immediate efficacy of different fluid replacement. AIM: To determine the impact of different TPE replacement fluid regimens on haemostatic assays. METHODS: Prospective observational multi-centre cohort study in adult patients 18 years and older evaluating haemostatic changes between four different TPE regimens: (1) 5% human albumin solution (Alb) only, (2) 50:50 mix of 5% Alb + modified gelatin, (3) 70:30 mix of 5% Alb and normal saline (NS), and (4) solvent-detergent, virus-inactivated fresh frozen plasma (FFP) (either alone or combined with other fluids). Twenty-one haemostasis variables were analysed (procoagulant, anticoagulant and fibrinolytic factors) pre and post TPE sessions, including in vitro thrombin generation. Linear mixed modelling and canonical discriminant analyses were used to examine the effect of TPE fluid type on haemostatic variables. RESULTS: A total of 31 patients with up to 5 TPE sessions each (131 sessions in total) were enrolled. Out of 21 markers analysed using linear mixed modelling, the main effects of fluid type were found to be significant for 19 markers (P < 0.05), excluding plasminogen activator inhibitor-1 antigen and thrombin-anti-thrombin. Multivariate Analysis of Variance showed significant differences between the fluid types (Wilks' lambda = 0.07; F63,245.61  = 5.50; P < 0.0001) and this was supported by a canonical discriminant analysis, which identified the 4 most discriminating markers for fluid types as thrombin generation (lag-time, time-to Peak), fibrinogen and Factor V. In our analyses, the effect of FFP on haemostasis was significantly greater compared with other fluid types. Of the non-FFP fluids, 5% Alb + NS had a lower effect on haemostasis compared to other fluid types (Alb and modified gelatin + 5% Alb). CONCLUSION: Thrombin generation and fibrinogen discriminated better the effect of different TPE fluids on haemostasis and should be considered as potential markers to evaluate the immediate haemostatic effect of TPE procedures. The use of NS as a TPE replacement fluid had a distinctive impact on thrombin generation and fibrinogen responses compared to other non-FFP fluids.

Recommendations for procurement of starting materials by apheresis for advanced therapy medicinal products.

Activities involved in the production of certain advanced therapy medicinal products (ATMPs) require standardized approaches to mononuclear cell procurement to ensure the highest product quality, safety and process efficiency. These aims must be achieved while meeting regulatory and accreditation requirements for the procurement of mononuclear cells as starting materials. Mononuclear cells constitute the starting materials for many ATMPs, and this article sets out recommendations for procurement by clinical apheresis, addressing the variation among existing working practices and different manufacturers' requirements that currently poses a challenge when managing multiple different protocols.

Worldwide Network for Blood and Marrow Transplantation Special Article on Key Elements in Quality and Accreditation in Hematopoietic Stem Cell Transplantation and Cellular Therapy.

Hematopoietic stem cell transplantation (HSCT) represents an example of a highly complex and costly medical procedure with major applications in hematology and oncology. It is associated with life-threatening complications and, consequently, increased demands on healthcare resources. Although improving quality is an integral component of healthcare strategic planning, drivers of quality may be variable, and there is logical debate as to what drives quality in HSCT. Moreover, HSCT programs differ in structure and availability of resources, which drive the type of transplantations provided and determine what is affordable and/or economically feasible. The complexity of HSCT procedures with involvement of different stakeholders necessitates not only regulatory frameworks, but also robust quality systems to ensure consistent standards, demonstrate transparency for regulators, and define what quality means within the HSCT program. In an era of escalating healthcare complexity and heightened fiscal responsibility, transparency and accountability, accreditation contributes to ensuring that care meets the highest standards and can serve as a risk mitigation strategy. Quality management has become an indispensable tool for the management of a complex medical intervention such as HSCT. It allows the transplantation team to monitor its activities and identify areas for continuous improvement. The Worldwide Network for Blood and Marrow Transplantation invited a group of international experts in HSCT and quality management to work on providing a summary document about the key elements in quality and accreditation in HSCT and highlight the foremost challenges of implementing them, with a special focus on low- and middle-income economies.

