Search

ObjectivesUlcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by theOrthohepadnavirusgenus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis.DesignHBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing and correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors.C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control, with or without antibiotic treatment. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, chromatin immunoprecipitation assay with sequencing and RNA-sequencing were performed onin vitromodels of the gut barrier. HBx-silencing experiments were performedin vitroandin vivo.ResultsHBx was detected in about 45% of patients with UC and found to induce colonic inflammation in mice, while its silencing reverted the colitis phenotypein vivo. HBx acted as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering both innate and adaptive mucosal immunityex vivoandin vivo.ConclusionThis study described HBx as a contributor to the UC pathogenesis and provides a new perspective on the virome as a target for tailored treatments.

ObjectiveEffective medical therapy and validated trial outcomes are lacking for small bowel Crohn’s disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion.DesignModified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures.ResultsIn this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials.ConclusionStandardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

ObjectiveMirikizumab, a monoclonal antibody targeting the interleukin-23 p19 subunit, was effective in a Phase 2 study (NCT02589665) of moderately-to-severely active ulcerative colitis (UC). We studied mirikizumab’s impact on health-related quality of life (HRQoL).DesignHRQoL was evaluated using the Inflammatory Bowel Disease Questionnaire (IBDQ) and 36-Item Short Form Health Survey (SF-36) Physical Component Score (PCS) and Mental Component Score (MCS). Mixed effects models for repeated measures compared score changes between mirikizumab and placebo groups. Additional analyses evaluated associations between HRQoL score changes and achievement of efficacy endpoints at weeks 12 and 52.ResultsAt week 12, IBDQ improved compared with placebo for all mirikizumab groups except mirikizumab 50 mg (50 mg, p=0.073; 200 mg, pConclusionMirikizumab improved HRQoL in patients with moderately-to-severely active UC.

ObjectivesExisting scores are not accurate at predicting mortality in upper (UGIB) and lower (LGIB) gastrointestinal bleeding. We aimed to develop and validate a new pre-endoscopy score for predicting mortality in both UGIB and LGIB.Design and settingInternational cohort study. Patients presenting to hospital with UGIB at six international centres were used to develop a risk score for predicting mortality using regression analyses. The score’s performance in UGIB and LGIB was externally validated and compared with existing scores using four international datasets. We calculated areas under receiver operating characteristics curves (AUROCs), sensitivities, specificities and outcome among patients classified as low risk and high risk.Participants and resultsWe included 3012 UGIB patients in the development cohort, and 4019 UGIB and 2336 LGIB patients in the validation cohorts. Age, Blood tests and Comorbidities (ABC) score was closer associated with mortality in UGIB and LGIB (AUROCs: 0.81–84) than existing scores (AUROCs: 0.65–0.75; p≤0.02). In UGIB, patients with low ABC score (≤3), medium ABC score (4–7) and high ABC score (≥8) had 30-day mortality rates of 1.0%, 7.0% and 25%, respectively. Patients classified low risk using ABC score had lower mortality than those classified low risk with AIMS65 (threshold ≤1) (1.0 vs 4.5%; pConclusionsIn contrast to previous scores, ABC score has good performance for predicting mortality in both UGIB and LGIB, allowing early identification and targeted management of patients at high or low risk of death.

Patients with Crohn’s disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies.

