Uncontrolled bleeding accounts for a significant proportion of early traumatic deaths, and almost always occur within the first six hours of injury. In previous randomised controlled trials (RCTs) of transfusion for injured patients with major bleeding the median time to haemorrhagic death, in trauma systems with rapid transport from injury to hospital was 2-2.6 hours from admission [ [1] Fox EE Holcomb JB Wade CE Bulger EM Tilley BC Group PS. earlier endpoints are required for hemorrhagic shock trials among severely injured patients. Shock. 2017; 47: 567-573 Crossref PubMed Scopus (80) Google Scholar ]. Acute Traumatic Coagulopathy (ATC) occurs within minutes of injury and is evident prior to the arrival of patients in hospital [ [2] Floccard B Rugeri L Faure A et al. Early coagulopathy in trauma patients: an on-scene and hospital admission study. Injury. 2012; 43: 26-32 Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar ]. Non-blood component transfusions e.g. crystalloid, do not enable oxygen delivery to the tissues, produce haemodilution of circulating clotting factors, are non-haemostatic, and are harmful to the endothelium. Balanced resuscitation, so called damage control resuscitation which priorities red blood cells with plasma based products has been shown to have restorative effects on the endothelium, ameliorate ATC and improve survival.

Topic: 31. Transfusion medicine Background: No standardized or universally accepted definition for massive transfusion (MT) currently exists, making it difficult to compare safety and efficacy data across studies on critically bleeding patients. The Bleeding Academic Research Consortium successfully standardized definitions for major bleeding in both surgical and non-surgical patients, providing proof of principle for a similar approach to be adopted for the definition of MT. Aims: To identify and evaluate all MT definitions used in randomized controlled trials (RCTs) to date to inform the development of an international consensus definition for MT. Methods: We performed a scoping review of RCTs related to MT. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Cumulative Index to Nursing and Allied Health Literature, and Transfusion Evidence Library were searched from inception until 11 August 2022 without language restriction. Ongoing trials were sought from CENTRAL, ClinicalTrials.gov, and World Health Organisation International Clinical Trials Registry Platform. To be eligible for inclusion, studies were required to: (1) be an RCT; (2) include an adult patient population with an acquired bleeding disorder who had received, or were anticipated to receive, an MT in any clinical setting; and (3) have a specified definition for MT. Conference abstracts, opinion pieces, clinical guidelines, narrative reviews, post hoc analyses, laboratory-only studies, and studies including only paediatric or non-human subjects were excluded. Results: Of the 8,460 distinct references identified from the initial search, 30 studies were included (19 published, 11 ongoing). Several landmark trials on critically bleeding patients, including CRASH-2, were excluded as they did not report a definition for MT. Table 1 highlights the lack of uniformity in MT definitions used to date. Fifteen distinct definitions of MT have been used in RCTs across 4 different specialties (trauma, obstetrics/gynecology, cardiothoracic surgery, and orthopedic surgery) since 1986. Most were based on number of units of RBCs or whole blood administered within a certain time interval. None included other blood products (e.g., platelets, plasma), and some did not specify a time interval during which administration needed to take place. The most common definition of MT (featuring in 10/30 = 33% of studies) was the classic definition of ≥10 units of RBCs in 24 hours (h), with a trend in more recent studies towards the use of shorter time frames (e.g., ≥4 RBCs in 6 h in the TrauCC study registered in 2016 and T-STORHM study published in 2019; ≥3 RBCs in 1 h in a Spanish trial registered in 2017 and the PROCOAG study published in 2021). The classic definition (≥10 RBCs in 24 h) was favored in trauma (featuring in 9/15 = 60% of trauma trials), whereas the most frequently used definition in obstetrics/gynecology was >5 units of whole blood (featuring in 3/6 = 50% of obstetrics/gynecology trials). Summary/Conclusion: Significant heterogeneity exists in the definitions used for MT in RCTs to date. Our findings provide a basis for the development of a consensus definition for MT (e.g., through a modified Delphi process) that can be applied consistently across future trials, which balances the strengths and weaknesses of previous definitions in a specialty-specific manner.Keywords: Transfusion, Bleeding, Blood transfusion

Abstract Objective Compare 30‐day mortality among patients receiving the specific reversal agent andexanet alfa versus replacement prothrombin complex concentrate (PCC) in the management of direct‐acting oral anticoagulant (DOAC)–related bleeds. Methods Two patient‐level datasets were used: ANNEXA‐4, a prospective, single‐arm trial of patients taking apixaban or rivaroxaban who received andexanet alfa and ORANGE, a prospective, observational study of anticoagulated patients in UK hospitals, some of whom received PCC. Patients were propensity score matched based on demographic and clinical characteristics. Subgroup analyses were performed by bleed type (intracranial hemorrhage [ICH], gastrointestinal [GI], other). Relative risk (RR) of all‐cause 30‐day mortality was calculated. Results 322 ANNEXA‐4 patients treated with andexanet alfa (mean age = 77.7 years; 64.9% ICH) were matched with 88 ORANGE patients treated with PCC (mean age = 74.9 years, 67.1% ICH). Adjusted 30‐day mortality for patients treated with andexanet alfa (14.6%) was lower than patients treated with PCC (34.1%; RR, 0.43; 95% CI, 0.29–0.63). In the ICH subgroup, patients treated with andexanet alfa had lower mortality (15.3%) than patients treated with PCC (48.9%; RR, 0.31; 95% CI, 0.20–0.48). Mortality risk was lowest for patients in the GI subgroup but did not differ significantly by treatment (12.2% for andexanet alfa vs 25.0% for PCC; RR, 0.49; 95% CI, 0.21–1.16). Conclusions In this propensity score–matched comparison across 2 independent datasets, adjusted 30‐day mortality rates were lower for patients treated with andexanet alfa than in matched patients receiving PCC. This indirect comparison was limited in that it could not account for several highly predictive variables including GCS score, hematoma volume, and expected survival. Further research is warranted to confirm the mortality differences between reversal/replacement agents for DOAC‐related bleeding.

Objective The ACROBAT pilot trial of early cryoprecipitate for severe postpartum haemorrhage used deferred consent procedures. Pretrial discussions with a patient and public involvement group found mixed views towards deferred consent. This study aimed to build an understanding of how the deferred consent procedures worked in practice, to inform plans for a full-scale trial. Setting Qualitative interview study within a cluster-randomised pilot trial, involving four London maternity services. Participants Individual interviews were conducted postnatally with 10 women who had received blood transfusion for severe postpartum haemorrhage and had consented to the trial. We also interviewed four ‘recruiters’—two research midwives and two clinical trials practitioners who conducted trial recruitment. Results Consent procedures in the ACROBAT pilot trial were generally acceptable and the intervention was viewed as low risk, but most women did not remember much about the consent conversation. As per trial protocol, recruiters sought to consent women before hospital discharge, but this time pressure had to be balanced against the need to ensure women were not approached when distressed or very unwell. Extra efforts had to be made to communicate trial information to women due to the exhaustion of their recovery and competing demands for their attention. Participant information was further complicated by explanations about the cluster design and change in transfusion process, even though the consent sought was for access to medical data. Conclusion Our findings indicate that deferred consent procedures raise similar concerns as taking consent when emergency obstetric research is occurring—that is, the risk that participants may conflate research with clinical care, and that their ability to process trial information may be impacted by the stressful nature of recovery and newborn care. A future trial may support more meaningful informed consent by extending the window of consent discussion and ensuring trial information is minimal and easy to understand. Trial registration number ISRCTN12146519.