Presenting ADAMTS13 antibody and antigen levels predict prognosis in immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder caused by antibodies against ADAMTS13. From the United Kingdom TTP registry, we undertook a prospective study investigating the impact of the presenting anti-ADAMTS13 IgG antibody and ADAMTS13 antigen on mortality. A total of 312 episodes involving 292 patients over 87 months were included; 68% were female, median age 46 (range, 11-88 years), and median presenting ADAMTS13 of <5% (range, <5%-18%). The mortality rate was 10.3% (n = 32); 68% of patients had a raised troponin at presentation conferring a sixfold increase in mortality compared with those with normal troponin levels (12.1% vs 2.0%, P = .04). Twenty-four percent had a reduced Glasgow Coma Score (GCS) at presentation with a ninefold increase in mortality (20% vs 2.2% for normal GCS at presentation, P < .0001). Mortality increased with higher anti-ADAMTS13 antibody levels and lower ADAMTS13 antigen levels. Those with antibody levels in the upper quartile (antibody >77%) had a mortality of 16.9% compared with 5.0% for the lowest quartile (antibody <20%) (P = .004). Those with an antigen level in the lowest quartile (antigen <1.5%) had a mortality of 18% compared with 3.8% for the highest quartile (antigen >11%) (P = .005). The synergistic effect of anti-ADAMTS13 IgG antibody in the upper quartile and ADAMTS13 antigen in the lowest quartile had the highest mortality of 27.3%. We conclude that both anti-ADAMTS13 IgG antibody and ADAMTS13 antigen levels correlate with outcome in TTP with increased cardiac and neurological involvement and increased mortality.

Acute Respiratory Distress Syndrome and Posterior Reversible Encephalopathy Syndrome following Rituximab Therapy.

The anti-CD20 monoclonal antibody rituximab is associated with rare but significant adverse events, notably posterior reversible encephalopathy syndrome (PRES) and acute respiratory distress syndrome (ARDS). We report a case of concomitant ARDS and PRES developing after rituximab therapy for treatment of cryoglobulinaemic vasculitis. There are 7 reported cases of PRES complicating rituximab use. PRES onset varied from immediate to 21 days after administration. All patients recovered completely, and rituximab was reintroduced in half of the cases. The occurrence of ARDS in association with rituximab is rarer. Only 3 confirmed cases exist, and ARDS may occur as a delayed reaction.

Benefits of an expanded use of plasma exchange for anti-neutrophil cytoplasmic antibody-associated vasculitis within a dedicated clinical service.

BACKGROUND: Current recommendations for ANCA-associated vasculitis (AAV) support its management within a dedicated clinical service. Therapies for AAV are imperfect with many patients failing to achieve disease control and others experiencing disease relapse. Plasma exchange (PEX) may be beneficial especially when the kidney is involved. METHODS: Within a new, dedicated service we retrospectively assessed, over a 6-year period, the benefits of PEX in two patient cohorts, discriminated by PEX treatment alone. Patients received PEX alongside standard of care if they fulfilled any of the following criteria: 1. serum creatinine >500 µmol/l or dialysis-requiring renal failure, 2. alveolar haemorrhage, 3. renal biopsy showing ≥30 % focal and necrotising lesions ± cellular crescents. Outcome measures included disease remission and relapse, cumulative immunosuppression, and morbidity and mortality. RESULTS: Of 104 new patients, 58 patients received PEX at presentation, 46 did not. Cyclophosphamide and/or rituximab dosing was similar for both groups. Although patients receiving PEX had poorer renal function, a higher C-reactive protein and disease activity score at presentation disease remission rate was similar in both groups (no PEX vs. PEX: 96 % vs. 98 %). The PEX group entered remission quicker (no PEX vs. PEX: 3.9 ± 4.0 vs. 2.8 ± 1.3 months, p < 0.05), with a lower 3-month cumulative glucocorticoid dose (no PEX vs. PEX: 2.5 ± 0.4 vs. 2.3 ± 0.2 g, p < 0.001). Relapse was similar between groups but adverse events lower in the PEX group. CONCLUSIONS: PEX may be of benefit in AAV. Larger, longer randomised controlled trials are now needed.

