De-escalation of corticosteroids and clonal remission in UBA1 mutation-driven VEXAS syndrome with 5-azacytidine.

Not available.

A Delphi study to establish consensus on a definition of major bleeding in adult trauma.

BACKGROUND: The majority of potentially preventable deaths in trauma are due to uncontrolled hemorrhage and occur early after injury. How major bleeding is defined is integral to early identification and treatment of this group of high-risk patients. However, there is no consensus on a definition of major bleeding in trauma. The aim of this Delphi study was to develop a consensus definition for research, with transfusion used as a surrogate marker of bleeding. STUDY DESIGN AND METHODS: Trauma experts from three international groups were invited to take part in an online Delphi survey. Over the course of four rounds, the group developed a number of definitions of major bleeding and reached consensus on a new definition. RESULTS: Forty-four trauma experts agreed to become members of the Delphi panel, and 30 of 44 (68%) completed all four rounds. The panel agreed to exclude the historical massive transfusion definition (≥10 units of red blood cells within 24 hours). Consensus was reached on a new definition for use in clinical research: 4 or more units of any blood component within 2 hours of injury. CONCLUSION: This Delphi process has yielded a pragmatic transfusion-based definition of major bleeding. The consensus definition differs from historical definitions: a shorter time frame to reflect the acuity of bleeding, and multiple blood components in keeping with a balanced approach to resuscitation. The definition developed may be best suited to mature trauma systems (reflecting the demographics of the expert panel), and could be used to guide registry data recording and to characterize patients at risk of major bleeding.

Regional outcomes of severe acute respiratory syndrome coronavirus 2 infection in hospitalised patients with haematological malignancy.

OBJECTIVES: We sought to characterise the outcomes of patients with haematological malignancy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hospital in our regional network of 7 hospitals. METHODS: Consecutive hospitalised patients with haematological malignancy and SARS-CoV-2 infection were identified from 01/03/2020 to 06/05/2020. Outcomes were categorised as death, resolved or ongoing. The primary outcome was preliminary case fatality rate (pCFR), defined as the number of cases resulting in death as a proportion of all diagnosed cases. Analysis was primarily descriptive. RESULTS: 66 Patients were included, overall pCFR was 51.5%. Patients ≥ 70 years accounted for the majority of hospitalised cases (42, 63%) and fatalities (25, 74%). Mortality was similar between females (52%) and males (51%). Immunosuppressive or cytotoxic treatment within 3 months of the diagnosis of SARS-CoV-2 infection was associated with a significantly higher pCFR of 70%, compared with 28% in those not on active treatment (P = .0013, 2 proportions z test). CONCLUSIONS: Mortality rates in patients with haematological malignancy and SARS-CoV-2 infection in hospital are high supporting measures to minimise the risk of infection in this population.

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.

BACKGROUND: There is increasing interest in the timely administration of concentrated sources of fibrinogen to patients with major traumatic bleeding. Following evaluation of early cryoprecipitate in the CRYOSTAT 1 trial, we explored the use of fibrinogen concentrate, which may have advantages of more rapid administration in acute haemorrhage. The aims of this pragmatic study were to assess the feasibility of fibrinogen concentrate administration within 45 minutes of hospital admission and to quantify efficacy in maintaining fibrinogen levels ≥ 2 g/L during active haemorrhage. METHODS: We conducted a blinded, randomised, placebo-controlled trial at five UK major trauma centres with adult trauma patients with active bleeding who required activation of the major haemorrhage protocol. Participants were randomised to standard major haemorrhage therapy plus 6 g of fibrinogen concentrate or placebo. RESULTS: Twenty-seven of 39 participants (69%; 95% CI, 52-83%) across both arms received the study intervention within 45 minutes of admission. There was some evidence of a difference in the proportion of participants with fibrinogen levels ≥ 2 g/L between arms (p = 0.10). Fibrinogen levels in the fibrinogen concentrate (FgC) arm rose by a mean of 0.9 g/L (SD, 0.5) compared with a reduction of 0.2 g/L (SD, 0.5) in the placebo arm and were significantly higher in the FgC arm (p < 0.0001) at 2 hours. Fibrinogen levels were not different at day 7. Transfusion use and thromboembolic events were similar between arms. All-cause mortality at 28 days was 35.5% (95% CI, 23.8-50.8%) overall, with no difference between arms. CONCLUSIONS: In this trial, early delivery of fibrinogen concentrate within 45 minutes of admission was not feasible. Although evidence points to a key role for fibrinogen in the treatment of major bleeding, researchers need to recognise the challenges of timely delivery in the emergency setting. Future studies must explore barriers to rapid fibrinogen therapy, focusing on methods to reduce time to randomisation, using 'off-the-shelf' fibrinogen therapies (such as extended shelf-life cryoprecipitate held in the emergency department or fibrinogen concentrates with very rapid reconstitution times) and limiting the need for coagulation test-based transfusion triggers. TRIAL REGISTRATION: ISRCTN67540073 . Registered on 5 August 2015.