Background The limited supply of universal plasma has resulted in transfusion of ABO incompatible plasma to patients. As the need to implement whole blood transfusion in pre-hospitals setting rises, the lowest cut-off for anti-A/anti-B that does not cause haemolysis remains unknown. In this first scoping review, we aimed to determine the lowest ABO titre and volume reported in the literature to cause haemolysis from ABO incompatible plasma transfusions (plasma, platelets, cryoprecipitate, and whole blood). Methods We searched several databases from inception to April 2022, including all study types. Three independent reviewers extracted and reviewed the data. Primary outcome was the anti-A and anti-B titre (measured by IgM or IgG) that resulted in measurable haemolysis following ABO incompatible plasma transfusion. Results We identified 5681 citations, of which 49 studies were eligible, reporting a total of 62 cases (34 adults, 14 children and 14 did not specify age). The methods for antibody measurement and antibody type (IgG or IgM) varied significantly between studies. Component volumes were poorly reported. The most common component responsible for the haemolysis was apheresis platelets followed by pooled platelets and whole blood. Most haemolytic cases reported were due to anti-A. The lowest anti-A titre reported to cause haemolysis (children and adults) was 32 (IgG), while for anti-B it was 512 (IgG and IgM) for adults, 16,384 for paediatrics (IgG and IgM) and 128 (IgM) in cases where the age was not specified. The lowest reported volume associated with haemolysis were 100 ml (adults) and 15 ml (children). Of the 62 15 (24%) died. Conclusion The lowest titre reported to cause haemolysis was an anti-A of 32. ABO mismatch plasma transfusion may be associated with significant mortality. There is a need to agree/standardise methods for ABO titration measurement internationally for plasma components and agree the lowest anti-A/anti-B titre for transfusing ABO mismatched plasma.

TransfusionEarly View COMMENTARY Toward a more complete understanding of who will benefit from prehospital transfusion Mark H. Yazer, Corresponding Author Mark H. Yazer myazer@itxm.org orcid.org/0000-0001-6740-2758 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Correspondence Mark H. Yazer, Vitalant, 3636 Blvd of the Allies, Pittsburgh, PA 15213, USA. Email: myazer@itxm.orgSearch for more papers by this authorAndrew P. Cap, Andrew P. Cap U.S. Army Institute of Surgical Research, Department of Medicine, Uniformed Services University, Bethesda, Maryland, USASearch for more papers by this authorElon Glassberg, Elon Glassberg Israeli Defense Forces, Medical Corps, Israel; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel, The Uniformed Services University of the Health Sciences, Bethesda, Maryland, USASearch for more papers by this authorLaura Green, Laura Green Barts Health NHS Trust, London, UK Blizard Institute, Queen Mary, University of London, London, UK NHS Blood and Transplant, London, UKSearch for more papers by this authorJohn B. Holcomb, John B. Holcomb Center for Injury Science, Department of Surgery, University of Alabama at Birmingham, Birmingham, USASearch for more papers by this authorMansoor A. Khan, Mansoor A. Khan Department of Abdominal Surgery and Medicine, University Hospitals Sussex, Sussex, UKSearch for more papers by this authorErnest E. Moore, Ernest E. Moore Department of Surgery, Ernest E Moore Shock Trauma Center at Denver Health, University of Colorado Denver, Denver, Colorado, USASearch for more papers by this authorMatthew D. Neal, Matthew D. Neal Pittsburgh Trauma and Transfusion Medicine Research Center, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorGavin D. Perkins, Gavin D. Perkins Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK; Critical Care Unit, Heartlands Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UKSearch for more papers by this authorJason L. Sperry, Jason L. Sperry Division of Trauma and General Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorPatrick Thompson, Patrick Thompson Atem Ltd., Andover, UKSearch for more papers by this authorDarrell J. Triulzi, Darrell J. Triulzi Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorPhilip C. Spinella, Philip C. Spinella orcid.org/0000-0003-1721-0541 Departments of Surgery and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this author Mark H. Yazer, Corresponding Author Mark H. Yazer myazer@itxm.org orcid.org/0000-0001-6740-2758 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Correspondence Mark H. Yazer, Vitalant, 3636 Blvd of the Allies, Pittsburgh, PA 15213, USA. Email: myazer@itxm.orgSearch for more papers by this authorAndrew P. Cap, Andrew P. Cap U.S. Army Institute of Surgical Research, Department of Medicine, Uniformed Services University, Bethesda, Maryland, USASearch for more papers by this authorElon Glassberg, Elon Glassberg Israeli Defense Forces, Medical Corps, Israel; Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel, The Uniformed Services University of the Health Sciences, Bethesda, Maryland, USASearch for more papers by this authorLaura Green, Laura Green Barts Health NHS Trust, London, UK Blizard Institute, Queen Mary, University of London, London, UK NHS Blood and Transplant, London, UKSearch for more papers by this authorJohn B. Holcomb, John B. Holcomb Center for Injury Science, Department of Surgery, University of Alabama at Birmingham, Birmingham, USASearch for more papers by this authorMansoor A. Khan, Mansoor A. Khan Department of Abdominal Surgery and Medicine, University Hospitals Sussex, Sussex, UKSearch for more papers by this authorErnest E. Moore, Ernest E. Moore Department of Surgery, Ernest E Moore Shock Trauma Center at Denver Health, University of Colorado Denver, Denver, Colorado, USASearch for more papers by this authorMatthew D. Neal, Matthew D. Neal Pittsburgh Trauma and Transfusion Medicine Research Center, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorGavin D. Perkins, Gavin D. Perkins Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK; Critical Care Unit, Heartlands Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UKSearch for more papers by this authorJason L. Sperry, Jason L. Sperry Division of Trauma and General Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorPatrick Thompson, Patrick Thompson Atem Ltd., Andover, UKSearch for more papers by this authorDarrell J. Triulzi, Darrell J. Triulzi Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this authorPhilip C. Spinella, Philip C. Spinella orcid.org/0000-0003-1721-0541 Departments of Surgery and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USASearch for more papers by this author First published: 07 July 2022 https://doi.org/10.1111/trf.17012Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Objectives To describe the protocol for a multinational randomised, parallel, superiority trial, in which patients were randomised to receive early high-dose cryoprecipitate in addition to standard major haemorrhage protocol (MHP), or Standard MHP alone. Background Blood transfusion support for trauma-related major bleeding includes red cells, plasma and platelets. The role of concentrated sources of fibrinogen is less clear and has not been evaluated in large clinical trials. Fibrinogen is a key pro-coagulant factor that is essential for stable clot formation. A pilot trial had demonstrated that it was feasible to deliver cryoprecipitate as a source of fibrinogen within 90 min of admission. Methods Randomisation was via opaque sealed envelopes held securely in participating Emergency Departments or transfusion laboratories. Early cryoprecipitate, provided as 3 pools (equivalent to 15 single units of cryoprecipitate or 6 g fibrinogen supplementation), was transfused as rapidly as possible, and started within 90 min of admission. Participants in both arms received standard treatment defined in the receiving hospital MHP. The primary outcome measure was all-cause mortality at 28 days. Symptomatic thrombotic events including venous thromboembolism and arterial thrombotic events (myocardial infarction, stroke) were collected from randomisation up to day 28 or discharge from hospital. EQ5D-5Land Glasgow Outcome Score were completed at discharge and 6 months. All analyses will be performed on an intention to treat basis, with per protocol sensitivity analysis. Results The trial opened for recruitment in June 2017 and the final patient completed follow-up in May 2022. Discussion This trial will provide firmer evidence to evaluate the effectiveness and cost-effectiveness of early high-dose cryoprecipitate alongside the standard MHP in major traumatic haemorrhage.

