ACTIVATION OF COAGULATION AND INFLAMMATION IN TRAUMA (ACIT)

Initiated in 2008 the ongoing study entitled "Activation of Coagulation and Inflammation in Trauma (ACIT)" serves as a platform for the enrolment of adult trauma patients in the Emergency Department setting, and the standardised collection of clinical data and patient blood. These study materials support multiple analyses to describe the body's response to injury and blood transfusion therapy. Originally a United Kingdom-based study, other high volume trauma centres have since contributed to a combined recruitment of over 3500 trauma patients to ACIT, from countries including Denmark, Germany, Norway, the Netherlands, Sweden and the United States of America.

Within minutes of injury, up to 1 in 4 severely injured patients develop a clotting dysfunction, termed Acute Traumatic Coagulopathy (ATC) that exacerbates bleeding and increases transfusion requirements, morbidity and mortality. ACIT is designed to identify the clinically significant mechanisms by which the body’s inflammation and coagulation pathways are activated immediately following major trauma. It also allows the monitoring of any change in functional blood coagulation, during the course of treatment with blood components and procoagulant agents. The study is revealing how trauma leads to coagulopathy and a perturbed inflammatory response, which leads to increased transfusion requirements and adverse outcome in terms of organ failure and death.

FINDINGS

Diagnosing Coagulopathy

A key barrier to the enhanced treatment of haemorrhaging trauma patients was the absence of rapid and robust tool for the diagnosis ATC and prediction of massive transfusion need. Laboratory coagulation tests and existing Point of Care devices were found to be unavailable or inaccurate to identify and guide treatment of ATC.

Rotational thromboelastometry (ROTEM®) has been used to analyse over 2,200 ACIT trauma patients' functional clotting response to both injury and transfusion. ATC has been found to have a specific ROTEM® signature which can be detected within five minutes and can alert clinicians to a trauma patient at greater risk of major bleeding, in whom intensive transfusion management may improve outcome (Davenport et al. 2011).

Blood sample collection

The inclusion of pre-hospital blood sampling to the ACIT protocol is critically important. Until 2019, the study recruited patients on arrival to the emergency department; sometimes up to two hours following injury. This has meant that in the early years of this study, we were not fully able to understand the early physiology and biochemical changes that occur immediately after injury. 

Now, multiple blood samples are collected to allow us to explore the changes occurring in the body of patients who suffered traumatic injuries. In particular, four blood samples are taken in the hospital during the week after the traumatic event, the first one early upon admission to the emergency department and the others after one, three and seven days. Up to three additional samples are collected in severely bleeding patients requiring early multiple blood transfusions. Each blood sample, equivalent to twelve teaspoonfuls, is partially sent to the hospital laboratory for clinical measurements of blood clotting and inflammation and partly processed and stored in a registered tissue bank. The stored samples are then used for more in-depth analyses and measurements in the research laboratory. These tests allow us to learn more about the failure of the body’s normal blood clotting, the benefit of blood transfusions and other interventions, and the relationship between genetic, immune, and inflammatory responses and body functions in the days following the trauma. Pre-hospital blood samples will thus help pave the way for the development of novel interventions to improve patient outcomes.

Clotting dysfunction

Analysis of ACIT study patients has demonstrated that an early reduction in levels of substrate for clot formation and an increase in clot breakdown (i.e. fibrinolysis) are common in trauma patients and likely to play a significant role in ATC pathophysiology. We demonstrated that increased fibrinolysis is common in trauma patients with 1 in 8 trauma patients presenting to the Emergency Department with a severe occult fibrinolysis, representing a previously unrecognised cohort of trauma patients with higher transfusion requirements, morbidity and mortality. These novel findings imply that transfusion therapy for coagulopathic bleeding and patient outcomes can be enhanced by a greater focus on early Fibrinogen and anti-fibrinolytic administration (Rourke et al. 2012).

Improving treatment

Whilst considered a preventable major cause of death, the current management of coagulopathic bleeding trauma patients comprises the protocol–lead transfusion of red blood cells and clotting product supplements (e.g. plasma, fibrinogen, platelets, procoagulant concentrates). This empiric practice is conducted blind to the type and severity of ATC they may have - or indeed even if they do not have coagulopathy.

