Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - TACTIC (Targeted Action for Curing Trauma Induced Coagulopathy)

Project Context and Objectives:
Trauma is the world’s 4th leading cause of death and the number one cause of lost life years. The burden of disease is highest in children and young adults, with half of all trauma deaths being related to blood loss. Furthermore, one in four severely injured and shocked patients develop a clotting dysfunction (i.e. trauma-induced coagulopathy; TIC) within minutes of injury that exacerbates on-going blood loss and makes surgical repair very difficult. European research for the global enhancement of trauma care, and specifically bleeding coagulopathic patients, needs to be coordinated, conducted and translated into clinical practice and policy and the TACTIC project addresses this pivotal challenge.

Project Results:
The main objectives are in work package one (WP1) to continuously ensure the timely and complete delivery of the TACTIC program, according to legal and ethical requirements, as well as those of the FP7 Health program. The management of TACTIC is coordinated by Partner 1 who has efficiently administered this task including implementing an organizational structure encompassing a project steering committee, communication with the EC officers and the consortium and implementing two amendments to the FP7-TACTIC contract. The coordinator advises and supports the other partners in all aspects concerning fulfilling the administrative requirements of the TACTIC project.
The overall objectives of WP2 are to establish and maintain a sustainable infrastructure to ensure the standardized collection, consolidation, and distribution of the Consortium’s clinical samples and associated trauma patient data. To date, we have designed and implemented a centralised project Biobank (Partner 1 in Copenhagen) and a tissue-linked study patient Registry (Partner 5 in London) that enable the robust collection, transfer, storage and analysis of both pre-existing locally-housed trauma patients’ materials and prospective TACTIC study materials. By April 2018, 5,877 samples from legacy research subjects are stored in the centralised Biobank in Copenhagen, and the current version of the patient Registry is v4.3 (04 September 2017). The biobank and the registry successfully underpin work on the TACTIC project at multiple sites, and will continue to be updated and developed to provide maximum support to and benefit for all consortium partners.
WP3 focused on the comparison of existing clinical management strategies regarding trauma haemorrhage. Local massive transfusion protocols and clinical practice of each TACTIC partner are described in the publication “Diversity in clinical management and protocols for the treatment of major bleeding trauma patients across European level I Trauma Centres” by Schäfer et al. In addition, results from a large scale online survey focusing on the diversity and heterogeneity in clinical practice for the management of bleeding trauma patients across Europe are published in “Infrastructure and clinical practice for the detection and management of trauma-associated haemorrhage and coagulopathy” by Driessen et al. The analysis for determination and comparison of costs and outcome associated with existing strategies for the management of trauma haemorrhage and TIC is ongoing. Significant progress is made in developing the decision analytical model following the description of the health economic model. For the cost-effectiveness analysis including all parameters and costs, data will be requested by TACTIC partners.

In WP4 the objective is to specify the pathophysiology and underlying mechanisms of TIC. For this purpose, we have investigated blood samples from 2,385 trauma patients. The whole blood was analyzed by whole blood viscoelastic haemostatic assays and the plasma was analyzed for pro -and anticoagulant coagulation factors, fibrinolytic factors and endothelial biomarkers. Single nucleotide polymorphism (SNP) analysis was performed on 1.812 patients investigating SNP´s for coding for β-adrenergic receptors, syndecan-1, heparan sulphate, sE-selectin, thrombomodulin, endothelial protein C receptor (EPCR), protein C) and prostacyclin receptors. To date these data have been used to develop three scientific manuscripts in alignment with the objectives and in collaboration with WP5, WP6 and WP8 (see below).
In WP5 data were analysed on 2287 prospectively followed trauma patients from the TACTIC database and it was managed to define coagulopathy on both ROTEM and TEG profiles, in terms of relationship to admission INR. Thresholds for identification of hypofibrinogenaemia, hyperfibrinolysis and thrombocytopenia were incorporated into new algorithms for ROTEM, TEG and conventional coagulation tests. A paper describing the performance of both devices (ROTEM® and TEG®) and including the resulting algorithms was recently published (epub ahead of print) in Annals of Surgery - Data-driven Development of ROTEM and TEG Algorithms for the Management of Trauma Hemorrhage: A Prospective Observational Multicenter Study. Ann Surg. 2018 May 23 (WP4, WP5, WP6). The algorithms are utilized in the ongoing RCT (WP8). Additionally, we have identified a large cohort of patients whose hyperfibrinolytic coagulopathy is not identified by viscoelastic assays (or other assays). This is a vitally important group to recognize as many clinicians withhold antifibrinolytic therapy without diagnostic evidence of hyperfibrinolysis. We identified a new mechanism for this fibrinolysis and explained why this group is occult to the diagnostic tests. This is now published in The S100A10 pathway mediates an occult hyperfibrinolytic subtype in trauma patients in Annals of Surgery 2018 (WP4, WP5) and will lead to new management approaches and to new diagnostic approaches to this group.
Furthermore, The Salzburg database is currently being revised and cleared for data entered between 2005-2017; once this process is finished and the up-dated dataset is available, TASH neo derived from the TACTIC database on > 2000 patients will be finally validated. A draft version of the publication has been compiled and will be up-dated accordingly for rapid publication in a peer reviewed scientific journal of impact.