BACKGROUND:Early plasma transfusion for management of bleeding, particularly trauma, is associated with better outcomes. Improving the availability/safety of plasma transfusion for patients is essential for transfusion services. The aim of this study is to evaluate the hemostatic capacity of methylene-blue (MB) liquid (not frozen) plasma over time.MATERIALS AND METHODS:Twenty whole blood-derived plasma units collected from male donors were separated and processed within 18 h of collection. Individual plasmas were treated with MB and stored in liquid status at 2-6°C for 14 days. A range of coagulation assays, including thrombin generation, rotational thromboelastometry (ROTEM), and Thrombodynamics were tested at different time-points, together with bacterial growth.RESULTS:Apart from Factor (F)XII, other coagulation factors (fibrinogen, FV, FVIII, FXI) reduced significantly after MB treatment, with levels remaining stable except for FVIII afterward. By day 14, most clotting factors were >0.7 IU/ml, apart from FVIII. There was a disproportionate decrease in Protein S (PS) activity compared to free PS antigen and by day 14 its value was ~50%. There was no significant difference in maximum clot formation (ROTEM) and clot-density (Thrombodynamics) over time. Endogenous thrombin potential (Thrombin-Generation), clot-size, and velocity index (Thrombodynamics) decreased significantly over time consistent with clotting factor reduction. There was no bacterial growth.CONCLUSIONS:MB-treated liquid plasma stored at 2-6°C can be used for up to 14 days: the long shelf-life, the liquid status, and the MB treatment will improve its availability for management of bleeding as well as providing a safe component from pathogens.

BACKGROUND:The association between international-normalised-ratio (INR) correction and mortality in patients with major bleeding on vitamin-K-antagonists (VKA) is important for evaluating the efficacy of reversal agents for oral anticoagulants. OBJECTIVES:We evaluate if INR correction (defined as ≤1.3) following intervention in major bleeding on VKA is associated with better survival, and if there is a dose-response relationship between Vitamin K (VK) and INR correction. METHODS:Data on patients' characteristics, haematological management and 30-day outcomes reported by 32 UK hospitals (October 2013-August 2016) were analysed. Associations between INR correction and: (a) 30-day mortality; (b) VK dose were estimated using multivariable logistic regression, using multiple imputation to handle missing INR values. RESULTS:Of 1771 patients, 77%, 73% and 33% received prothrombin-complex-concentrate (PCC), VK (92% intravenous) and red cells and fresh frozen plasma transfusion respectively. Proportionally more intracranial haemorrhage (ICH) cases (87%) than non-ICH cases (69%) received PCC. VK administration did not vary by ICH group, with 10 mg (33%) and 5 mg (28%) doses being the most common. Higher doses of VK (10 mg) were more likely to correct INR than lower doses (5 mg). Post-intervention INR > 1.3 in treated patients was associated with 3.2 (95%CI: 2.1-4.9) times higher odds of death within 30 days, compared with INR ≤ 1.3, with no difference between ICH and non-ICH. CONCLUSIONS:INR correction after intervention to manage major bleeding on VKA is associated with better survival. Higher VK doses (10 mg) improve INR correction more than lower doses (5 mg) in major bleeding, but further studies are warranted to compare the relative benefits/risks of 5 mg versus 10 mg doses.

BACKGROUND:Current management principles of hemorrhagic shock after trauma emphasize earlier transfusion therapy to prevent dilution of clotting factors and correct coagulopathy. London's Air Ambulance (LAA) was the first UK civilian prehospital service to routinely offer prehospital red blood cell (RBC) transfusion (phRTx). We investigated the effect of phRTx on mortality.METHODS:Retrospective trauma database study comparing mortality before implementation with after implementation of phRTx in exsanguinating trauma patients. Univariate logistic regression was performed for the unadjusted association between phRTx and mortality was performed, and multiple logistic regression adjusting for potential confounders.RESULTS:We identified 623 subjects with suspected major hemorrhage. We excluded 84 (13.5%) patients due to missing data on survival status. Overall 187 (62.3%) patients died in the before phRTx period and 143 (59.8%) died in the after phRTx group. There was no significant improvement in overall survival after the introduction of phRTx (P = 0.554). Examination of prehospital mortality demonstrated 126 deaths in the pre-phRTx group (42.2%) and 66 deaths in the RBC administered group (27.6%). There was a significant reduction in prehospital mortality in the group who received RBC (P < 0.001).CONCLUSIONS:phRTx was associated with increased survival to hospital, but not overall survival. The "delay death" effect of phRTx carries an impetus to further develop inhospital strategies to improve survival in severely bleeding patients.

SummaryThe lack of antidotes for activated factor X‐inhibitor direct oral anticoagulants (DOACs) means that management of bleeding consists largely of existing supportive therapies. This study aimed to: (i) examine the relative frequency of DOAC‐related major bleeding in relation to DOAC prescriptions over the study period; (ii) describe the presentation and haematological management of DOAC‐related major bleeding; and (iii) evaluate the association between the use of prothrombin‐complex‐concentrate (PCC) and in‐hospital mortality. Over a 3‐year period, 32 UK hospitals submitted data on haematological management of DOAC‐related bleeding. Data consisted of 421 episodes (67%, 21%, 11% and 1% on rivaroxaban, apixaban, dabigatran and edoxaban respectively) of major bleeding on DOACs. The proportion of major bleeds on DOACs and DOAC prescriptions increased throughout the study. Overall, 44% and 37% of patients presented with gastrointestinal bleeding and intracranial haemorrhage (ICH) respectively. Drug concentrations were seldom measured. Compared to no PCC, there was a borderline evidence that receiving low dose PCC (≤25 iu/kg) was associated with better outcomes in terms of mortality (sub‐distribution hazard ratio: 0·15; 95% confidence interval: 0·02–1·19; P = 0·07): but this was not the case for higher doses. DOAC concentrations are seldom measured. There was no evidence of benefit for PCC on in‐hospital mortality.