Phenotypic and functional characterization of macrophages with therapeutic potential generated from human cirrhotic monocytes in a cohort study.

BACKGROUND AIMS: Macrophages have complex roles in the liver. The aim of this study was to compare profiles of human monocyte-derived macrophages between controls and cirrhotic patients, to determine whether chronic inflammation affects precursor number or the phenotype, with the eventual aim to develop a cell therapy for cirrhosis. METHODS: Infusion of human macrophages in a murine liver fibrosis model demonstrated a decrease in markers of liver injury (alanine transaminase, bilirubin, aspartate transaminase) and fibrosis (transforming growth factor-ß, α-smooth muscle actin, phosphatidylserine receptor) and an increase in markers of liver regeneration (matrix metalloproteinases [MMP]-9, MMP-12 and TNF-related weak inducer of apoptosis). CD14+ monocytes were then isolated from controls. Monocytes were matured into macrophages for 7 days using a Good Manufacturing Practice-compatible technique. RESULTS: There was no significant difference between the mean number of CD14+ monocytes isolated from cirrhotic patients (n = 9) and controls (n = 10); 2.8 ± SEM 0.54 × 10(8) and 2.5 ± 0.56 × 10(8), respectively. The mean yield of mature macrophages cultured was also not significantly different between cirrhotic patients and controls (0.9 × 10(8) ± 0.38 × 10(8), with more than 90% viability and 0.65 × 10(8) ± 0.16 × 10(8), respectively. Maturation to macrophages resulted in up-regulation of a number of genes (MMP-9, CCL2, interleukin [IL]-10 and TNF-related weak inducer of apoptosis). A cytokine and chemokine polymerase chain reaction array, comparing the control and cirrhotic macrophages, revealed no statistically significant differences. CONCLUSIONS: Macrophages can be differentiated from cirrhotic patients' apheresis-derived CD14 monocytes and develop the same pro-resolution phenotype as control macrophages, indicating their suitability for clinical therapy.

Preoperative predictors for allogenic blood transfusion in hip and knee arthroplasty for rheumatoid arthritis.

INTRODUCTION: To identify the preoperative predictors of requirement for postoperative allogenic blood transfusion following hip and knee joint arthroplasty. MATERIALS AND METHODS: We analysed the retrospective data on patients with rheumatoid arthritis who had undergone either total hip or knee arthroplasty at a single university teaching hospital. Factors of age, sex, procedure type, preoperative haemoglobin, blood transfusion data, comorbidities and body mass index were investigated for association with postoperative allogenic blood after hip or knee arthroplasty. RESULTS: Three hundred and forty nine cases of patients with rheumatoid arthritis were reviewed. 21 % (n = 72) required allogenic blood transfusion. The only significant predictive preoperative factors associated with postoperative blood transfusion were a low preoperative haemoglobin (Hb) level (p < 0.001), procedure of total hip arthroplasty (p = 0.008), a previous history of myocardial infarction (p = 0.038) and previous allogenic blood transfusion (p = 0.03). A preoperative haemoglobin <120 g/l was associated with a tenfold increase in transfusion requirement. All patients with a preoperative Hb level <90 g/l were transfused. CONCLUSIONS: The ability to identify those within this high-risk group who are likely to receive blood transfusion allows for an informed, appropriate and cost effective approach to blood management strategies.

A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation.

RATIONALE: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury. OBJECTIVES: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation. METHODS: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours. MEASUREMENTS AND MAIN RESULTS: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups. CONCLUSIONS: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.

Rotational thrombolelastometry produces potentially clinical useful results within 10 min in bleeding emergency department patients: the DEUCE study.