In WP6 the objectives are to define the functional and molecular changes due to the existing therapy, and to deliver patient-matched treatment algorithms to be used in WP8.
By studying the patients in the trauma registry we found that high ratios of FFP and platelets to RBC reduced fibrinolysis and improved whole blood haemostasis evaluated by ROTEM and TEG and that these can be used to monitor trauma patient haemostasis during the acute bleeding phase. WP6 collaborated with WP5 on the abovementioned paper on treatment algorithms that are being tested in the WP8 iTACTIC RCT. The paper on the control arm is published in British Journal of Surgery: Combined effect of therapeutic strategies for bleeding injury on early survival, transfusion needs and correction of coagulopathy (2017).
Another aim of this WP was to personalize treatment, results were stratified according to age, the presence of shock or the presence of traumatic brain injury (TBI). The effect of ROTEM parameters for all patients as a whole group was compared to the patients that complied to specific ROTEM threshold values of coagulopathy, as determined in WP5.

The overall objectives of WP7 are to unite the clinical expertise of Partners 1-6 with the industry Partners 7 (Haemonetics Corp.) and 8 (TEM Innovations GmbH) to develop an application (‘the app’) to facilitate the rapid implementation of new knowledge from TACTIC and the integration of viscoelastic haemostatic assays (VHA) into the clinical work stream.
We have developed the app as intended and in collaboration with Partners 7 (Haemonetics Corp.) and 8 (TEM Innovations GmbH), and have made various improvements to the app interface in the light of user feedback and the more complex logical expression required by the revised iTACTIC algorithm. We have also developed a ‘gamification’ of the app to enable both evaluation of the app outside the operating room and future training with the app. We have performed an initial evaluation of the app involving 16 participants specialising in trauma at the Royal London Hospital. The evaluation involves trauma scenarios (developed by an anaesthetist) and compares two conditions: a control condition in which the standard ROTEM VHA display is embedded and the participant is provided with a paper print-out of the algorithm; and experimental condition in which the dynamic ROTEM VHA trauma display is embedded. Evaluation and further development of the app are continuing (including the use of the TEG algorithm), and we remain on track to provide a solution that will greatly assist clinicians in the rapid and successful identification and management of coagulopathic bleeding. We are also exploring the possibility of producing a web-based version of the app that can be used as an e-learning resource.
WP8 should conduct a clinical trial comparing the effect of VHA treatment algorithm versus local empiric treatment on patient outcome. The ongoing RCT iTACTIC (WP8) aims at comparing resuscitation of massively bleeding trauma patients monitored by Viscoelastic Haemostatic Assays (VHAs) versus conventional coagulation tests (CCTs). iTACTIC is one of the main goals of the TACTIC project and is the first RCT to apply algorithms developed based on a large cohort of trauma patients (WP5) in the attempt to optimize resuscitation of critically ill trauma patients. As the trial is aiming at improving the treatment of Trauma Induced Coagulopathy (TIC), the primary endpoint is the proportion of subjects alive and free of massive transfusion at 24 hours. Secondary endpoints include other relevant outcome measures. Both study arms (VHA and CCT) are based on optimal empiric resuscitation based on a MTP aiming at a ratio of 1:1:1 of blood components (RBC 1 : plasma 1 : platelets 1) in addition to Tranexamic Acid (TXA). The Intervention arm applies VHA-guiding of further resuscitation with blood products, procoagulant factors and antifibrinolytics. In the Control arm, CCTs are used to guide further resuscitation with blood products and procoagulant factors. The protocol has recently been published in Trials: iTACTIC – implementing treatment algorithms for the correction of trauma induced coagulopathy: study protocol for a multicenter randomized controlled trial 2017. Enrolment into the RCT started on 1st June 2016, with a 7 months delay. The RCT enrolled at the predicted rate, and the application for a 6-month extension for the RCT and the project was approved (Grant agreement 602771, 31st January 2018). Simultaneously, Nottingham University Hospital was accepted as an additional study site, in order to speed up enrolment. These changes were incorporated in a substantial amendment in March 2017. In addition, the TEG threshold for hyperfibrinolysis was adjusted based on further data analyses, a per protocol definition was added, it was decided to perform a subgroup analysis on severe head injured patients, and the SAE reporting was simplified. As of 30 April 2018, a total of 360 participants have been enrolled into the study. The most recent review by the DSMB relates to the first 300 patients, for which a total of 155 Serious Adverse Events (SAEs) had been reported. These data are currently under review by the DSMB

WP9 focuses on the dissemination of information and results generated within the project to fundamental and clinical scientific colleagues, to the media (e.g. popular scientific and lay press, TV, radio), to the key stakeholders on health policy and decision-making levels and to other interested parties. Project partners have so far published five scientific articles that are mentioned in the above text. We have also held an invitation-only meeting at the Kavli Royal Society International Centre, Chicheley Hall, to lay the groundwork for international position statements on (1) Definitions and mechanisms of trauma-induced coagulopathy (TIC), (2) Diagnostic tests and precision in monitoring TIC and (3) Management of TIC and trauma haemorrhage (in times of precision medicine). TACTIC research has been presented at 11 national and international conferences, and via project partner websites and other teaching resources. There have also been three TACTIC research exchange programme students (with more planned), and five PhD theses have so far been written based on data from the TACTIC programme.

Potential Impact:
The TACTIC project final results will transform trauma management and research internationally. Firstly, a unique European research infrastructure encompassing leading trauma centres in 5 European countries is established with a validated online data registry (Partner 5) and biobank (Partner 1). This enables future research possibilities in the European trauma population and will also attract new European trauma sites to the existing network. Furthermore, for the first time it is possible to analyse in detail the molecular biomarkers of TIC and to couple this to results from functional viscoelastical haemostatic assays. Consequently, we have already developed novel haemostatic resuscitation algorithms (WP4-WP6) that is now being evaluated in the first randomized clinical trial (RCT) addressing this topic (WP8).
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