Trauma is the most frequent cause of death in 15–44 yr olds in England and Wales.1Public Health EnglandMajor causes of death and how they have changed.2017https://www.gov.uk/government/publications/health-profile-for-england/chapter-2-major-causes-of-death-and-how-they-have-changedGoogle Scholar Bleeding accounts for 40% of all injury-related deaths and remains the leading preventable cause of trauma mortality, with healthcare costs to the National Health Service (NHS) exceeding £150 million per annum.2Campbell H.E. Stokes E.A. Bargo D.N. et al.Quantifying the healthcare costs of treating severely bleeding major trauma patients: a national study for England.Crit Care. 2015; 19: 276Crossref PubMed Scopus (24) Google Scholar Over the past 10 yrs, NHS England has instituted a series of initiatives to improve the care of trauma patients including the designation of regional trauma networks, best practice tariffs, and development of clinical care guidelines. There are 23 major trauma centres (MTCs) in England now commissioned to provide centralised care at high volume specialist institutions. Major trauma networks have produced rapid and tangible improvements in processes of care including time to CT scanning and length of hospital stay,3Cole E. Lecky F. West A. et al.The Impact of a pan-regional inclusive trauma system on quality of care.Ann Surg. 2016; 264: 188-194Crossref PubMed Scopus (59) Google Scholar which are associated with a 19% increase in risk-adjusted survival from severe injury.4Moran C.G. Lecky F. Bouamra O. et al.Changing the system — major trauma patients and their outcomes in the NHS (England) 2008–17.E Clin Med. 2018; Google Scholar Each year, more than 20 000 patients sustain major trauma (injury severity score >15), of which nearly 5000 will suffer life-threatening haemorrhage and an estimated 1550 will die as a result of bleeding.5Stanworth S. Davenport R. Curry N. et al.Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice.Br J Surg. 2016; 103: 357-365Crossref PubMed Scopus (83) Google Scholar The nationwide trauma system, with concentrated access to patients in high volume centres, provides an unprecedented opportunity to advance care for injured people in the UK, with the potential to deliver high-quality clinical trials on a national scale. A quarter of major trauma patients who are bleeding present with abnormal blood clotting tests before any intervention (i.e. fluid or blood transfusion) is administered. This is known as acute traumatic coagulopathy (ATC), which is associated with higher rates of bleeding, increased morbidity and a four-fold increase in the risk of death.6Brohi K. Singh J. Heron M. Coats T. Acute traumatic coagulopathy.J Trauma. 2003; 54: 1127-1130Crossref PubMed Scopus (1262) Google Scholar Fibrinogen is the key pro-coagulant factor needed for stable clot formation and effective haemostasis but decreases rapidly and significantly during trauma haemorrhage7Rourke C. Curry N. Khan S. et al.Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.J Thromb Haemost. 2012; 10: 1342-1351Crossref PubMed Scopus (393) Google Scholar in association with increased fibrinolysis.8Raza I. Davenport R. Rourke C. et al.The incidence and magnitude of fibrinolytic activation in trauma patients.J Thromb Haemost. 2013; 11: 307-314Crossref PubMed Scopus (353) Google Scholar Fibrinogen metabolism is altered in ATC with hypothermia and acidosis producing differential effects on fibrinogen synthesis and breakdown. Fibrinogen is the primary substrate of blood clots; therefore, some will be consumed during clot formation and some lost via direct fibrinogenolysis. Low fibrinogen concentration at hospital admission is independently associated with in-hospital, 24 h, and 28 day mortality.7Rourke C. Curry N. Khan S. et al.Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.J Thromb Haemost. 2012; 10: 1342-1351Crossref PubMed Scopus (393) Google Scholar Patients have a greater than three-fold increase in the odds of dying with fibrinogen <1 g L−1 compared with those with a normal fibrinogen concentration (1.5–3.5 g L−1).9McQuilten Z.K. Wood E.M. Bailey M. Cameron P.A. Cooper D.J. Fibrinogen is an independent predictor of mortality in major trauma patients: a five-year statewide cohort study.Injury. 2017; 48: 1074-1081Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar For the past decade, blood transfusion for trauma patients in haemorrhagic shock has followed a damage control resuscitation (DCR) strategy, in essence a balanced resuscitation with blood components and minimal use of crystalloid or colloid.10Cannon J.W. Khan M.A. Raja A.S. et al.Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma.J Trauma Acute Care Surg. 2017; 82: 605-617Crossref PubMed Scopus (221) Google Scholar Major haemorrhage protocols (MHPs) or massive transfusion protocols (MTPs) now preferentially enable trauma teams to deliver an empiric fixed ratio transfusion of red blood cells (RBCs), fresh frozen plasma (FFP), platelets, and fibrinogen. The PROPPR trial found that high RBC:FFP:platelet ratios reduced deaths from exsanguination with a shorter time to haemostasis in trauma patients.11Holcomb J.B. Tilley B.C. Baraniuk S. et al.Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial.JAMA. 2015; 313: 471-482Crossref PubMed Scopus (1469) Google Scholar More recently, the PAMPER trial found improved survival at 24 h and 30 days with early FFP transfusions compared with standard treatment.12Sperry J.L. Guyette F.X. Brown J.B. et al.Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock.N Engl J Med. 2018; 379: 315-326Crossref PubMed Scopus (396) Google Scholar The primary source of fibrinogen replacement in the UK remains cryoprecipitate with national guidelines recommending replacement when levels decrease to less than 1.5 g L−1 as part of an MHP.13Hunt B.J. Allard S. Keeling D. et al.A practical guideline for the haematological management of major haemorrhage.Br J Haematol. 2015; 170: 788-803Crossref PubMed Scopus (152) Google Scholar We have shown previously in a large UK study that despite MHPs, there is a significant delay in administration of cryoprecipitate to bleeding trauma patients with an average time to first transfusion of >3 h.5Stanworth S. Davenport R. Curry N. et al.Mortality from trauma haemorrhage and opportunities for improvement in transfusion practice.Br J Surg. 2016; 103: 357-365Crossref PubMed Scopus (83) Google Scholar Death from haemorrhage typically occurs early (median time to death is 1.65 h14Holcomb J.B. Transport time and preoperating room hemostatic interventions are important: improving outcomes after severe truncal injury.Crit Care Med. 2018; 46: 447-453Crossref PubMed Scopus (63) Google Scholar); therefore, many patients will die before receiving a concentrated fibrinogen product. Early clinical data from uncontrolled observational studies suggest that fibrinogen supplementation improves outcomes for trauma haemorrhage by improving clot strength and reducing blood loss, and is associated with increased survival in both military and civilian settings.15Winearls J. Campbell D. Hurn C. et al.Fibrinogen in traumatic haemorrhage: a narrative review.Injury. 2017; 48: 230-242Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar To date clinical trials of fibrinogen supplementation in trauma have been limited to relatively small feasibility or pilot RCTs, with none powered for a primary mortality endpoint. Several small trials (<100 patients per study) in hospital have used fibrinogen concentrate as replacement therapy for fibrinogen, with coagulation results being the main endpoints: FiiRST16Nascimento B. Callum J. Tien H. et al.Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial.Br J Anaesth. 2016; 117: 775-782Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar (Fibrinogen in the initial Resuscitation of Severe Trauma; NCT02203968), RETIC17Innerhofer P. Fries D. Mittermayr M. et al.Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial.Lancet Haematol. 2017; 4: e258-e271Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar (REversal of Trauma Induced Coagulopathy; NCT01545635), and E-FIT118Curry N. Foley C. Wong H. et al.Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial.Crit Care. 2018; 22: 164Crossref PubMed Scopus (56) Google Scholar (Early-Fibrinogen In Trauma 1; ISRCTN67540073) all demonstrated feasibility of early infusion of supplemental fibrinogen for the majority of patients with an associated rapid increase in plasma fibrinogen concentration. The RETIC study was terminated early for safety reasons because of the high proportion of patients in the comparator arm (FFP group) who required rescue for correction of trauma-induced coagulopathy compared with those in the fibrinogen concentrate group. The European prehospital trial FIinTIC19Maegele M. Zinser M. Schlimp C. Schochl H. Fries D. Injectable hemostatic adjuncts in trauma: fibrinogen and the FIinTIC study.J Trauma Acute Care Surg. 2015; 78: S76-S82Crossref PubMed Scopus (34) Google Scholar (Fibrinogen in Trauma-Induced Coagulopathy; NCT01475344) found physicians were able to administer fibrinogen concentrate in the field with an improved coagulation profile on arrival at hospital. Finally, both FEISTY (Fibrinogen Early In Severe Trauma studY; NCT02745041) and ProoF-iTH (Pilot randomized trial of Fibrinogen in Trauma Haemorrhage; NCT02344069) have completed recruitment with results awaited. For cryoprecipitate, there is only a single feasibility RCT in trauma—CRYOSTAT-120Curry N. Rourke C. Davenport R. et al.Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial.Br J Anaesth. 2015; 115: 76-83Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar (ISRCTN55509212), which provided pilot data for CRYOSTAT-2. CRYOSTAT-1 demonstrated that it was feasible to deliver cryoprecipitate within 90 min of admission, and suggested that early cryoprecipitate therapy maintained blood fibrinogen levels of more than 1.8 g L−1 during resuscitation with a signal for reduced mortality. Of the two therapeutic options available for fibrinogen replacement (cryoprecipitate and fibrinogen concentrate), only the former is recommended for management of acquired bleeding disorders in the UK, and remains the product of choice in North America, Australia, and some European countries. Cryoprecipitate is derived from FFP and consists of factor VIII, fibrinogen, von Willebrand factor, factor XIII, fibronectin, and other plasma proteins such as alpha-2 antiplasmin that decreases fibrinolysis.21McRoyan D.K. McRoyan C.J. Sauter K.L. Liu P.I. Daniel S.J. Antithrombin III, plasminogen, plasmin, and alpha-2-antiplasmin in donor blood and plasma components.Ann Clin Lab Sci. 1985; 15: 165-170PubMed Google Scholar In the UK, cryoprecipitate is pooled from five to six single plasma donations and undergoes two to three freeze–thaw cycles before transfusion. Variability in clotting factor levels in blood donors means that the fibrinogen concentration in cryoprecipitate varies. A systematic review comparing the efficacy of cryoprecipitate and fibrinogen concentrate found very little high quality data to draw meaningful conclusions.22Jensen N.H. Stensballe J. Afshari A. Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: a systematic review.Acta Anaesthesiol Scand. 2016; 60: 1033-1042Crossref PubMed Scopus (50) Google Scholar Across the four studies that were included in this review, there was no difference in fibrinogen increment, transfusion requirement, thromboembolic events, or bleeding. In vitro and ex vivo work have shown that these two blood products lead to similar improvements in coagulopathy during trauma haemorrhage, and the effects are dependent on fibrinogen concentration rather than formulation.7Rourke C. Curry N. Khan S. et al.Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.J Thromb Haemost. 