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Periodic Report Summary 2 - 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.
The main objectives are in work package one (WP1) to 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. In WP2 the main objectives 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. In WP3 the overall aim is to compare trauma patient coagulation, outcomes and costs in response to different existing transfusion strategies and in WP4 to determine trauma patient biomarker profiles of coagulation, endothelial damage and shock. In WP5 we should define Viscoelastic Haemostatic Assay (VHA) diagnostic criteria of ‘normal’ and ‘coagulopathic’ patients and also map biomarker signatures to the VHA profiles. 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. WP7 should determine barriers to the acceptance of VHA by trauma clinicians to develop a “trauma” display. WP8 should conduct a clinical trial comparing the effect of VHA treatment algorithm versus local empiric treatment on patient outcome. WP9 should disseminate information and results generated within the project to relevant parties.

Project Results:
The management of TACTIC (WP1) is coordinated by Partner 1 who has efficiently administered this task including implementing an organizational structure encompassing a project steering committee, executive committee and a management steering group. Project steering group meetings are organized every six months and chaired by WP1. The coordinator advises and supports the other Partners in all aspects concerning fulfilling the administrative requirements of the TACTIC project.
In WP2 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. The biobank and the registry now 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.
TACTIC workflow between and from the work packages

WP3 focused on the comparison of existing clinical management strategies regarding trauma haemorrhage across the six project participating European Level 1 trauma centres. Results are available 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. Costs of the current local treatment were calculated for each study site considering in-hospital resource use items such as blood products, surgical interventions, days spent on ICH, overall in-hospital and on ventilation, medications. To allow a comparison between the six centres, patients were sub-grouped with respect to their risk for massive transfusion and their survival probability by using self-developed and validated stratification scores. Additionally, a health economic model was developed to assess the costs and effects of the two treatment algorithms of the TACTIC-embedded clinical trial iTACTIC (WP8), which also includes patients’ outcomes. For this, quality of life questionnaires were designed by WP3 partners accordingly.
In WP4 more than 4,000 blood samples from ~1,600 trauma patients admitted to Trauma Centers at six different Partner sites were analysed and statistically investigated. Partner 5 measured 25 biomarkers of bleeding coagulopathy and Partner 1 measured 6 biomarkers of vasculopathic coagulopathy. Partner 5 has used cluster analysis to analyse data and has identified several potentially different patterns of the coagulation system in trauma patients. Specifically in period 2, Partner 5 has been working on dimensionality reduction and has successfully reduced the number of identified clusters. Half of these are found to be associated with coagulopathy. Furthermore, the underlying patterns of coagulation proteins and admission injury characteristics and physiology are being used by Partner 5 to determine putative mechanisms for each coagulopathy for future investigation. The final step will be to match these to diagnostic criteria using the viscoelastic devices which Partner 5 is currently working on. Data are currently being collated for preparation into manuscripts. Partner 1 initiated preliminary analysis of the endothelial biomarkers measured over time, but due to database issues, Partner 1 is currently awaiting a cleaned dataset to continue the analysis. It is expected that the data analyses will be conducted in the next Reporting Period and reveal critical pathophysiologic traits of the different types of coagulopathy.
In WP5 data has been analysed on 2287 prospectively followed trauma patients in the TACTIC database and it was managed to define coagulopathy on both ROTEM and TEG profiles, in terms of relationship to admission INR. We have also assessed performance of the devices in the identification of hypofibrinogenaemia, hyperfibrinolysis and thrombocytopenia, and identified thresholds for each of these. These have been incorporated into new algorithms for ROTEM, TEG and conventional coagulation tests. This constitutes one of the main outputs of the TACTIC programme. A paper describing the performance of both devices (ROTEM® and TEG®) and including the resulting algorithms will be submitted to peer review journal shortly. The algorithms are utilized in the ongoing RCT (WP8). Furthermore, we have worked on refining the published „TASH“-Score (Maegele et al., Vox Sang 2011) developed to predict the need for massive transfusion (MT). In order to increase its clinical applicability we have reduced the number of variables from seven to three and including, for the first time, a functional parameter of coagulation, e.g. the ROTEM®variable FIBTEM, which indicates fibrin polymerisation. The novel score, termed „TASH-neo“-Score, was developed based upon 349 datasets from trauma patients, yielding an AUCROC of 0.920, which was superior to the conventional „TASH“-Score. The current and ongoing work aims to increase the predictive power of the newly introduced „TASH-neo“-Score.
