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

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.

A prospective study to assess serum level of soluble thrombomodulin as early marker of acute traumatic coagulopathy in polytrauma patients

Background: Coagulopathy following major trauma is conventionally attributed to activation of coagulation factors. We hypothesized that early coagulopathy is due to tissue hypoperfusion and investigated thrombomodulin (TM) as early marker of endothelial injury in poly trauma patient.Methods: This was a prospective cohort study of major trauma patients admitted to a single trauma center. Blood was drawn within 10 minutes of arrival for analysis of TM. We assess its association with blood transfusion, length of hospital stays and mortality.Results: A total of 90 patients were enrolled. An increasing lactate was associated with high soluble TM. High TM was significantly associated with increased mortality, blood transfusion requirements, hospital stay.Conclusions: Acute traumatic coagulopathy (ATC) occurs only in the presence of tissue hypoperfusion which we have measured in form of lactate and coagulopathy measured using international normalized ratio (INR) as standard. Admission serum TM can be predictive of clinical outcomes following major trauma.

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

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.

Protocol for a multicentre prehospital randomised controlled trial investigating tranexamic acid in severe trauma: the PATCH-Trauma trial

IntroductionHaemorrhage causes most preventable prehospital trauma deaths and about a third of in-hospital trauma deaths. Tranexamic acid (TXA), administered soon after hospital arrival in certain trauma systems, is an effective therapy in preventing or managing acute traumatic coagulopathy. However, delayed administration of TXA appears to be ineffective or harmful. The effectiveness of prehospital TXA, incidence of thrombotic complications, benefit versus risk in advanced trauma systems and the mechanism of benefit remain uncertain.Methods and analysisThe Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH-Trauma study) is comparing TXA, initiated prehospital and continued in hospital over 8 hours, with placebo in patients with severe trauma at risk of acute traumatic coagulopathy. We present the trial protocol and an overview of the statistical analysis plan. There will be 1316 patients recruited by prehospital clinicians in Australia, New Zealand and Germany. The primary outcome will be the eight-level Glasgow Outcome Scale Extended (GOSE) at 6 months after injury, dichotomised to favourable (GOSE 5–8) and unfavourable (GOSE 1–4) outcomes, analysed using an intention-to-treat (ITT) approach. Secondary outcomes will include mortality at hospital discharge and at 6 months, blood product usage, quality of life and the incidence of predefined adverse events.Ethics and disseminationThe study was approved by The Alfred Hospital Research and Ethics Committee in Victoria and also approved in New South Wales, Queensland, South Australia, Tasmania and the Northern Territory. In New Zealand, Northern A Health and Disability Ethics Committee provided approval. In Germany, Witten/Herdecke University has provided ethics approval. The PATCH-Trauma study aims to provide definitive evidence of the effectiveness of prehospital TXA, when used in conjunction with current advanced trauma care, in improving outcomes after severe injury.Trial registration numberNCT02187120.

Fibrinogen Replacement Therapy for Traumatic Coagulopathy: Does the Fibrinogen Source Matter?

Fibrinogen is the first coagulation protein to reach critically low levels during traumatic haemorrhage. There have been no differential effects on clinical outcomes between the two main sources of fibrinogen replacement: cryoprecipitate and fibrinogen concentrate (Fg-C). However, the constituents of these sources are very different. The aim of this study was to determine whether these give rise to any differences in clot stability that may occur during trauma haemorrhage. Fibrinogen deficient plasma (FDP) was spiked with fibrinogen from cryoprecipitate or Fg-C. A panel of coagulation factors, rotational thromboelastography (ROTEM), thrombin generation (TG), clot lysis and confocal microscopy were performed to measure clot strength and stability. Increasing concentrations of fibrinogen from Fg-C or cryoprecipitate added to FDP strongly correlated with Clauss fibrinogen, demonstrating good recovery of fibrinogen (r2 = 0.99). A marked increase in Factor VIII, XIII and α2-antiplasmin was observed in cryoprecipitate (p < 0.05). Increasing concentrations of fibrinogen from both sources were strongly correlated with ROTEM parameters (r2 = 0.78–0.98). Cryoprecipitate therapy improved TG potential, increased fibrinolytic resistance and formed more homogeneous fibrin clots, compared to Fg-C. In summary, our data indicate that cryoprecipitate may be a superior source of fibrinogen to successfully control bleeding in trauma coagulopathy. However, these different products require evaluation in a clinical setting.

Prevalence of Acute Traumatic Coagulopathy in Acutely Traumatized Dogs and Association with Clinical and Laboratory Parameters at Presentation

Objective The aim of this study was to determine the prevalence of acute traumatic coagulopathy (ATC) and identify associated clinical and laboratory parameters including rotational thromboelastometry. Study Design Dogs presenting within 6 hours after trauma were allocated to the ATC or non-ATC group based on thromboelastometry analysis (ex-tem S, in-tem S, fib-tem S). ATC was defined as ≥2 hypocoagulable parameters in 1 profile and ≥ 1 hypocoagulable parameter in an additional profile. Parameters used were ex-tem and in-tem clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), maximum lysis and fib-tem MCF. Clinical and laboratory parameters at presentation, animal trauma triage (ATT) score, transfusion requirement and outcome were compared. Logistic regression was used to identify independent factors associated with ATC. Results Eleven of 33 dogs presented with ATC and showed ex-tem CT and CFT prolongation and reduced MCF amplitude in all profiles (all p < 0.001). pH (p = 0.043) and potassium concentration (p = 0.022) were significantly lower and bleeding (p = 0.027) and plasma transfusions (p = 0.001) more common in dogs with ATC. Time after trauma (p = 0.040) and Animal Trauma Triage score (p = 0.038, including haematocrit as confounding factor) were associated with the presence of ATC. Conclusion Acute traumatic coagulopathy is more common in traumatized dogs than previously reported. Acute traumatic coagulopathy was associated with acidosis, Animal trauma triage score, time after trauma and higher transfusion needs. Coagulation abnormalities include ex-tem CT and CFT prolongations and decreased clot strength.

Tranexamic acid in trauma-induced coagulopathy

Trauma is still the leading cause of death in the world among the population under the age of 45 and bleeding is the dominant cause of early mortality in one third of all injured. Coagulopathy in trauma is directly related to the outcome and is considered to be the most significant preventable cause of death. Trauma-induced coagulopathy is a complex, multifactorial disorder that can be roughly divided into three phases. The entity of acute traumatic coagulopathy is characterized as an endogenous hemostatic disorder that occurs in the first few minutes of injury associated with tissue damage caused by severe trauma and hemorrhagic shock, regardless of external factors. The pathogenesis of trauma-induced coagulopathy is not fully known and is still the subject of research. According to the latest recommendations of the European Guide for the Management of Massive Bleeding and Coagulopathy in Trauma, tranexamic acid should be used as soon as possible, and no later than three hours after the injury in a patient who is bleeding or at risk of significant bleeding. Its prehospital application should be considered. In the light of new knowledge, the question of the justification and safety of the free use of tranexamic acid in trauma has been raised. The use of tranexamic acid in trauma-induced coagulopathy is a simple and affordable therapeutic approach that should be used in the prehospital period in those patients who are bleeding or at risk of significant bleeding. The implementation of this therapy in our country has not yet come to life.