2012; 10: 1342-1351Crossref PubMed Scopus (393) Google Scholar In most European countries, fibrinogen concentrate is the main product for replacing fibrinogen because of its increased viral safety profile, standardised concentration of fibrinogen, freedom from blood incompatibility issues, and benefits of room temperature, near patient storage, or both. However, it is important to emphasise that the two products differ not only in their contents, but also in cost. Several factors contribute to a calculation of cost, not just to the product itself, but also processing, storage, administration, geographical location, and type of product used, with some reporting the unit cost of cryoprecipitate to be one-quarter of the cost per gram of fibrinogen concentrate.23Wong H. Curry N. Do we need cryoprecipitate in the era of fibrinogen concentrate and other specific factor replacement options?.ISBT Sci Ser. 2018; 13: 23-28Crossref Google Scholar An economic evaluation from the USA confirmed that even after cryoprecipitate wastage, fibrinogen concentrate is at least twice as expensive.24Okerberg C.K. Williams 3rd, L.A. Kilgore M.L. et al.Cryoprecipitate AHF vs. fibrinogen concentrates for fibrinogen replacement in acquired bleeding patients — an economic evaluation.Vox Sang. 2016; 111: 292-298Crossref PubMed Scopus (46) Google Scholar No study has yet been of sufficient size to assess the comparative clinical efficacy of the two formulations. Results are awaited from two larger randomised control trials comparing cryoprecipitate vs fibrinogen concentrate: the FEISTY trial (NCT02745041) and the FIBRES (FIBrinogen REplenishment in Surgery) trial (NCT03037424) in cardiothoracic surgery. FIESTY compares the time to fibrinogen supplementation and FIBRES is a non-inferiority trial with the number of components transfused within 24 h as the primary endpoint. In the UK-based E-FIT1 trial, median time to administration of fibrinogen concentrate was 40 min and therefore comparable with timelines for thawing and delivering cryoprecipitate. Until conclusive evidence is provided for survival benefit or cost savings, cryoprecipitate looks set to remain the primary source of fibrinogen therapy in the UK. It is likely that in the near future the speed of delivering cryoprecipitate will be improved, and one option could be extending the shelf life of thawed cryoprecipitate (like FFP), making it readily available. Currently there exists clinical equipoise for which product is the most effective for replenishing fibrinogen stores, supporting haemostasis during traumatic coagulopathy and improving survival. Aside from possible outcome benefits of early fibrinogen replacement, there are risks to consider with administration of any blood component and potential thrombotic complications for all procoagulant therapies.25Klovaite J. Nordestgaard B.G. Tybjærg-Hansen A. Benn M. Elevated fibrinogen levels are associated with risk of pulmonary embolism, but not with deep venous thrombosis.Am J Resp Crit Care Med. 2013; 187: 286-293Crossref PubMed Scopus (36) Google Scholar Finally, there is the wider cost analysis that relates not only to the product itself but also to blood bank logistics, wastage, and administration. Although low fibrinogen concentration is associated with poor outcomes, the threshold considered as critically low is not well established. Traditionally a cut-off of <1.0 g L−1 was used as the critical threshold. A non-linear relationship has been shown between plasma fibrinogen concentration and mortality, with an inflection point for increased mortality at 2.3 g L−1.26Hagemo J.S. Stanworth S. Juffermans N.P. et al.Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study.Crit Care. 2014; 18: R52Crossref PubMed Scopus (125) Google Scholar This is markedly higher than previously acknowledged and suggests fibrinogen should be replaced earlier and more readily during bleeding. Precisely what threshold should be used to trigger fibrinogen replacement is yet to be conclusively defined, and as such guidelines vary internationally. The British Society of Haematology13Hunt B.J. Allard S. Keeling D. et al.A practical guideline for the haematological management of major haemorrhage.Br J Haematol. 2015; 170: 788-803Crossref PubMed Scopus (152) Google Scholar recommends transfusion of two pools of cryoprecipitate below 1.5 g L−1 and current European guidelines27Rossaint R. Bouillon B. Cerny V. et al.The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition.Crit Care. 2016; 20: 100Crossref PubMed Scopus (680) Google Scholar recommend using a threshold of 1.5–2.0 g L−1 or viscoelastic signs of a functional fibrinogen deficit. The National Institute for Health and Care Excellence (NICE) guideline for major haemorrhage in trauma patients does not specifically mention fibrinogen replacement therapy as part of an MHP.28National Institute for Health and Care ExcellenceMajor trauma: assessment and initial management. NICE, London2016Google Scholar In 2016 there were more than 1100 MHP activations across the national trauma system in England with nearly a quarter receiving a prehospital blood transfusion [personal communication with UK Trauma Audit and Research Network (TARN)]. Although the triggers for MHP activation are broadly similar across institutions, the timing and ratios of blood components vary widely with significant differences in when and how much fibrinogen is given (Table 1). Importantly, no MHP calls for empiric transfusion of cryoprecipitate before the fourth unit of RBCs has been administered. Clearly, a gap exists between current UK practice, recommendations for fibrinogen replacement, and the evidence of potential benefit for maintaining a normal level of primary substrate during major trauma haemorrhage.Table 1Current national practice of fibrinogen replacement in major haemorrhage protocols (MHPs) in 24 major trauma centres (England and Northern Ireland). IQR, inter-quartile rangeMajor trauma centres, n24Inclusion of cryoprecipitate in MHP packs, n (%) MHP pack one2 (8) MHP pack two13 (54) MHP pack three22 (92)Specific laboratory trigger for cryoprecipitate?13 (54)Viscoelastic haemostatic assay guided?4 (17)Average units before first cryoprecipitate, median (IQR) Packed red blood cells4.5 (4–8) Fresh frozen plasma4.0 (4–8)Ratio of cryoprecipitate to packed red blood cells, median (IQR) Packed red blood cells 4 units0 (0–0) Packed red blood cells 8 units0.8 (0–1.3) Packed red blood cells 12 units1.1 (0.8–1.7) Open table in a new tab CRYOSTAT-1 demonstrated that early cryoprecipitate is able to rapidly restore fibrinogen.20Curry N. Rourke C. Davenport R. et al.Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial.Br J Anaesth. 2015; 115: 76-83Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar About 10% of all cryoprecipitate is transfused to injured patients, and no large study has yet evaluated the clinical importance of fibrinogen therapy in trauma. CRYOSTAT-2 (ISRCTN 14998314) is the first RCT to evaluate whether early administration of high-dose cryoprecipitate, in addition to standard major haemorrhage therapy, improves survival from traumatic bleeding. The study is funded by a progressive partnership between the National Institute of Health Research–Health Technology Assessment Programme (£1.8 million) and Bart's Charity (£0.5 million) to enable recruitment at approximately 30 trauma centres across the UK (all 23 MTCs in England) and five Level 1 US institutions. The research is being directed by a collaboration of the Centre for Trauma Sciences at the Royal London Hospital and Queen Mary, University of London (trial sponsors), and managed by the NHS Blood & Transplant Clinical Trials Unit. The primary endpoint of CRYOSTAT-2 is all-cause mortality at 28 days with secondary endpoints evaluating early deaths (6 and 24 h), late deaths (6 and 12 months), transfusion requirements, hospital resource use, quality of life measures, safety outcomes for arterial and venous thrombotic events, and discharge destination. The trial intervention consists of early fibrinogen supplementation in the form of three pools of cryoprecipitate, providing approximately 6 g of fibrinogen, within 90 min of admission in addition to standard (local) MHP. The comparator arm is the standard (local) MHP alone. Overall trial recruitment will be 1568 patients and is powered to detect a mortality difference of 7% between the two groups assuming a baseline mortality of 26%. Dosing of fibrinogen for the trial was chosen using results from ex vivo coagulation testing and CRYOSTAT-1 pilot data with the aim of increasing blood fibrinogen levels by 1–1.5 g L−1 and to maintain levels of more than 2 g L−1 during bleeding.7Rourke C. Curry N. Khan S. et al.Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes.J Thromb Haemost. 2012; 10: 1342-1351Crossref PubMed Scopus (393) Google Scholar A 6 g dose of fibrinogen, as cryoprecipitate or fibrinogen concentrate, resulted in significant increases in thromboelastometry clot strength values, suggestive of clinical efficacy. The first UK patient was recruited in August 2017, and with 18 MTCs open to recruitment, 348 patients have been enrolled to date. It is anticipated that US sites will open in early 2019 and recruitment is expected to be completed by late 2020. The trial design has drawn on many of the important lessons learned from previous trials in major trauma haemorrhage. A conservative absolute mortality difference of 7% we believe is realistic and comparable with mortality differences observed in the PROPPR (Pragmatic Randomized Optimal Platelet and Plasma Ratios), COMBAT (Control of Major Bleeding After Trauma), and PAMPer (Prehospital Air Medical Plasma) clinical trials. With a pragmatic trial design, the CRYOSTAT-2 trial has enabled other MTCs to participate in the study regardless of existing research infrastructure. Furthermore, trauma patients arrive at hospital any time of day or night and the practical nature of the trial allows for 24/7 recruitment by clinical teams, and where appropriate, randomisation led by transfusion teams. Patients are eligible for CRYOSTAT-2 if:1.The participant is judged to be an adult (according to local practice, e.g. 16 yrs or older in UK) and has sustained severe traumatic injury.2.The participant is deemed by the attending clinician to have ongoing active haemorrhage. AND REQUIRES:3.Activation of the local MHP for management of severe blood loss. AND HAS STARTED or HAS RECEIVED:4.At least one unit of any blood component (in hospital). Participants are excluded if they are transferred from another hospital, more than 3 h have elapsed from the time of injury, or injuries are deemed incompatible with life. All participants will be enrolled in the study under an initial waiver of consent because of the emergency nature of the trial and mental incapacity of the patient. Consent will be provided in the first instance by a professional or personal consultee where appropriate, until the patient regains capacity, at which point research personnel seek informed consent for their continuation in the study. Further details of the study including the full study protocol are available at http://www.cryostat2.co.uk. The international research spotlight now shines brightly on trauma resuscitation with two major clinical trials from the USA published in 2018 in the New England Journal of Medicine (PAMPER12Sperry J.L. Guyette F.X. Brown J.B. et al.Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock.N Engl J Med. 2018; 379: 315-326Crossref PubMed Scopus (396) Google Scholar) and the Lancet (COMBAT29Moore H.B. Moore E.E. Chapman M.P. et al.Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial.Lancet. 2018; 392: 283-291Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar). CRYOSTAT-2 is the first clinical trial to harness the unrivalled research potential of the national system in England (22 major trauma networks) and key hubs in the devolved nations. Support from National Blood Transfusion Services across the UK, alongside extensive cooperation at individual blood banks, has made it possible to deliver a complex trial across multiple sites with engagement from key stakeholder specialties in trauma care. In little over a decade the NHS has regionalised trauma care and is now capable of recruiting the very sickest patients with life-threatening haemorrhage into a clinical trial day or night. Peak recruitment to CRYOSTAT-2 is running at more than 50 patients per month, which is testament to the creativity and dedication of study sites in screening and identifying patients; rapid communication and randomisation processes between the emergency department and blood bank; and delivery of a time-dependent intervention. Long-term outcome data utilising the existing resource of the UK National Trauma database (TARN) has helped reduce overall running costs. The early successful recruitment to pragmatic trials in trauma resuscitation, and in many centres recruiting above target, are encouraging signs for the future of UK trauma research. The national trauma network has revolutionised care for the injured patient and now provides the foundation on which to deliver cutting edge human discovery science and clinical trials of international standing. UK trauma research may not yet have come of age, but it appears much closer now than ever before. Writing paper: MM, RD. Co-chief investigators: KB, SS. Co-investigators: RD, NC, LC, JB. Development of the CRYOSTAT-2 protocol: CF, HT. Trial management: CF, JL. Data collection and analysis: AR. Critical review of paper: all authors. Development of statistical analysis: HT. NC has received investigator led research funding from CSL Behring and is a Consultant for LFB. The other authors have no conflicts of interest to declare. National Institute of Health Research–Health Technology Assessment Programme (£1.8m) Grant 15/57/02 and Bart's Charity (£0.5 million). Scholarship for high-quality post-graduate training from the Fondazione Cassa Rurale di Trento, Italy (to AR).

