Clinical & experimental characterisation of acute traumatic coagulopathy

Abstract

Acute traumatic coagulopathy (ATC) is a recently identified entity describing an early impairment of haemostasis after injury. Retrospective observational studies have associated it with a significant increase in patient morbidity and mortality. It does not appear to be caused by conventional mediators of haemorrhagic coagulopathy, such as iatrogenic haemodilution or hypothermia. Rather, it has been postulated that it is endogenous systemic anticoagulation modulated by activation of the protein C pathway in response to shock and tissue injury.

The aims of this thesis were to characterise the aetiology and clinical significance of ATC and test the hypothesis that activated protein C plays a functional role in the pathophysiology of this condition. A retrospective analysis of patients admitted to 5 major international trauma centres was performed. Admission prothrombin times were correlated with aetiological variables and clinical outcomes. A structured literature review was subsequently conducted to identify the strengths and weaknesses of existing animal models of traumatic coagulopathy. Novel rodent (rat and mouse) models of ATC were then developed to elucidate how it develops.

Clinical data on 3646 trauma patients identified a significant and dose-dependent increase in mortality and transfusion requirements with admission prothrombin time ratio > 1.2. The incidence of ATC co-associated with both the degree of tissue injury and the depth of haemorrhagic shock. Literature review identified a general failure of animal models to accurately simulate the clinical trajectory of injury. Specifically, only one (mouse) model of ATC was identified. Novel rodent models of ATC were developed that demonstrated endogenous coagulopathy in response to 60 minutes of haemorrhagic shock, with or without significant tissue injury. This was mediated predominantly by autogenous haemodilution and activated protein C anticoagulation.

Acute traumatic coagulopathy is an endogenous impairment of haemostasis that develops in response to severe haemorrhagic shock. Manipulation of the protein C pathway may represent a novel therapeutic strategy for reducing blood loss and improving outcomes after injury.