Blood products and procoagulants in traumatic bleeding: use and evidence.

PURPOSE OF REVIEW: Death from uncontrolled haemorrhage is one of the leading causes of trauma-related mortality and is potentially preventable. Advances in understanding the mechanisms of trauma-induced coagulopathy (TIC) have focused attention on the role of blood products and procoagulants in mitigating the sequelae of TIC and how these therapies can be improved. RECENT FINDINGS: A host of preclinical and clinical studies have evaluated blood product availability and efficacy in trauma. Recently published randomized controlled trials have investigated the ratio of platelet:plasma:red cell transfusion and the role of early cryoprecipitate in trauma. Demand for readily available plasma has led to changes particularly in the use of thawed group A plasma. Furthermore, ex-vivo and early clinical work has demonstrated variations in the haemostatic activity of different plasma, platelet and whole blood products. A number of multicentre trials are in progress aiming to answer key questions regarding tranexamic acid, procoagulant factor and fibrinogen concentrates and their effect on trauma outcomes. SUMMARY: There are promising results from ex-vivo studies in manufacturing and storage of blood products to optimize haemostatic activity and availability, particularly with alternative plasma and platelet products and whole blood. There is an urgent need for these products needs to be tested prospectively.

Traumatic coagulopathy in the older patient: analysis of coagulation profiles from the Activation of Coagulation and Inflammation in Trauma-2 (ACIT-2) observational, multicenter study.

BACKGROUND: Most studies describing traumatic coagulopathy have used data from patient cohorts with an average age of between 35 and 45 years. The last 10 years has seen a steep increase in the number of patients admitted with significant injury and bleeding who are older than the age of 65 years. Many coagulation protein levels alter significantly with normal aging, and it is possible that traumatic coagulopathy has a different signature with age. OBJECTIVES: The aim of this study was to report the coagulation profiles, including standard and extended laboratory, as well as viscoelastic hemostatic assays, stratified according to age to explore age-related differences in hemostatic capability. METHODS: In total, 1576 patients were analyzed from 6 European level 1 trauma centers. RESULTS: As age increased, there was evidence of higher fibrinogen, greater thrombin generation, greater clotting factor consumption, and greater activation of fibrinolysis. Despite this, shock and severe injury led to the same pattern of changes within age groups: lower procoagulant factors (including fibrinogen), increased fibrinolysis, and higher levels of activated protein C. Thromboelastography and rotational thromboelastometry tests detected traumatic coagulopathy with prolongation of R/clotting time and reductions in clot amplitudes in each age cohort. Advancing age strongly correlated with higher fibrinogen levels and greater fibrinolysis. CONCLUSION: Age-related coagulation changes are evident in injured patients. Broadly, similar patterns of coagulation abnormalities are seen across age groups following severe injury/shock, but thresholds for single clotting factors differ. Age-related differences may need to be considered when clinical treatments (eg, transfusion therapy) are indicated.

RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia.