ObjectiveTo perform an economic evaluation of tranexamic acid (TXA) versus no-TXA, in addition to current clinical practice, for acute gastrointestinal bleeding, using the results of the HALT-IT trial (NCT01658124), a large randomised controlled trial which included 11 937 patients.DesignA cost-effectiveness modelling analysis, performed over a lifetime time horizon.SettingThe analysis was performed from a UK health service perspective.ParticipantsThe model includes adults with acute gastrointestinal bleeding.Outcomes measuresThe model reports costs in Great British pounds in 2021 and outcomes as life years (LYs) and quality-adjusted life years (QALYs). Cost-effectiveness was evaluated using incremental cost-effectiveness ratios (ICERs), reported as the cost per QALY gained.MethodsA Markov model was developed to calculate the overall costs and health outcomes of TXA administration versus no-TXA. The model used data of the treatment effectiveness from the HALT-IT trial, which showed that TXA administration for acute gastrointestinal bleeding did not reduce all-cause mortality (risk ratio 1.03, 95% CI 0.92 to 1.16) compared with no-TXA. Data on health-related quality of life, costs and long-term mortality risks were derived from the literature. Costs and effects are discounted at 3.5% per annum.ResultsTXA was associated with marginally fewer LYs and QALYs, and lower costs, than treatment without TXA. The ICER associated with no-TXA was £1576 per LY gained and £2209 per QALY gained. No-TXA was 64% likely to be cost-effective at a £20 000 willingness-to-pay threshold, while TXA was 36% likely to be cost-effective.ConclusionThough inexpensive, TXA administration for patients with acute gastrointestinal bleeding is unlikely to be cost-effective.

ObjectiveWe evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment.DesignDisease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo.ResultsInter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608–0.649).ConclusionAll four existing histological indices were similarly reliable and responsive based on this dataset.

Recently in Gut , Gottlieb et al summarised considerations for endoscopy central reading in IBD clinical trials.1 Achieving endoscopic remission is an important measure of therapeutic efficacy, and most Crohn’s disease (CD) trials now require video-recorded ileocolonoscopy at screening and for evaluation of the primary outcome. While the Crohn’s Disease Endoscopic Index of Severity (CDEIS)2 and the Simplified Endoscopic Score for Crohn’s Disease (SES-CD)3 are commonly used instruments, Gottlieb et al correctly highlight that these scores are sensitive to missing data if one or more of the five ileocolonic segments are not examined. Bowel segments may not be visualised if there is an impassable stricture, when the bowel preparation is poor or if there are technical challenges precluding procedure completion. In these situations, appropriately handling missing data is essential because the total endoscopic score may not be reflective of the actual disease burden. We empirically evaluated the effect of different methods for handling missing data from non-visualised segments on the SES-CD and CDEIS. Ileocolonoscopy videos from baseline and week 12 in the Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing (EXTEND) trial were used.4 EXTEND was a randomised, placebo-controlled trial evaluating adalimumab in patients with moderate-to-severe CD. Six methods of handling missing segments were applied: 1. No imputation: non-visualised segments ignored. 2. Worst …

The Robarts Histopathology Index (RHI) is a recently validated instrument that measures histological disease activity in ulcerative colitis.1 Given the increasing importance and use of histology in UC as a treatment outcome, additional evaluation and clarification of the definitions for histological remission and response using the RHI is needed. During the development of the RHI, we demonstrated that most patients in clinical or endoscopic remission had an RHI≤6. However, an RHI≤6 should not be used to define histological remission as was recently suggested by Magro et al .2 Rather, the minimal criteria for histological remission should be the absence of neutrophils from the mucosa (both lamina propria and epithelium), as neutrophils have long been used to define histologically active disease.3 Furthermore, the presence of mucosal neutrophils in biopsies from patients in clinical remission predicts clinical relapse.4 Using the RHI, an absence of mucosal neutrophils is defined as RHI≤3 with the additional requirement of subscores of 0 for lamina propria neutrophils and 0 for neutrophils in epithelium. Given that basal plasmacytosis has also been suggested as an important histological predictor of adverse outcomes,5 an alternate histological endpoint that requires both the absence of mucosal neutrophils and basal plasmacytosis defined as an RHI≤1 could be attractive. However, this composite definition might be too …

A biosimilar is a biological medicine that enters the market subsequent to expiration of the patent of an original reference product and its similarity to the reference medicine exhibits ‘no clinically meaningful differences in terms of quality, safety and efficacy’.1 In practice, patents protect a reference product for 10 years after its approval before registration for a similar biological medicine can be applied for.1 The term ‘biosimilar’ is recognised by all regulators, but synonyms include ‘similar biotherapeutic product’ (WHO) and ‘subsequent-entry biologic’ (Canada).2 Biopharmaceutical agents are derived from living cells or organisms and are usually complex proteins. Therefore, regulators are establishing novel specific approval pathways for biosimilars that differ from those for chemical generics. Since the first approval in 2005, several biosimilars of somatropin (human growth hormone), filgrastim (granulocyte colony-stimulating factor, G-CSF) and epoetin (erythropoietin) have become available in Europe. Currently, 12 biosimilars are authorised in the European market, and numerous others, including monoclonal antibodies (mAbs), have applied for authorisation.3 ,4 This subject has received increasing attention in gastroenterology, because the patent on infliximab is due to expire and regulatory approval for two biosimilar infliximabs have already been filed for to the European Medicines Agency (EMA). One of these molecules is already available for patient care in South Korea.4 ,5 Biological agents are currently in widespread use for the treatment of chronic inflammatory diseases. As recently as in 2000, only two of the world's top 10 grossing drugs were biological agents. In 2012, estimates are that seven are biological agents, of which adalimumab and infliximab lead the list.6 The long duration of development and high manufacturing costs are cited as the main contributors to the high cost of biological agents. For example, the average yearly cost of infliximab treatment for Crohn's disease in …

Lower GI bleeding (LGIB) is a common reason for emergency hospital admission, although there is paucity of data on presentations, interventions and outcomes. In this nationwide UK audit, we describe patient characteristics, interventions including endoscopy, radiology and surgery as well as clinical outcomes.Multicentre audit of adults presenting with LGIB to UK hospitals over 2 months in 2015. Consecutive cases were prospectively enrolled by clinical teams and followed for 28 days.Data on 2528 cases of LGIB were provided by 143 hospitals. Most were elderly (median age 74 years) with major comorbidities, 29.4% taking antiplatelets and 15.9% anticoagulants. Shock was uncommon (58/2528, 2.3%), but 666 (26.3%) received a red cell transfusion. Flexible sigmoidoscopy was the most common investigation (21.5%) but only 2.1% received endoscopic haemostasis. Use of embolisation or surgery was rare, used in 19 (0.8%) and 6 (0.2%) cases, respectively. 48% patients underwent no inpatient investigations. The most common diagnoses were diverticular bleeding (26.4%) and benign anorectal conditions (16.7%). Median length of stay was 3 days, 13.6% patients rebled during admission and 4.4% were readmitted with bleeding within 28 days. In-hospital mortality was 85/2528 (3.4%) and was highest in established inpatients (17.8%, p0.0001) and in patients experiencing rebleeding (7.1%, p0.0001).Patients with LGIB have a high burden of comorbidity and frequent antiplatelet or anticoagulant use. Red cell transfusion was common but most patients were not shocked and required no endoscopic, radiological or surgical treatment. Nearly half were not investigated. In-hospital mortality was related to comorbidity, not severe haemorrhage.

INTRODUCTION: Acute lower gastrointestinal bleeding (LGIB) is a common indication for emergency hospitalisation worldwide. In contrast to upper GIB, patient characteristics, modes of investigation, transfusion, treatment and outcomes are poorly described. There are minimal clinical guidelines to inform care pathways and the use of endoscopy, including (diagnostic and therapeutic yields), interventional radiology and surgery are poorly defined. As a result, there is potential for wide variation in practice and clinical outcomes. METHODS AND ANALYSIS: The UK Lower Gastrointestinal Bleeding Audit is a large nationwide audit of adult patients acutely admitted with LGIB or those who develop LGIB while hospitalised for another reason. Consecutive, unselected presentations with LGIB will be enrolled prospectively over a 2-month period at the end of 2015 and detailed data will be collected on patient characteristics, comorbidities, use of anticoagulants, transfusion, timing and modalities of diagnostic and therapeutic procedures, clinical outcome, length of stay and mortality. These will be audited against predefined minimum standards of care for LGIB. It is anticipated that over 80% of all acute hospitals in England and some hospitals in Scotland, Wales and Northern Ireland will participate. Data will be collected on the availability and organisation of care, provision of diagnostic and therapeutic GI endoscopy, interventional radiology, surgery and transfusion protocols. ETHICS AND DISSEMINATION: This audit will be conducted as part of the national comparative audit programme of blood transfusion through collaboration with specialists in gastroenterology, surgery and interventional radiology. Individual reports will be provided to each participant site as well as an overall report and disseminated through specialist societies. Results will also be published in peer-reviewed journals. The study has been funded by National Health Services (NHS) Blood and Transplant and the Bowel Disease Research Foundation and endorsed by the Association of Coloproctology of Great Britain and Ireland.