WP6 has described results of viscoelastic values in response to transfusion therapy in the first periodic report. WP6 collaborates with WP5 on the above mentioned paper on treatment algorithms. 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). Differential responses of viscoelastic values to treatment was identified within these subgroups, which can be summarized as follows:
- Administration of a high ratio of platelets to red blood cells has a more profound effect on improving deranged ROTEM values of clot formation than high ratio of plasma to red blood cells
- Patients with traumatic brain injury show a greater response to platelets and fibrinogen in terms of correction of deranged ROTEM values of coagulopathy when compared to other patient populations.
- Patients with shock show a greater response to tranexamic acid in terms of correction of deranged ROTEM values of coagulopathy when compared to patients without shock
- It was not feasible to study the effect of dose, which would enable recommendations of the use of different doses in specific patient populations.
For TEG, data did not allow for stratification according to patient group, as there were insufficient data. The paper on personalized treatment is also being edited by the group. The paper on the control arm is accepted for publication.
In WP7 we 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. Progress has also been made interfacing the application to the new ROTEM Sigma, and we have had enthusiastic support from TEM in this activity. Finally, a ‘gamification’ of the app is being developed to enable both evaluation of the app outside the operating room and future training with the app. Development of the app is continuing, and is on track to provide a solution that will greatly assist clinicians in the rapid and successful identification and management of coagulopathic bleeding.
The 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 Coaguloptahy (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. All final approvals for the RCT were in place on 31st May 2016, and enrolment into the RCT started on 1st June 2016. As of 31st October 2016 a total of 88 participants have been enrolled, with a safety analysis of the first 50 enrolled patients currently being performed by an independent DSMB. Due to a delayed trial start we will not hit our goal recruitment number on time and thus have invited 4 new clinical sites to participate in iTACTIC.
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. In this reporting period the TACTIC research exchange program was successfully continued, with 2 placements in London and Copenhagen. Due to this program young researchers increased their experience in clinical research. These exchanges also promote the exchange of knowledge and ideas between EC centres. Several publications from the TACTIC group were accepted by high ranking peer-reviewed scientific journals. In addition, attention was given to the TACTIC project at various national meetings in and outside the partners’ hospitals, as well as at international trauma courses and conferences. This has facilitated our aim of reaching out to (future) end-users of the knowledge gained in the TACTIC project, with the fundamental aim to save lives from trauma casualties with life threatening bleeding!
We publish all relevant information regarding the TACTIC project on our dedicated website . Here not only scientific publications are available but also information regarding the TACTIC project as a whole including the participating Partners.

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 6 European countries is established with a validated online data registry (Partner 5) and biobank (Partner 1). This will enable 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 will become 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 will be evaluated in the first randomized clinical trial (RCT) addressing this topic (WP8). Already, we have extremely detailed data at the biomarker level that are linked to patient management and outcome and we are currently developing several important scientific manuscripts addressing TIC and its management soon to be published in open access journals to the scientific community. Also, importantly, we have calculated the health-economic costs, at the different partner sites, of the existing therapies. Thus, together with similar data from the RCT also the economic consequence of novel resuscitation strategies will be provided at an individual, hospital and societal level to inform both clinicians and health policy developers (WP3&WP8). In WP7 we focus on improving the clinical utility of using existing VHA by developing a novel software especially designed for trauma patients in collaboration with our commercial partners Haemonetics Corp. and TEM. This has resulted in a prototype that will be tested among the partners and further developed using data from the RCT and this will be an important tool for effective international implementation of best practice guidelines that will be the result of the TACTIC project.

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