Leukemia-associated chimeric oncoproteins often act as transcriptional repressors, targeting promoters of master genes involved in hematopoiesis. We show that CRABPI (encoding cellular retinoic acid binding protein I) is a target of PLZF, which is fused to RARalpha by the t(11;17)(q23;q21) translocation associated with retinoic acid (RA)-resistant acute promyelocytic leukemia (APL). PLZF represses the CRABPI locus through propagation of chromatin condensation from a remote intronic binding element culminating in silencing of the promoter. Although the canonical, PLZF-RARalpha oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARalpha-PLZF binds to this remote binding site, recruiting p300, inducing promoter hypomethylation and CRABPI gene up-regulation. In line with these observations, RA-resistant murine PLZF/RARalpha+RARalpha/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARalpha APL. RARalpha-PLZF confers RA resistance to a retinoid-sensitive acute myeloid leukemia (AML) cell line in a CRABPI-dependent fashion. This study supports an active role for PLZF and RARalpha-PLZF in leukemogenesis, identifies up-regulation of CRABPI as a mechanism contributing to retinoid resistance, and reveals the ability of the reciprocal fusion gene products to mediate distinct epigenetic effects contributing to the leukemic phenotype.

Safety and efficacy of iron therapy on reducing red blood cell transfusion requirements and treating anaemia in critically ill adults: A systematic review with meta-analysis and trial sequential analysis.

PURPOSE: To evaluate the safety (risk of infection) and efficacy (transfusion requirements, changes in haemoglobin (Hb)) of iron therapy in adult intensive care unit (ICU) patients. MATERIALS AND METHODS: We systematically searched seven databases for all relevant studies until January 2018 and included randomized (RCT) studies comparing iron, by any route, with placebo/no iron. RESULTS: 805 participants from 6 RCTs were included. Iron therapy, by any route, did not decrease the risk of requirement for a red blood cell (RBC) transfusion (Risk ratio (RR) 0.91, 95% CI 0.80 to 1.04, p = 0.15) or mean number of RBCs transfused per participant (mean difference (MD) -0.30, 95% CI -0.68 to 0.07, p = 0.15). Iron therapy did increase mean Hb concentration (MD 0.31 g/dL, 95% CI 0.04 to 0.59, p = 0.03). There was no difference in infection (RR 0.95, 95% CI 0.79 to 1.19, p = 0.44). Trial Sequential Analysis suggests that the required participant numbers to detect or reject a clinically important effect of iron therapy on transfusion requirements or infection in ICU patients has not yet been reached. CONCLUSION: Iron therapy results in a modest increase in Hb. The current evidence is inadequate to exclude an important effect on transfusion requirements or infection.

Antithrombotics in trauma: management strategies in the older patients.

The ageing population has resulted in a change in the demographics of trauma, and older adult trauma now accounts for a growing number of trauma admissions. The management of older adult trauma can be particularly challenging, and exhibits differences to that of the younger age groups affected by trauma. Frailty syndromes are closely related with falls, which are the leading cause of major trauma in older adults. Comorbid disease and antithrombotic use are more common in the older population. Physiological changes that occur with ageing can alter the expected clinical presentation of older persons after injury and their susceptibility to injury. Following major trauma, definitive control of hemorrhage remains essential for improving outcomes. In the initial assessment of an injured patient, it is important to consider whether the patient is taking anticoagulants or antiplatelets and if measures to promote hemostasis such as reversal are indicated. After hemostasis is achieved and bleeding has stopped, longer-term decisions to recommence antithrombotic agents can be challenging, especially in older people. In this review, we discuss one aspect of management for the older trauma patients in greater detail, that is, acute and longer-term management of antithrombotic therapy. As we consider the health needs of an ageing population, rise in elderly trauma and increasing use of antithrombotic therapy, the need for research in this area becomes more pressing to establish best practice and evidence-based care.

Venous thromboembolism: risk of recurrence and long-term anticoagulation.

Recurrence following initial treatment for venous thromboembolism is a significant cause of morbidity and mortality. Balancing the risks of recurrence against the risks of long-term anticoagulation is essential for optimizing patient outcomes.