Investigating thrombo-inflammation associated with cardiovascular diseases

Cardiovascular disease (CVD), including heart disease and stroke are leading causes of mortality in the UK and worldwide. CVD is a multifactorial disease in which the number of risk factors correlates with disease progression and worse outcome. Common to the comorbidities and risk factors for CVDs is inflammation, which occurs through the crosstalk between inflammatory leukocytes, platelets and the vascular endothelium. Systemic inflammation is a potent prothrombotic stimulus, and inflammatory mechanisms upregulate procoagulant factors, downregulate natural anticoagulants and inhibit fibrinolytic activity. Thus, inflammation can beget local thrombosis, and thrombosis can amplify inflammation.

Ischemia reperfusion injury (I/RI) is a common complication of CVDs. The interdependent connection of both thrombosis and inflammation in eliciting a detrimental pro-thrombotic and pro-inflammatory state after I/RI has led to the concept of thrombo-inflammation. A thrombo-inflammatory state has been shown to be present in a number of common diseases including myocardial infarction, stroke, deep vein thrombosis, acute kidney disease, peripheral artery disease, infectious diseases, cancer and disseminated intravascular coagulation (DIC). During reperfusion, the rapid inflammatory response that ensues leads to microvascular dysfunction involving the adherence of platelets and neutrophils at ischaemic vascular lesions, which increase the risk of secondary thrombotic events and further tissue injury. Thus, thrombogenesis is being considered as a potentially promising target for anti-thrombotic therapy.

Inflammation and hypercoagulability have been shown to link arterial and venous thrombosis and epidemiological studies have focussed on the presence of risk factors including hypertension, chronic kidney disease, obesity, diabetes, smoking and more recently coronavirus 2 (SARS-CoV-2) infection (which is associated with coagulopathy causing venous and arterial thrombosis). Interestingly, patients with venous thrombosis are at increased risk of arterial thrombosis and patients with arterial thrombosis are at increased risk of venous thrombosis. Furthermore, the global burden of thrombo-inflammation is likely to increase with the ageing population, because both thrombosis and inflammation increase with age.

A number of cellular constituents are involved in thrombo-inflammation, with neutrophils and platelets playing key roles. However, it remains poorly understood how neutrophil-platelet interactions are regulated under various thrombo-inflammatory disease conditions. We recently discovered a novel role for platelets in inflammation resolution, uncovering a major role for anti-inflammatory pro-resolving mediator Annexin A1 (AnxA1) which was able to suppress integrin (α_IIbβ₃) activation via small GTPase Ras-related protein 1, Rap1, altering platelet phenotype from pathogenic to regulatory in cerebral I/RI. This study was the first to link AnxA1 with integrin signalling, supporting AnxA1 as an anti-thrombotic agent.

This project focuses on further understanding and characterising thrombo-inflammation in different disease states, with a particular focus on the role of platelets beyond just haemostasis and thrombosis. Major clinical importance will be to define the drivers and molecular mechanisms regulating thrombo-inflammation in specific disease states, providing mechanistic insight into both inflammation and thrombosis as central pathological processes to CVDs. Additionally, we will focus on pharmacologically manipulating the thrombo-inflammatory profile to promote its resolution. Collectively, we aim to develop novel strategies to not only protect against I/RI, but to provide new therapeutic possibilities for patient populations with a thrombo-inflammatory phenotype.

Meet the Principal Investigator(s) for the project

Professor Felicity Gavins - Felicity read Pharmacology at the University of Sunderland, where she also embarked on an industrial placement year at Bayer Pharmaceuticals in Slough. After completing her BSc (Hons), she moved to London to study for a Ph.D. in Pharmacology at Queen Mary University London, supported by the British Heart Foundation (BHF). Felicity was then awarded a BHF Junior Research Fellowship to undertake further research both in the UK and the USA. In 2007 Felicity joined Imperial College London to take up a Lectureship position in the Centre for Integrative Mammalian Physiology and Pharmacology (CIMPP). This was shortly followed by a senior lectureship and the appointment to Deputy Head of The Centre of Neurodegeneration & Neuroinflammation. In 2013 she accepted an academic position in the USA at Louisiana State University Health Sciences Center-Shreveport (LSUHSC-S) and was appointed Director of The Small Animal Imaging Facility. Felicity is a Fellow of the British Pharmacological Society and of the Royal Society of Biology. She joined Brunel University London in August 2019 as Professor of Pharmacology and Royal Society Wolfson Fellow, and is the Director of The Centre for Inflammation Research and Translational Medicine (CIRTM). Throughout her academic career, Felicity has worked with and served on numerous national and international research councils, medical charities and learned societies. She has published widely in her field and received a number of awards and honours for her work. She has received funding for her research from a range of funders including: the Royal Society and the Wolfson Foundation (RSWF), the British Heart Foundation (BHF), the Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council (BBSRC), the American Heart Association (AHA), and the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI). Felicity continues to be actively involved in public and patient organizations which has been immensely instructive for her research. She is also dedicated to promoting mentoring and collaborative research, along with facilitating mentoring of post-doctoral fellows/early-career investigators.

Related Research Group(s)

Inflammation Research and Translational Medicine - Driving scientific innovation and discovery for diagnosis, treatment, and management of cardiovascular disease, inflammatory and immune disorders, microbial resistance, and cancer.

Project last modified 27/09/2024