Introduction Cirrhosis is a complex acquired disorder of coagulation with a recent paradigm shift in understanding to consider cirrhosis as a pro-thrombotic disorder. It is a frequent indication for transfusion of blood components, both for prophylaxis and for treatment of bleeding, although indications and patterns of blood use are poorly characterised. Methods All NHS trusts with representation on the BSG membership list were invited to take part in a national audit. Data were collected prospectively on conseutive admissions with a confirmed diagnosis of liver cirrhosis over a 4 week period, with follow up to discharge/death/day 28. Specific information was requested on use of blood components, including indication, type of component and laboratory indices prior to transfusion. Standards were defined against guidelines on the use of red blood cells (RBCs), fresh frozen plasma (FFP), platelets and cryoprecipitate. Results Data on 1313 consecutive patients with cirrhosis (mean age 58 years, 65% male) were collected from 85 hospitals. The predominant aetiology was alcohol (70%; 921/1313); 74% of admissions were for features of decompensation; and 21% (275/1313) cases had a positive septic screen. 30% (391/1313) of all admissions were transfused a blood component; in 61% (238/391) this was for treatment of bleeding and in 39% (153/391) for prophylaxis. In patients transfused for bleeding (81%, 192/238 for gastrointestinal bleeding), 92% (220/238) received RBCs, 32% (77/238) FFP, 14% (34/238) platelets and 4% (10/238) cryoprecipitate; in patients with bleeding who received RBCs, the Hb threshold was >8 g/dL prior to RBC transfusion in 31% (69/220) cases. For prophylaxis the majority (61%, 94/153) received transfusion in the absence of a planned procedure. In patients transfused for prophylaxis prior to a procedure (59/153): 19% (3/16) received FFP at an INR ≤1.5 for high risk procedures and 33% (6/18) received FFP at an INR ≤2 for low risk procedures; 36% (9/25) received platelet transfusion at a platelet count >50 prior to a procedure. The most frequent procedures resulting in prophylactic transfusion were paracentesis (18/59), surgery (15/59) and endoscopy (10/59). In-hospital venous thromboembolism was documented in 2% (29/1313) cases. Case fatality during follow up was 10% overall (128/1313) with decompensated cirrhosis (41%; 52/128) as the most frequent cause of death. Conclusion Patients with cirrhosis are frequently transfused during hospitalisation. This audit highlights areas where greater scrutiny of blood component use is required, particularly in the group transfused for prophylaxis of bleeding. Further work is needed to improve patterns of blood use in cirrhosis to ensure patients are not exposed to unnecessary transfusion and its attendant harms. Disclosure of Interest None Declared.

