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P
rimary Objective:
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.  
1. On coagulation:
Aim:
•     To identify the key derangements in coagulation and fibrinolysis following trauma
 
•     To identify and characterize the subsequent hypercoagulable state (although trauma patients are more likely to bleed initially, they subsequently develop a state where they are more likely  to form blood clots, leading to deep venous thrombosis, pulmonary embolism and death). A four channel thromboelastometry (RoTEM and TEG) will be used to detect coagulopathic derangements and fibrinolysis and determine the response to blood component therapy.
•     To validate the effectiveness of RoTEM or TEG for guiding transfusion practice after trauma.
•     To   develop   a   prediction   model  for   massive   transfusion  requirements   and  the development of organ injury following trauma. This will allow us to identify patients who might benefit for early intervention to prevent these complications and reduce the death rate following severe injury.  
H
ypothesis on coagulation:
•     Acute traumatic coagulopathy is caused by tissue hypoperfusion through the systemic activation of anticoagulant and fibrinolytic pathways (the body’s anticlotting mechanisms) and can be detected by RoTEM and TEG.
•     Early coagulopathy leads to exhaustion of the anticoagulant system andup−regulation of antifibrinolytic systems, resulting in a hypercoagulable state.
•     Subsequent transfusion of red cells and blood component therapy has specific effects on the acute coagulopathy, which may be beneficial or harmful dependent on the current clinical state.
•     Massive transfusion requirements (the need to replace a person’s entire volume of blood, or more than 10 units of blood) can be predicted by initial physiological variables and  immediate  analysis  of  coagulation  parameters  by  RoTEM.  Conversely,  the requirement for blood component therapy might be reduced by targeted measurement of coagulation  function  and  biomarkers  during  transfusion,  as  it  can  be  guided  by RoTEM.
•     Coagulation  is  linked  to  innate  immunity  cellular  responses,  which  may  include (neutrophil derived) nucleosomes and serine proteases, as well as microvesicles  
2. On Inflammation:
Aim:
•     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.  
H
ypothesis on inflammation:
•     There is a dose−dependent effect of the severity of trauma on coagulation, fibrinolytic and endothelial cell function. These correlate with activation of a pathological systemic inflammatory response which leads to ALI, ARDS, AKI & MOF
•     There is a dose-dependent effect of the degree and duration of tissue hypoperfusion on coagulation, fibrinolytic and endothelial cell function. These correlate with activation of a pathological systemic inflammatory response which leads to ALI, AKI & MOF.
•     While  tissue  trauma  and  cellular  hypoperfusion  are  different  initiators,  the  resulting activation  of  the coagulation  and  inflammatory systems is identical and is the final common pathway in acute lung injury. Tissue trauma and cellular hypoperfusion have an additive effect on the development of ALI, AKI & MOF.
•     ALI, AKI & MOF can be predicted in the first hours after trauma based on trauma severity scores,  tissue damage,  severity and  duration  of  tissue hypoperfusion,  with biochemical markers of coagulation or inflammation.