scholarly journals O1: DISCOVERING NOVEL THERAPEUTICS TO TREAT ACUTE TRAUMATIC COAGULOPATHY (ATC)

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
A Thaventhiran ◽  
C Thiemermann ◽  
K Brohi ◽  
JL Tremoleda ◽  
RA Davenport
Keyword(s):  
Activated Protein C ◽  
Blood Component ◽  
Trauma Patients ◽  
Factor V ◽  
The Novel ◽  
Acute Traumatic Coagulopathy ◽  
Antifibrinolytic Drugs ◽  
The Uk ◽  
Novel Therapeutic ◽  
Traumatic Coagulopathy

Abstract Introduction In the UK, 17,000 people die from injury each year, with uncontrolled bleeding the most significant cause of preventable mortality. Acute Traumatic Coagulopathy (ATC) exacerbates bleeding through the failure of blood-clotting with accelerated clot breakdown that mechanistically is driven by activated Protein C (aPC). No targeted therapy to treat the underlying cause of ATC exists with treatment limited to blood component resuscitation and antifibrinolytic drugs to prevent premature clot breakdown. Method Two hundred fifty-four bleeding trauma patients had Factor V and aPC measured on arrival and during resuscitation. A preclinical ATC model was used to test the novel therapeutic recombinant Factor V (rFV), which is resistant to aPC mediated cleavage. Mice underwent combined injury and pressure controlled-blood loss with intervention at 30-minutes to represent a clinically relevant model. Coagulopathy was measured by ROTEM and biomarkers of coagulation/fibrinolysis. Result Admission levels of FV were 38% lower (83 vs 134u/dL, p<0.0001), deteriorated during resuscitation to 65% of normal after transfusion of eight RBC units and were inversely related to aPC levels. Compared to vehicle, animals treated with rFV had reduced coagulopathy (Clot Strength at 5 minutes: 31 vs 24mm, p<0.01) and significantly improved survival (80% vs 44%, p≤ 0.001). Conclusion FV falls significantly during bleeding in trauma patients and in the murine model, rFV improved coagulation suggesting it may represent a potential therapeutic target for ATC. Take-home message Directly targeting the cause of ATC represents a novel therapeutic strategy in trauma and may improve survival after major haemorrhage by directly improving clot function.

scholarly journals Activated Protein C Drives the Hyperfibrinolysis of Acute Traumatic Coagulopathy

2017 ◽  
Vol 126 (1) ◽  
pp. 115-127 ◽  
Author(s):  
Ross A. Davenport ◽  
Maria Guerreiro ◽  
Daniel Frith ◽  
Claire Rourke ◽  
Sean Platton ◽  
...  
Keyword(s):  
Murine Model ◽  
Protein C ◽  
Major Trauma ◽  
Activated Protein C ◽  
Genetic Mutation ◽  
Trauma Patients ◽  
Acute Traumatic Coagulopathy ◽  
Rotational Thromboelastometry ◽  
Level 1 Trauma Center ◽  
Traumatic Coagulopathy

Abstract Background Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors’ objective was to determine the predominant pathophysiology of acute traumatic coagulopathy. Methods First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed. Results In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C–mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation. Conclusions Activated protein C–associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage.

scholarly journals An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice

2021 ◽  
Author(s):  
Bilgimol Chumappumkal Joseph ◽  
Byron Y Miyazawa ◽  
Charles Esmon ◽  
Mitchell J Cohen ◽  
Annette von Drygalski ◽  
...  
Keyword(s):  
Driving Forces ◽  
Severe Bleeding ◽  
Trauma Patients ◽  
Factor V ◽  
Activity Levels ◽  
Normal Range ◽  
Acute Traumatic Coagulopathy ◽  
Liver Laceration ◽  
Traumatic Bleeding ◽  
Traumatic Coagulopathy

Acute traumatic coagulopathy (ATC) occurs in ≈30% of trauma patients and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond, is able to reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by APTT prolongation and reductions of FV, FVIII, and fibrinogen, but not FII and FX. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as the consequence of severe bleeding. SuperFVa prophylaxis prior to liver laceration reduced bleeding, prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. SuperFVa intervention started after the development of ATC stabilized bleeding, reversed the prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding.

Validation of the COAST score for predicting acute traumatic coagulopathy: A retrospective single-centre cohort study

Trauma ◽  
2019 ◽  
Vol 22 (2) ◽  
pp. 112-117
Author(s):  
Sophie Thorn ◽  
Martin Tonglet ◽  
Marc Maegele ◽  
Russell Gruen ◽  
Biswadev Mitra
Keyword(s):  
Cohort Study ◽  
Early Identification ◽  
Adverse Outcomes ◽  
Trauma Patients ◽  
Operating Characteristics ◽  
Hospital Data ◽  
Single Centre ◽  
Acute Traumatic Coagulopathy ◽  
Simple Method ◽  
Traumatic Coagulopathy

Purpose Early identification of trauma patients at risk of developing acute traumatic coagulopathy is important in initiating appropriate, coagulopathy-focused treatment. A clinical acute traumatic coagulopathy prediction tool is a quick, simple method to evaluate risk. The COAST score was developed in Australia and we hypothesised that it could predict coagulopathy and bleeding-related adverse outcomes in other advanced trauma systems. We validated COAST on a single-centre cohort of trauma patients from a trauma centre in Belgium. Methods The COAST score was modified to suit available data; we used entrapment, blood pressure, temperature, major chest injury and abdominal injury to calculate the score. Acute traumatic coagulopathy was defined as international normalised ratio >1.5 or activated partial thromboplastin time >60 s upon arrival of the patient to the hospital. Data were extracted from the local trauma registry on patients that presented between 1 January and 31 December 2015. Results In all, 133 patients met the inclusion criteria (>16 years old, available COAST and outcome data) for analysis. The COAST score had an area under the receiver operating characteristics curve of 0.941 (95% CI: 0.884–0.999) and at COAST ≥3, it had 80% sensitivity and 96% specificity. The score also identified patients with higher rates of mortality, blood transfusion and emergent surgery. Conclusion This retrospective cohort study demonstrated the utility of the COAST score in identifying trauma patients who are likely to have bleeding-related poor outcomes. The early identification of these patients will facilitate timely, appropriate treatment for acute traumatic coagulopathy and minimise the risk of over-treatment. It can also be used to select patients with acute traumatic coagulopathy for trials involving therapeutic agents targeted at acute traumatic coagulopathy.

Plasma ADAMTS13 Activity Associates with Injury Severity in Pediatric Trauma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3777-3777
Author(s):  
Jenny K. McDaniel ◽  
Ilan I Maizlin ◽  
Michelle C. Shroyer ◽  
Morgan E. Banks ◽  
Jean-Francois Pittet ◽  
...  
Keyword(s):  
Injury Severity ◽  
Pediatric Trauma ◽  
Initial Presentation ◽  
Trauma Patients ◽  
Adamts13 Activity ◽  
Acute Traumatic Coagulopathy ◽  
Time Period ◽  
Increased Risk ◽  
Significant Difference ◽  
Traumatic Coagulopathy