Introduction Gastrointestinal (GI) bleeding is a common medical emergency and an important cause of morbidity and mortality in high, middle and low income countries. Despite advances in resuscitative, pharmacological and endoscopic therapy, re-bleeding occurs in 10% of patients with non-variceal bleeding and up to 25% of those with variceal bleeding and is an important predictor of death. Excessive fibrinolysis may play an important role both in the failure to control initial bleeding and in the precipitation of re-bleeding through premature breakdown of blood clots at sites of vascular injury. This raises the possibility that an antifibrinolytic drug administered following GI bleeding could limit severity of bleeding and transfusion requirements. Methods HALT-IT has been designed as a large, pragmatic randomised controlled trial which aims to quantify the efficacy and safety of tranexamic acid (TXA) in adults with significant acute upper or lower gastrointestinal bleeding. The trial will determine the effect of early administration of TXA on mortality, morbidity, blood transfusion, surgical intervention and health status in patients with GI bleeding. The primary outcome is death in hospital within 28 days of randomisation. Secondary outcomes include re-bleeding, need for surgery or radiological intervention, blood product transfusion and thromboembolic events. Results UK recruitment began in August 2013. By January 2014, a total of 507 patients were randomised across 26 actively recruiting sites, averaging a recruitment rate of 20 patients per week. Centralised and statistical data monitoring ensures trial participants meet inclusion criteria and allows real time monitoring of event rates for the primary and secondary outcomes. The results will be presented by intention to treat and a pre-specified subgroup analysis will also determine the treatment effect in patients with liver cirrhosis and variceal bleeding. Conclusion HALT-IT aims to recruit 8000 participants in hospitals worldwide and recruitment is ahead of schedule based upon a strong performance in the UK. The success of the trial to date has been dependent upon multi-disciplinary and societal engagement as well as infrastructural support provided by NIHR research networks. The results will add to our expanding knowledge about the role of tranexamic acid as an agent for patients with significant bleeding. It is anticipated that the full trial results will be available in 2017. Disclosure of Interest None Declared.

Introduction Acute upper gastrointestinal bleeding (AUGIB) accounts for over 70,000 hospital admissions in the UK annually. Its incidence is likely to rise due to an ageing population and increasing burden of liver disease. Data on the healthcare costs and health-related quality of life (HRQoL) associated with this condition are sparse. Methods The TRIGGER trial is a cluster randomised feasibility trial evaluating restrictive versus liberal red cell transfusion for patients with AUGIB. The study collected data on resource use, costs and outcomes during hospitalisation and up to day 28 to explore the feasibility of gathering inputs required for a cost-effectiveness analysis. Resource use data were collected during the inpatient episode on the use of laboratory tests, medications, blood components, endoscopy and endoscopic therapy, clinical events including ischaemic/thromboembolic events and length of hospital stay (LOS) by ward type. Data were also collected on primary and secondary care resource use, as well as informal care/days off work, post-discharge to day 28. Resource use for each patient was multiplied by national unit costs to generate an estimate of the costs of AUGIB to 28 days. HRQoL was measured on a scale anchored at 0 (death) and 1 (full health), using the EuroQol EQ-5D-3L questionnaire at day 28. Results 936 patients were enrolled into TRIGGER between August 2012 and March 2013 in 6 UK hospitals. Preliminary analyses show that the mean (standard error (SE)) cost of the inpatient episode was £1,914 (£78) per patient. LOS was a key cost driver; mean LOS was 5.4 days with an associated cost of £1431. Additional cost drivers included: (1) red cell transfusion, with a mean of 1.6 units transfused per patient at a cost of £197; (2) endoscopy, with mean of 0.8 endoscopies per patient at a cost of £169. Mean (SE) costs from hospital discharge to 28 days were £293 (£22) per patient. The main cost driver post discharge was readmission to hospital; 12% of patients were readmitted within 28 days for a mean of 4.8 days. The mean cost associated with readmission across all patients was £127. HRQoL was on average (SE) 0.68 (0.01) at 28 days. Conclusion The mean cost up to 28 days for patients presenting with AUGIB is £2,207. At 28 days, the mean HRQoL in patients who have experienced an AUGIB is well below the average population level of 0.86. This is the first study to provide detailed estimates of the costs and HRQoL associated with AUGIB in the UK. These data can be used by healthcare providers and researchers to inform the design of subsequent cost-effectiveness analyses of interventions for AUGIB. Disclosure of Interest None Declared.