BACKGROUNDThe Barkey Plasmatherm (BP; Barkey GmbH & Co. KG) can thaw plasma at 37°C and 45°C. No studies have assessed thawing times or hemostatic qualities of plasma thawed at 45°C with BP. This study assessed fresh frozen plasma (FFP) thawing times with use of BP at 37°C and 45°C and Thermogenesis ThermoLine (TT; Helmer Scientific) at 37°C and compared the hemostatic quality of LG‐Octaplas (Octapharma) with use of BP at 37°C and 45°C with TT at 37°C.STUDY DESIGN AND METHODSThe thawing time of FFP (pairs or fours) was assessed using BP at 37°C and 45°C (not prewarmed and prewarmed) and TT at 37°C. Hemostasis was assessed in LG‐Octaplas at 5 minutes, 24 hours, 48 hours, and 120 hours after thawing with use of the three methods.RESULTSThawing time for two units was 13.44 minutes using TT, the same as using BP at 37°C (12.94 min not prewarmed; 12.20 min prewarmed) or 45°C (12.38 min not prewarmed), but longer than using BP prewarmed to 45°C (11.31 min, p < 0.001). Thawing time for four units was 13.41 minutes using TT, shorter than using BP at 37°C (17.19 min not prewarmed, 18.47 min prewarmed; both p < 0.001) or 45°C (15.03 min not prewarmed, p = 0.012; 15.22 min prewarmed, p = 0.004). There was no reduction in hemostatic markers in LG‐Octaplas with use of BP at 37°C or 45°C compared to TT.CONCLUSIONBP is quicker than TT by 2 minutes when thawing two units of FFP if it is prewarmed to 45°C. BP is slower than TT by at least 2 minutes when thawing four units of FFP at 37oC. There was no significant difference in the hemostatic qualities of plasma whether thawed at 37°C or 45°C.

