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.

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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 (αIIbβ3) 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.