Abstract Background: Acute traumatic coagulopathy occurs in both pediatric and adult trauma patients and is associated with an increased risk of mortality. Trauma patients not only have increased risk for hemorrhagic complications, but also are at increased risk for thrombosis due to multiple factors including local tissue injury, inflammation, and immobility. The complex underlying pathophysiology of coagulation abnormalities associated with traumatic injury have yet to be fully elucidated. Additionally, there are significant differences in the hemostatic system of pediatric patients compared to adults. Objectives: The purpose of this study was to determine the levels of coagulation parameters including von Willebrand factor (VWF) antigen and ADAMTS13 activity in pediatric trauma patients and evaluate for possible association with injury severity and/or mortality. Methods: This study utilized plasma specimens collected from pediatric trauma patients that presented to our institution over a 2-year time period. The specimens were collected at initial presentation and 24 hours later. The injury severity was estimated using both the Glasgow Coma Scale (GCS) and Injury Severity Score (ISS). A cohort of control samples was obtained from pediatric patients for elective surgical procedures over the same time period. Plasma VWF antigen was determined by a sandwich ELISA; plasma ADAMTS13 activity was determined by FRETS-VWF73. The results were determined by nonparametric tests for the differences in median values. Results: A total of 106 trauma patient samples at initial time point, 78 trauma samples at 24 hour time point, and 54 control samples were obtained and utilized for study. There were statistically significant differences (p<0.05) in the plasma levels of VWF antigen, ADAMTS13 activity, and the ratio of ADAMTS13 activity to VWF antigen for the trauma patient samples at initial presentation when compared to controls (Table 1). At 24 hours, there were still statistically significant differences between ADAMTS13 activity and the ratio of ADAMTS13 activity to VWF antigen in trauma patients compared to controls, but there was no significant difference in VWF antigen between the two cohorts (Table 2). There was a significant difference between the decrease in ADAMTS13 activity and injury severity as estimated by ISS ³ 15 or GCS < 8 at both time points; however, ADAMTS13 activity was not statistically different in survivors vs. non-survivors. A higher VWF antigen level at initial presentation was the only factor found to be significantly different in non-survivors. Conclusions: This study demonstrates significant differences in plasma ADAMTS13 activity and VWF antigen in pediatric trauma patients compared to controls. In patients with more severe injuries as estimated by GCS and ISS, there was also a significant association with decreased levels of ADAMTS13 activity. These finding may underlie part of the prothrombotic propensity in microcirculation that occurs in patients post-trauma. Further investigation is warranted to better understand the mechanisms of acute traumatic coagulopathy and potential prognostic factors, and to determine the most effective interventions for acute traumatic coagulopathy in the pediatric population. Disclosures Zheng: Ablynx: Consultancy; Alexion: Research Funding.

scholarly journals Early Identification of Acute Traumatic Coagulopathy Using Clinical Prediction Tools: A Systematic Review

Medicina ◽  
2019 ◽  
Vol 55 (10) ◽  
pp. 653 ◽  
Author(s):  
Thorn ◽  
Güting ◽  
Maegele ◽  
Gruen ◽  
Mitra
Keyword(s):  
Systematic Review ◽  
Blood Pressure ◽  
Prediction Models ◽  
Scoring Systems ◽  
Trauma Patients ◽  
Clinical Prediction ◽  
Acute Traumatic Coagulopathy ◽  
Prediction Tools ◽  
Populations At Risk ◽  
Traumatic Coagulopathy

: Background and objectives: Prompt identification of patients with acute traumatic coagulopathy (ATC) is necessary to expedite appropriate treatment. An early clinical prediction tool that does not require laboratory testing is a convenient way to estimate risk. Prediction models have been developed, but none are in widespread use. This systematic review aimed to identify and assess accuracy of prediction tools for ATC. Materials and Methods: A search of OVID Medline and Embase was performed for articles published between January 1998 and February 2018. We searched for prognostic and predictive studies of coagulopathy in adult trauma patients. Studies that described stand-alone predictive or associated factors were excluded. Studies describing prediction of laboratory-diagnosed ATC were extracted. Performance of these tools was described. Results: Six studies were identified describing four different ATC prediction tools. The COAST score uses five prehospital variables (blood pressure, temperature, chest decompression, vehicular entrapment and abdominal injury) and performed with 60% sensitivity and 96% specificity to identify an International Normalised Ratio (INR) of >1.5 on an Australian single centre cohort. TICCS predicted an INR of >1.3 in a small Belgian cohort with 100% sensitivity and 96% specificity based on admissions to resuscitation rooms, blood pressure and injury distribution but performed with an Area under the Receiver Operating Characteristic (AUROC) curve of 0.700 on a German trauma registry validation. Prediction of Acute Coagulopathy of Trauma (PACT) was developed in USA using six weighted variables (shock index, age, mechanism of injury, Glasgow Coma Scale, cardiopulmonary resuscitation, intubation) and predicted an INR of >1.5 with 73.1% sensitivity and 73.8% specificity. The Bayesian network model is an artificial intelligence system that predicted a prothrombin time ratio of >1.2 based on 14 clinical variables with 90% sensitivity and 92% specificity. Conclusions: The search for ATC prediction models yielded four scoring systems. While there is some potential to be implemented effectively in clinical practice, none have been sufficiently externally validated to demonstrate associations with patient outcomes. These tools remain useful for research purposes to identify populations at risk of ATC.

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