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Over the past decades, advances in emergency medical systems, trauma surgery and trauma resuscitation have allowed patients who would otherwise have died before arrival in a hospital to reach hospital and receive emergent treatment of their life-threatening injuries. After a traumatic injury, hemorrhage is responsible for over 35% of pre-hospital deaths and over 40% of deaths within the first 24 hours. A cascade of life-threatening medical problems can begin with severe hemorrhage, and many of these occur simultaneously: 1) hemorrhage, 2) impaired resuscitation, 3) shock, 4) inflammation and 5) coagulopathy.
The nature of this coagulopathy is currently unclear, and there are no tests that have sufficiently characterised it. As such, it is currently impossible to immediately assess the nature or degree of derangement of the clotting system and no exact tools to guide therapy are available. Recent data suggests that the use of rotation tromboelastometry (RoTEM) in trauma predicts the need for a massive transfusion. Many patients who are bleeding get inadequate numbers of blood products. Conversely, patients may be given blood products unnecessarily, potentially leading to all the complications associated with blood transfusion, including depression of the immune system, which is critical in major trauma patients. Validation of the effectiveness of RoTEM to guide transfusion practice after trauma has not been performed to date. This study aims to define diagnostic thresholds and determine optimal transfusion strategies. Although they may survive this critical phase of their care, many of these bleeding trauma patients will still die. Death, which usually occurs one to six weeks later, is due to a progressive failure of body systems – a syndrome called multiple organ failure (MOF). There is currently no specific treatment for multiple organ failure. Patients are supported on ventilators, dialysis machines and other organ support devices while the process runs its course. Patients who survive multiple organ failure may spend months in hospital, years in rehabilitation, and are usually left with some permanent disability. Recent studies suggest that this late mortality due to multiple organ failure may be due to the body’s responses to tissue damage and to blood loss that occur immediately following injury. There is a significant body of both basic science and clinical evidence that implicates the activation and dysregulation of the coagulation and inflammatory systems in the development of multiple organ failure. However, most of this data comes from research into sepsis. The mechanisms for the activation of the relevant pathways in trauma however, and their relationship to clinical disease and outcomes have yet to be delineated. Identification of these key pathways will provide new directions for drug development and perhaps a specific treatment for post-traumatic multiple organ failure. We postulate two mechanisms for the activation of these systems in trauma: tissue damage itself, and cellular hypoperfusion.
1. Tissue damage Two studies, the first from our associate group at the Royal London Hospital, have shown that trauma patients may arrive in the emergency department with severely deranged blood coagulation.[6,7] Patients with coagulopathy were three to four times more likely to die than those without. The incidence of coagulopathy was closely related to the severity of injury, and not to the volumes of fluid administered, suggesting that the injury load itself was responsible for the activation of the coagulation systems. The mechanisms by which tissue injury activates the coagulation and inflammatory systems have not been studied previously.
2. Tissue hypoperfusion / hypoxia Ischemia following hemorrhagic shock is known to lead to multiple organ failure and increased mortality. Several studies have shown that the severity of shock on admission correlates with eventual outcome. Karim Brohi, from our associate group at the Royal London Hospital, has finished a study examining the duration of tissue ischemia, as measured by base deficit and lactate, and found that even when sub-clinical tissue ischemia persists for over 12 hours, mortality is 38%, over twice that of patients who do not suffer a prolonged ischemic episode. Tissue hypoxia leads to endothelial injury and priming of cellular and humoral components of the inflammatory pathways.   Goals and expected outcomes The entire pattern of activation of the inflammatory and coagulation systems has not been fully elucidated in trauma patients, and it remains unknown how this results in multiple organ failure and death. It is increasingly clear that the endothelium plays an important role in activation of the inflammatory and coagulopathic cascades which occur in trauma. Observational studies suggest that early transfusion of high quantities of plasma may decrease risk of organ failure. However, transfusion ’overload’ has also been associated with organ failure. Thereby, transfusion is a double-edged sword. Tissue materials are needed to study endothelial and epithelial processes as well as the response of these processes to transfusion therapy in more detail with the aim to derive clinically useful markers of early coagulopathy and the response to transfusion Conversely, we expect that identifying those patients without coagulopathy identifies specific pathways of coagulation during massive transfusion that can serve as targets of intervention aimed at reducing organ failure. Identifying key junctures in the pathways that could targeted for drug discovery and development programs will allow us to better understand which patients may benefit from procoagulant agents such as recombinant factor VIIa. Goal is
  • to identify the clinically significant mechanisms and pathways by which coagulation and inflammation are activated immediately following major trauma and how these result in the observed clinical sequelae of this in terms of bleeding, transfusion requirements, organ injury, multiple organ failure and death.
  • To elucidate the effect of derangements in coagulation, fibrinolytic and endothelial cell function on the inflammatory response and the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), Acute Kidney Injury (AKI), multiple organ failure (MOF), and death.
  • To process and store samples for subsequent proteomic and genomic techniques to identify new loci for investigation, targeting drug discovery and identification of genetic susceptibility to poor outcome following trauma.
  • To process and store samples for subsequent DNA typing and analysis. There appears to be a background race and genetic susceptibility to the effects of trauma. These alterations may well lie within the coagulation and inflammatory systems. Early identification of patients at risk may, in the future, allow therapy to be targeted depending on patients’ racial background or even specific genetic make-up.
Patients Inclusion criteria
Trauma patients who have sustained a blunt or penetrating trauma and for whom the traumateam has been activated
Exclusion criteria
  • Age 5% of their body surface area
  • Patients taking anticoagulant medication other than aspirin (<650mg/day)
  • Patients with a known bleeding diathesis
  • Patients with moderate to severe liver disease (Child’s classification B or C3)