The outcomes of patients developing major bleeding while on oral anticoagulants remain largely unquantified. The objectives of this study were to: (i) describe the burden of major hemorrhage associated with all available oral anticoagulants in terms of proportion of bleeds which are intracranial hemorrhages, in-hospital mortality and duration of hospitalization following major bleeding; (ii) identify risk factors for mortality; and (iii) compare the characteristics of major hemorrhage between cases treated with warfarin and direct oral anticoagulants for the subgroups of patients with atrial fibrillation or venous thromboembolism. This was a multicenter, 3-year prospective cohort study of patients aged ≥18 years on oral anticoagulants who developed major hemorrhage leading to hospitalization. The patients were followed up for 30 days or until discharge or death, whichever occurred first. In total 2,192 patients (47% female, 81% on warfarin, median age 80 years) were reported between October 2013 and August 2016 from 32 hospitals in the UK. Bleeding sites were intracranial (44%), gastrointestinal (33%), and other (24%). The in-hospital mortality was 21% (95% CI: 19%-23%) overall, and 33% (95% CI: 30%-36%) for patients with intracranial hemorrhage. Intracranial hemorrhage, advanced age, spontaneous bleeding, liver failure and cancer were risk factors for death. Compared to warfarin-treated patients, patients treated with direct oral anticoagulants were older and had lower odds of subdural/epidural, subarachnoid and intracerebral bleeding. The mortality rate due to major bleeding was not different between patients being treated with warfarin or direct oral anticoagulants. Major bleeding while on oral anticoagulant therapy leads to considerable hospital stays and short-term mortality.