Introduction Cirrhotics have multifactorial derangements in haemostasis commonly leading to transfusion of blood components for both prophylaxis and treatment of bleeding. Thrombin generation assays have recently demonstrated that the haemostatic balance in stable cirrhotics is preserved, despite the traditional dogma of “auto-anticoagulation”. It is unclear whether variceal bleeding is precipitated by only vascular abnormalities or due also due to deranged coagulation. We determined the thrombin generating capacity of decompensated cirrhotics presenting with acute variceal haemorrhage. Methods After ethical approval, blood was drawn from 14 cirrhotic patients on arrival to the Emergency Department with AVH prior to any transfusion of any blood components. 74 compensated, non-bleeding cirrhotics and 30 healthy volunteers were enrolled as comparators. Several components of thrombin generation were assayed with and without Protac ® , an activator of protein C. The ratio of endogenous thrombin potential with/without Protac ® (ETP ratio) was used an in index of hypercoagulability. Results Cirrhotics with AVH had a lower haemoglobin, platelet count and prolonged prothrombin time in comparison to stable, non-bleeding cirrhotics. Despite these conventional coagulation indices, cirrhotics with AVH had a shorter lagtime (2.7 min vs 2.8 min), time to peak thrombin generation (4.7 min vs 5.2 min), greater peak thrombin generation (376.5 vs 323.4 nM) and endogenous thrombin potential (ETP) (2035.9 vs 1682.7 nmol/l) compared to stable, non-bleeding cirrhotics. There was no significant difference in the ETP ratios between cirrhotics with AVH (0.80, 95% CI 0.68 to 0.91), non-bleeding cirrhotics (0.88, 95% CI 0.81 to 0.94) and healthy controls (0.79, 95% CI 0.74 to 0.84). Cirrhotics with AVH demonstrated massive upregulation of the procoagulant factor VIII (306% vs 192%) and downregulation of the anti-coagulants proteins C (44% vs 64%), S (75% vs 87%) and antithrombin (55% vs 72%) in comparison to stable cirrhotics. Conclusion The haemostatic balance in decompensated cirrhotics with variceal haemorrhage appears preserved, most likely due to massive upregulation of factor VIII and concomitant down regulation of proteins C, S and antithrombin. These results call into question the utility of conventional coagulation tests to guide replacement of coagulation factors in the form of FFP. Prospective studies using global tests of coagulation to guide therapeutic transfusion of blood components in bleeding cirrhotics are needed. Competing interests None declared.

Introduction Acute Upper Gastrointestinal Bleeding (AUGIB) accounts for 14% of all red blood cell (RBC) transfusions in England. Studies of RBC transfusion practice in critical care and cardiac surgery have shown widespread practice variation. Since there are no such data in AUGIB and, as a consequence of recent evidence that early transfusion is associated with adverse outcomes in AUGIB,1 the current study was designed to assess attitudes towards RBC transfusion practice in patients presenting with AUGIB. Methods A survey depicting six vignettes representing a range of clinical scenarios in AUGIB were piloted for content and emailed to practicing consultants and registrars in gastroenterology, acute medicine and upper gastrointestinal surgery through their member organisations. Respondents were asked to select a haemoglobin (Hb) trigger at which they would ordinarily transfuse red blood cells. Results were analysed using proportional odds models and robust standard errors were used to account for clustering. Results The overall response rate was 48% (815/1709). Transfusion triggers differed significantly between all six scenarios (p 9g/dl was chosen by only 13.3% of respondents to scenario 2 (young patient with features of shock). In comparison, a Hb trigger of >9 g/dl was chosen for 45.2% of respondents in scenario 4 representing an older patient with ischemic heart disease. 10 g/dl in all scenarios. The selected Hb trigger differed between clinical specialities. Surgeons selected a lower Hb transfusion trigger than physicians across all 6 scenarios ( p p 5 years). Only 70% of respondents reported familiarity with national guidelines for AUGIB. Most clinicians favoured a restrictive approach to transfusion, which is in part discordant with actual transfusion practice observed in the UK National Audit of AUGIB, where 15% of all early RBC transfusions were administered to patients with a Hb >10g/dL (38% of whom were haemodynamically stable) and to 50% of admissions with a presenting Hb 8.1–10 g/dl and haemodynamic stability. Conclusion There is widespread variation in attitudes towards RBC transfusion for AUGIB. Both clinician and patient characteristics influence RBC transfusion decisions. Clinical studies are needed to evaluate the safety and efficacy of differing blood transfusion strategies in AUGIB.