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.
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.
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.
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.
ISRCTN67540073 . Registered on 5 August 2015.
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.
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 RARα 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-RARα oncoprotein has no impact on PLZF-mediated repression, the reciprocal translocation product RARα-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/RARα+RARα/PLZF APL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARα APL. RARα-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 RARα-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.
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.
Abstract Background/Aims VEXAS syndrome, first described in 2020, is a haemato-inflammatory disease caused by a mutation in the gene-UBA1.This syndrome can coexist with or without Myelodysplastic ...syndrome. What makes this case interesting is its long and challenging diagnostic journey and the involvement of different clinical specialties such as dermatology, ophthalmology, rheumatology, respiratory, haematology, and stroke teams. Ultimately, two years after the initial presentation, this appeared to be the first case of VEXAS with confirmed genetic mutation in the region. VEXAS being a relatively new entity, treating clinician/s were not aware of the possibility initially. Therefore, spreading awareness regarding the clinical picture of VEXAS is prudent. This case report highlights rheumatological and dermatological manifestations of the disease to aid in the timely diagnosis and management of future cases. Methods We report a 74-year-old previously healthy male presented in 2021 with a rash on his legs, arms, and torso since October 2019. It was progressive, painful, palpable, erythematous, non-pruritic, intermittent rash, cleared with hyperpigmentation. He also had oligoarticular arthritis, constitutional symptoms, recurrent episodes of polychondritis, uveitis, bibasal lung fibrosis, and an ESR and CRP above 100. He also had lymphadenopathy above the diaphragm, but the biopsy only showed necrotic material, and the bone marrow biopsy did not show any features of haematological malignancy. After excluding infections, he was started on high-dose oral prednisolone for relapsing polychondritis. The skin and inflammatory markers improved immediately following high doses of steroids. However, whenever steroids were weaned down, even with the help of Methotrexate, his skin was flaring. He also had unprovoked DVT and, while on anticoagulation, developed occipital infarction. He had extensive skin involvement when he had to stop Methotrexate following a chest infection. Results The skin biopsy was inconclusive. There was no significant cytopenia but persistent macrocytosis even after stopping Methotrexate. As a result, he underwent a repeat bone marrow biopsy, which showed Vacuoles and gene UBA1 mutation in 2023. Conclusion The heterogeneity and complexity of the disease are due to multi-organ involvement, including skin, joints, eyes, lungs, blood vessels, and cartilage, simultaneously or cumulatively. Skin involvement in VEXAS can also be vast, ranging from neutrophilic dermatosis, erythema nodosum-like lesions, leukocytoclastic, or urticarial vasculitis. Cutaneous manifestations develop in the majority with VEXAS syndrome and can be the first presenting symptom in this new rare syndrome. Disclosure M. Gunawardena: None. L. Yalakki: None. R. Moitra: None. E.L. Williams: None. H. Wong: None. D. D'Cruz: None.
Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. ...We compared standard practice in the UK with shorter inter-donation intervals used in other countries.
In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants.
45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men for all listed symptoms), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups.
Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency.
NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation.
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.
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.
In total, 1576 patients were analyzed from 6 European level 1 trauma centers.
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.
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.
•Most studies that have informed treatment for trauma hemorrhage and its accompanying coagulopathy have relied on data from cohorts of young patients (average age, 35-45 years).•This large, multicenter, prospective study compares the coagulation profiles of injured patients across age groups from 16 years upward to determine whether age-related changes can be seen.•The same patterns of coagulation changes were seen in younger and older patient cohorts in response to injury (eg, low fibrinogen levels, high activated protein C levels, and hyperfibrinolysis).•For similar degrees of injury, higher fibrinogen levels, greater thrombin generation, and greater fibrinolysis were evident as age increased.
The epidemiology of major injury is changing as the population ages, revealing gaps in our understanding of the management of older patients with trauma-related bleeding. Physiology and haemostasis ...alter with normal ageing and could attenuate the response to bleeding in an older person. The aim of this thesis was to explore the impact of the ageing trauma demographic on the presentation and management of bleeding and coagulopathy in trauma. I conducted a systematic review to explore the evidence across age for the use of blood transfusion strategies in acute trauma haemorrhage. I identified 10 randomised controlled trials; older patients were not well represented. There were no randomised trials in older people or trials that evaluated interventions for different age groups. A Delphi study was undertaken to develop a new consensus research definition for major bleeding in trauma. This definition was applied to the Trauma Audit Research Network registry to assess the effect of age on risk factors for major bleeding. I found older patients with bleeding were less likely to present with tachycardia than younger patients. Multivariable logistic regression using seven risk factors (age, male gender, penetrating injury, mechanism of injury, hypotension and tachycardia and unstable pelvis) showed all were independently significantly associated with bleeding. I also identified a negative interaction between age and penetrating injury, and age and mechanism of injury. Multiple imputation was used to handle missing data and the significance of the risk factors in the imputation model was broadly similar to the complete case analysis model. The effect of age on coagulation and fibrinolytic parameters was assessed in a multicentre cohort study. In patients who did not receive tranexamic acid, after adjusting for key covariates including presence of bleeding and injury severity, I found older age was associated with heightened fibrinolytic activity and fibrinogen levels compared with younger age. The programme of work in this thesis has provided new data showing that age has a significant effect on the clinical presentation and risk factors for bleeding. Furthermore, coagulation and fibrinolytic parameters appear altered across age. These data are exploratory and hypothesis-generating. They inform future research areas to assess the effectiveness of different interventions including tranexamic acid across age, develop age-adapted transfusion protocols and prediction models for bleeding that take age into consideration.
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