Laura Green, Paula Bolton-Maggs, Craig Beattie, Rebecca Cardigan, Yiannis Kallis, Simon J Stanworth, Jecko Thachil and Sharon Zahra NHS Blood and Transplant, Barts Health NHS Trust, Blizard Institute, Queen Mary University of London, London, Serious Hazards of Transfusion Office, Manchester Blood Centre, Manchester, Dept of Anaesthesia, Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, NHS Blood and Transplant/Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, Department of Hepatology, Barts Health NHS Trust, London, Oxford University Hospitals NHS Trust/NHS Blood and Transplant, University of Oxford, Oxford, Haematology Department, Manchester Royal Infirmary, Manchester, and Scottish National Blood Transfusion Service, Edinburgh, UK

Transfusion MedicineVolume 27, Issue 3 p. 228-230 LETTER TO THE EDITOR Prevalence of maternal alloantibodies in a large teaching hospital and their impact on outcomes of fetuses/neonates L. Ainley, L. Ainley Barts Health NHS TrustSearch for more papers by this authorJ. R. Jardim, J. R. Jardim Barts Health NHS TrustSearch for more papers by this authorJ. Tan, J. Tan Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKSearch for more papers by this authorS. Beski, S. Beski Barts Health NHS TrustSearch for more papers by this authorE. M. RiosLeal, E. M. RiosLeal Barts Health NHS TrustSearch for more papers by this authorS. Allard, S. Allard Barts Health NHS Trust NHS Blood and TransplantSearch for more papers by this authorL. Green, Corresponding Author L. Green laura.green@nhsbt.nhs.uk Barts Health NHS Trust Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK NHS Blood and Transplant Correspondence: Dr Laura Green, NHS Blood and Transplant and Barts Health NHS Trust , Charcot Road, Colindale, NW9 5BG London, UK. Tel.: +44 20 8957 2756; fax: +44 20 8957 2838; e-mail: laura.green@nhsbt.nhs.ukSearch for more papers by this author L. Ainley, L. Ainley Barts Health NHS TrustSearch for more papers by this authorJ. R. Jardim, J. R. Jardim Barts Health NHS TrustSearch for more papers by this authorJ. Tan, J. Tan Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UKSearch for more papers by this authorS. Beski, S. Beski Barts Health NHS TrustSearch for more papers by this authorE. M. RiosLeal, E. M. RiosLeal Barts Health NHS TrustSearch for more papers by this authorS. Allard, S. Allard Barts Health NHS Trust NHS Blood and TransplantSearch for more papers by this authorL. Green, Corresponding Author L. Green laura.green@nhsbt.nhs.uk Barts Health NHS Trust Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK NHS Blood and Transplant Correspondence: Dr Laura Green, NHS Blood and Transplant and Barts Health NHS Trust , Charcot Road, Colindale, NW9 5BG London, UK. Tel.: +44 20 8957 2756; fax: +44 20 8957 2838; e-mail: laura.green@nhsbt.nhs.ukSearch for more papers by this author First published: 02 March 2017 https://doi.org/10.1111/tme.12399Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume27, Issue3June 2017Pages 228-230 RelatedInformation

Green, L., Cardigan, R., Beattie, C., Bolton-Maggs, P., Stanworth, S. J., Thachil, J., Kallis, Y. & Zahra, S. (2017), Addendum to the British Committee for Standards in Haematology (BCSH): Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant, 2004 (Br. J Haematol 2004,126,11-28). British Journal of Haematology, 178, 646–647. Joint UKBTS/HPA Professional Advisory Committee. (2015) UKBTS General Information 09 – Shelf-life of frozen plasma components following thawing, May 2015. Available at: www.transfusionguidelines.org.uk/document-library/ documents/shelf-life-of-frozen-plasma-components-following-thawing (accessed 16 June 2016). Neisser-Svae, A., Trawnicek, L., Heger, A., Mehta, T. & Triulzi, D. (2016) Five day stability of thawed plasma: solvent/detergent-treated plasma comparable with fresh-frozen plasma and plasma frozen within 24 hours. Transfusion, 56, 404–409.

This article discusses findings on schooling, pedagogy and notation in the life-experiences of amateur and professional visually-impaired musicians/music teachers, and the professional experiences of sighted music teachers who work with visually-impaired learners. The study formed part of a broader UK Arts and Humanities Research Council funded project, officially entitled “Visually-impaired musicians’ lives: Trajectories of musical practice, participation and learning”, but which came to be known as “Visually-impaired musicians’ lives” (VIML). VIML was led at the UCL Institute of Education, London, UK and supported by the Royal Academy of Music, London, and Royal National Institute of Blind People (RNIB) UK, starting in 2013 and concluding in 2015. It sourced “insider” perspectives from 225 adult blind and partially-sighted musicians/music teachers, and 6 sighted music teachers, through life history interviews and an international questionnaire, which collected quantitative and qualitative data. Through articulating a range of “insider” voices, this article examines some issues, as construed by respondents, around educational equality and inclusion in music for visually-impaired children and adults in relation to three main areas: the provision of mainstream schooling versus special schools; pedagogy, including the preparedness of teachers to respond to the needs of visually-impaired learners; and the educational role of notation, focusing particularly on Braille as well as other print media. The investigation found multifaceted perspectives on the merits of visually-impaired children being educated in either mainstream or special educational contexts. These related to matters such as access to specific learning opportunities, a lack of understanding of visually-impaired musicians’ learning processes (including accessible technologies and score media) in mainstream contexts, and concerns about the knowledge of music educators in relation to visual impairment. Regarding pedagogy, there were challenges raised, but also helpful areas for sighted music educators to consider, such as differentiation by sight condition and approach, and the varying roles of gesture, language, light and touch. There was diversity in musical participation of visually-impaired adult learners, along with some surprising barriers as well as opportunities linked to different genres and musical contexts, particularly in relation to various print media, and sight reading.

Understanding the coagulopathy of major-obstetric-haemorrhage (MOH) that leads to massive-transfusion (MT) is fundamental to improving outcomes. This study reports on the haematological features and transfusion management of women experiencing MT [defined as transfusion of ≥8 units of red blood cells (RBC) within 24 h of delivery]. One hundred and eighty-one cases [median (interquartile range; IQR) age 33 years (29-36)] were identified from all UK hospitals, using the UK Obstetric Surveillance System between July 2012 and June 2013. The median (IQR) estimated blood loss was 6 l (4·5-8). At presentation, the median platelet count was lowest for placenta accreta, compared with other causes, while the median prothrombin time and fibrinogen were <1·5 × mean normal and <3 g/l, respectively for all aetiologies. Median platelet count and fibrinogen fell to <75 × 10(9) /l and <2 g/l, respectively for all causes during bleeding, except for trauma. The median (IQR) units of RBC, fresh-frozen-plasma (FFP) and cryoprecipitate transfused were 10 (8-14), 6 (4-8) and 2 (2-4), respectively. The median time from the onset of bleeding to delivery of the first RBC unit was significantly shorter for women who delivered via elective caesarean section, compared with others. The coagulopathy of MT during MOH differs significantly depending on its cause, suggesting that more targeted transfusion strategies are required.