Applying the diagnostic capability of the ROTEM® in the context of trauma, the ACIT has demonstrated that current massive transfusion protocols (MTPs) do not correct coagulopathy (Khan et al. 2014).  Whilst this empiric transfusion practice clearly enhances haemorrhaging patient outcomes, our data have shown that there remains potential to rapidly diagnose the patients who would benefit most from the best possible intensive transfusion management, or indeed those who do not require precious blood and procoagulant resources. Our findings suggest that the observed depletion of clotting substrate levels, decreased clot strength and increased clot breakdown might be best addressed by a greater focus on MTPs that employ fibrinogen concentrates and anti-fibrinolytic agents.

As we continue the ACIT study, the findings will inform future changes in practice and greatly benefit individual patients and the NHS as a whole. Whilst recognised as being associated with increased transfusion requirements, morbidly and mortality, the most pertinent question relating to coagulopathy remains unanswered: will trauma patient survival improve if coagulation parameters are corrected?

Further Research

Expanding our research to include children

Trauma is an important cause of morbidity and mortality in children. Marked physical and physiological differences between children and adults result in clinically distinct injury patterns and physiological responses to injury which require different management. There is little evidence regarding the specific paediatric response to injury, with current therapies being derived from adult studies without consideration of these differences. From early 2020 we will begin recruiting children of all ages in order to better understand the paediatric response to injury, post injury organ dysfunction and whether established adult therapies such as tranexamic acid are also effective in children.  ‚Äč

Exploring Fibrinolysis

C4TS researchers have discovered that trauma patients exhibit a much greater degree of fibrinolysis activity than previously thought.  By measuring key proteins of fibrinolysis – such as plasmin-antiplasmin complex - in the blood obtained from trauma patients recruited to the ACIT study, the group has discovered evidence of fibrinolysis activation in almost two thirds of injured patients.  This discovery is significant because those with the greatest degree of fibrinolysis activation were found to have the worst clinical outcomes.  This implies that treatments which counteract fibrinolysis may be beneficial.

You can read more about this study here, and this page provides more information about fibrinolysis.

The Role of Tranexamic Acid

Tranexamic acid (TXA) is an anti-fibrinolytic drug which has been used for many years in specialties such as cardiac surgery.  There has been a growing interest in the potential benefits of TXA use in trauma.  The large international CRASH-2 randomised control trial investigated the effect of TXA on mortality in patients with suspected traumatic haemorrhage.  Patients who received TXA in CRASH-2 had a lower overall mortality.  However, the uptake of TXA into MHPs worldwide has been variable, with questions remaining regarding the mechanism of action of TXA in trauma haemorrhage and which patients are likely to benefit most from it?  C4TS are currently working towards answering these questions.

In one C4TS study investigating the relationship between TXA and trauma patient outcomes, we demonstrated that TXA use as part of a MHP is independently associated with a reduction in multi-organ failure and that TXA reduces overall mortality in patients who present with shock.

You can read more about this study here.

C4TS are continuing to explore the spectrum of fibrinolytic activity demonstrated by trauma patients and are currently investigating the effect of TXA on the coagulopathy and fibrinolysis that are central components of ATC.  We aim to bridge the knowledge gap regarding the mechanism of action of TXA in trauma haemorrhage.  Our current research has the potential to improve the management of the bleeding trauma patient worldwide and could contribute to reducing the 30 – 40 % of trauma deaths each year, which result from haemorrhage. 

Contact

Principal Investigator: Mr Ross Davenport

 

FIBRINOLYSIS

C4TS researchers have recently discovered that trauma patients exhibit a much greater degree of fibrinolysis activity than previously thought. This implies that treatments which counteract fibrinolysis may be beneficial.

CRASH 2

C4TS participated in the large international CRASH-2 randomised control trial investigated the effect of Tranexamic Acid (TXA) on mortality in patients with suspected traumatic haemorrhage.  Patients who received TXA in CRASH-2 had a lower overall mortality. 

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