Dysregulation of the fibrinolytic pathway during trauma induced coagulopathy

Traumatic injury accounts for 4.9 million deaths worldwide each year. Approximately 25% of trauma patients die within 6 h of injury from uncontrolled bleeding, termed trauma induced coagulopathy (TIC). TIC describes the overall failure of the blood clotting system to stop bleeding after injury. Understanding the cellular and molecular mechanisms that result in TIC will allow clinicians to direct effective treatments, significantly improving patient outcome and survival, resulting in a reduction in the number of deaths annually from TIC. My fellowship applies a combination of established in vitro trauma models and patient samples collected upon admission to hospital; plasma samples will be collected from patients recruited to the UK Study of Whole Blood in Frontline Trauma (SWIFT; ISRCTN23657907) trial and from trauma patients admitted to my local health board (NHS Grampian). Additionally, I will visit a world leader in the haemostasis field, Professor Robert Medcalf (Monash University, Melbourne, Australia), to learn novel techniques in trauma research while collecting and analysing blood samples from trauma patients recruited to the Fibrinogen Early In Severe Trauma Study 2 (FEISTY-2; NCT05449834) trial. My fellowship will investigate the molecular and cellular mechanisms responsible for uncontrolled bleeding after injury by addressing three key objectives: Objective 1: Determine the role of platelets and granule contents in susceptibility to fibrinolysis under flow We know platelets, tiny blood cells that stick together to initiate clot formation, are important in trauma, but the release and function of their granular proteins has not been studied. I will analyse platelet activation and granule release in FEISTY-2 patient samples. Additionally, I will visit my collaborator, Professor Cedric Ghevaert (University of Cambridge), to learn to manufacture synthetic platelets from human pluripotent stem cells to test in my in vitro trauma models and determine if they are a viable alternative to human donor platelets to treat traumatic bleeding. Objective 2: Determine changes in clot stability, resistance to fibrinolysis and the corresponding changes in fibrinolytic factors in different injury types It is unknown how the blood clotting response differs between injury types; i.e. blunt vs. penetrating injury. I will use in vitro models to mimic different injury types, combined with clinical data sets, to evaluate differences in clot structure and stability in these two injury types using microscopy and specialised haemostasis techniques (clot lysis and plasmin generation). Objective 3: Examine the time course of fibrinolysis after trauma to determine the beneficial and harmful effects of tranexamic acid Tranexamic acid (TXA) is an anti-fibrinolytic drug given to prevent bleeding, however, there is a short window of time (3h post-injury) where it can be used safely. My fellowship will investigate changes in key molecules of the blood clotting process over time to determine why TXA becomes harmful 3h post-injury. It is difficult to study these early time points in humans as samples are not available immediately after injury. My existing collaborators at the UK Defence Science & Technology Laboratory have a pig polytrauma model and will provide access to serial blood samples from the onset of injury, to allow me to study changes in blood clotting that may affect TXA efficacy and safety.