OBJECTIVES AND BACKGROUND: For the first time in the Emergency Department (ED), to assess the use of rotational thromboelastometry (ROTEM) in patients presenting with all-cause haemodynamic shock, specifically (a) to establish whether a 5- min (A5) or a 10-min result (A10) is accurate compared with a final maximum clot firmness (MCF) result; (b) to compare time to A10 and formal laboratory coagulation result; (c) to assess whether bleeding ED trauma, gastrointestinal and aortic aneurysm patients are coagulopathic according to ROTEM; and (d) to compare ROTEM results with formal laboratory coagulation parameters. METHODS: Patients presenting to the ED in haemodynamic shock were recruited. A citrated coagulation sample was taken and once a ROTEM researcher arrived in the ED, was subjected to ROTEM analysis. RESULTS: Between 28 September 2010 and 31 August 2011, 40 patients were recruited (15 gastrointestinal bleeds, 20 major trauma cases and five ruptured abdominal aortic aneurysms). A10 and MCF correlated well (κ=0.98); A5 and MCF correlated less well (κ=0.91). The mean time to result (SD) was 57 (28) min for the formal laboratory coagulation result and 50 (45) min for the ROTEM A10 result (including delay to start of analysis). Seven patients were coagulopathic on ROTEM. CONCLUSION: Eighteen percent of bleeding ED patients are coagulopathic using ROTEM including 25% of trauma patients. A 10-min ROTEM clot firmness (A10) is an excellent surrogate for MCF and allows a result to be obtained earlier than formal laboratory results and potentially within 10 min of the patient arriving in the ED.

Transfusion of prion-filtered red cells does not increase the rate of alloimmunization or transfusion reactions in patients: results of the UK trial of prion-filtered versus standard red cells in surgical patients (PRISM A).

This study, conducted for the UK Blood Transfusion Services (UKBTS), evaluated the clinical safety of red cells filtered through a CE-marked prion removal filter (P-Capt™). Patients requiring blood transfusion for elective procedures in nine UK hospitals were entered into a non-randomized open trial to assess development of red cell antibodies to standard red cell (RCC) or prion-filtered red cell concentrates (PF-RCC) at eight weeks and six months post-transfusion. Patients who received at least 1 unit of PF-RCC were compared with a control cohort given RCC only. About 917 PF-RCC and 1336 RCC units were transfused into 299 and 291 patients respectively. Twenty-six new red cell antibodies were detected post-transfusion in 10 patients in each arm, an overall alloimmunization rate of 4.4%. Neither the treatment arm [odds ratio (OR) 0.93, 95% confidence interval (CI) 0.3, 2.5] nor number of units transfused (OR 0.95, 95% CI 0.8, 1.1) had a significant effect on the proportion of patients who developed new alloantibodies. No pan-reactive antibodies or antibodies specifically against PF-RCC were detected. There was no difference in transfusion reactions between arms, and no novel transfusion-related adverse events clearly attributable to PF-RCC were seen. These data suggest that prion filtration of red cells does not reduce overall transfusion safety. This finding requires confirmation in large populations of transfused patients.

A review of blood component usage in a large UK emergency department after implementation of simple measures.

OBJECTIVES: To review clinical indications and demographics of transfusion and the patterns of blood component ordering, transfusion, wastage and traceability, before (2007) and after (2011) implementation of simple improvement strategies. METHODS: Retrospective case note review of all patients presenting to the Royal Infirmary of Edinburgh (RIE) Emergency Department (ED) for whom a blood component was requested and historic comparison. Improvement measures implemented between 2007 and 2011 included (1) formal staff education, (2) use of e-learning Module One Safe Transfusion Practice (traceability update, Medicines and Healthcare products Regulatory Agency (MHRA) traceability regulations and importance of returning completed blood component tags), (3) an ED resuscitation room blood fridge, (4) introduction of a dedicated ED transfusion consultant and ED transfusion link nurse and (5) the presence of an ED consultant on the Hospital Transfusion Group. RESULTS: Between 1st January and 31st December 2011, blood components were requested for 255 patient episodes, totalling 1034 individual units. 687 units (66.4%) of blood component were transfused, 248 components (24.0%) were recycled, 90 components (8.7%) were discarded and nine units (0.9%) were unaccounted for. There was a 64% reduction in blood component ordering (3209 vs 1034 units), a 39% reduction in blood component transfusion (1131 vs 687 units) and a 96% reduction in unaccounted units (214 vs 9 units) between 2007 and 2011. There was a rise in the median age of the patient for whom a transfusion request was made from 63.9 years in 2007 to 67.0 years in 2011. CONCLUSIONS: Blood component ordering, usage and traceability within the ED have improved significantly since 2007 following implementation of simple strategies. The age of ED transfusion recipients is increasing.

Successful implementation of strategies to transform Emergency Department transfusion practice.

Blood component transfusion is an important and lifesaving Emergency Department (ED) procedure. It is not however risk-free and careful consideration of its clinical benefit for each individual patient is therefore essential. In 2008, we audited the patterns of blood component usage in 2007 within our ED. This work revealed that whilst 3209 units of blood component were ordered only 39.5% were transfused, and 9.5% were unaccounted for. This was the first and only published detailed look at ED blood transfusion practices. We had to address our poor traceability (i.e. unaccounted for units), our high blood usage, and our ordering of units which were then not transfused as this can lead to wastage. Firstly, better links between the ED and the Scottish National Blood Transfusion Service (SNBTS) were established. A set of improvement measures were then implemented including better ED medical and nursing staff education, monthly traceability reports sent to the ED clinical management teams, the introduction of an ED transfusion guideline, moving our blood fridge into the resuscitation room, having a named ED transfusion consultant and ED transfusion link nurse, ED consultant representation on the Hospital Transfusion Group and finally increasing awareness of ED emergency transfusion with a rotational thromboelastometry (ROTEM) research programme. In 2012, we re-audited our practice looking at our blood component usage in 2011. There was a 64% reduction in blood component ordering (3209 vs. 1034 units), a 39% reduction in blood component transfusion (1131 vs. 687 units), a 68% increase in the proportion of ordered units that were transfused and a 96% reduction in unaccounted units (289 vs. 9 units) between 2007 and 2011. In attempting to cost the savings resulting from our changes we showed that SNBTS spent £306,437 less in 2011 compared to 2007 on handling and issuing ED transfusion requests. Our improvements are immediately generalizable across the UK and the potential savings to the NHS are enormous.

Aortic valve replacement in a Jehovah's Witness: a case of multi-disciplinary clinical management for bloodless surgery.

An 81-year-old female Jehovah's Witness (JW) patient with severe aortic stenosis required aortic valve replacement (AVR). However, the patient's religious beliefs precluded the use of primary blood components. Since the definitive treatment of AVR required bloodless open heart surgery, careful peri-operative plans were set forth by a multi-disciplinary team involving the cardiothoracic surgeon, haematologist and anaesthetist. The patient went on to successfully recover postoperatively. This case highlights: 1) The importance of carefully navigating through the most recent clinical and ethical protocol involved in the surgical management of JW's. 2) The importance of preparing individually tailored pre, intra and postoperative plans that are delivered through a multi-disciplinary clinical team to ensure the best and safest possible outcomes.

A review of blood product usage in a large emergency department over a one-year period.

OBJECTIVES: To establish blood product usage and wastage within a UK emergency department (ED). METHODS: A retrospective case note review of patients presenting to the ED requiring blood products. RESULTS: Between 1 January 2007 and 31 December 2007, 770 transfusion requests were identified, representing 3209 units of blood products. Gastrointestinal bleeding was the most frequent indication for blood product request. 39.5% (1204 units) of blood products ordered were transfused, 47.8% (1458 units) recycled (including 53.4%; 1260 units; of red cell concentrate; RCC), 3.2% (97 units) wasted and 9.5% (289 units) unaccounted for. Median age of recipients was 65 (IQR 46-78) years and 56% of all transfusions were given to patients over 60 years old. CONCLUSION: Patients receiving blood products are elderly. Up to half of all requested products are recycled having not being used for the indication for which they were requested, and 3% of blood products are wasted. With an ageing population and limited blood product availability, transfusion requests should be more carefully considered.