Title: Platelet-mediated immunomodulation after major trauma
Funder: The Academy of Medical Sciences

Abstract: The objective of this project is to determine how altered platelet activity after major trauma contributes to systemic inflammation and organ dysfunction. My specific aims are to characterise platelet immunological function in trauma patients with and without multiple organ dysfunction syndrome (MODS), and to investigate mechanisms by which platelets contribute to inflammation after injury. Trauma patients are at high risk of post-injury MODS, which is thought to result from a dysregulated or exaggerated immune response. In modern trauma systems, more patients are surviving to reach intensive care, and consequently MODS is an increasingly common cause of morbidity and mortality. However, there are currently no available therapeutics to prevent or mitigate MODS in trauma patients. Platelets are increasingly recognised as key contributors to immune responses. We and others have demonstrated profound alterations in platelet behaviour in the hours following major trauma, which contribute to an acute coagulopathy and uncontrolled bleeding. However, it is unclear how changes in platelet activity influence the immune response in the hours to days following severe injury. We hypothesise that trauma-induced alterations in platelet behaviour influence the overall immune response and consequently the development of MODS. We will perform detailed profiling of platelet immunological activity at multiple timepoints in a cohort of critically injured patients. Results from these experiments will be mapped to outcome data on organ dysfunction scores and mortality. In parallel, we will perform mechanistic studies exposing healthy platelets to conditions which mirror the post-injury intravascular milieu, to identify pathways leading to altered platelet behaviour.

Lay abstract: Injuries are a leading cause of death and disability worldwide. People who have been critically injured are at high-risk developing multiple organ failure, which is a major reason for prolonged critical illness, long-term disability and mortality. This state often involves organs that were not affected by the initial trauma itself, and is instead thought to result from an excessive or abnormal immune response to cell damage and severe blood loss. At present, there are no treatments to reverse or prevent this, and the underlying mechanisms are poorly understood. Platelets are small cell fragments that are best known for their role in blood clotting. However, they also have important functions in inflammation and wound healing, but it is not known whether platelet immunological activity is important in recovery from severe injury. Our previous work focused on how platelets influence blood clotting in injured patients, and found that platelet behaviour is rapidly and profoundly altered within the first two hours after major injury. The aim of this project is to determine how critical injury affects platelet immune function and how this influences patient outcomes, particularly organ failure. This project will examine platelets and platelet-mediated responses in multiple blood samples taken from severely injured humans within the ‘golden hours’ after injury and throughout the duration of critical illness. We believe that this is a hugely promising avenue to identify and develop new therapies which could mitigate or prevent organ failure, with huge potential to improve survival and quality of life after severe injury.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM