Interplay between inflammation and thrombosis in cardiovascular pathology

Abstract

Thrombosis is the most feared complication of cardiovascular diseases and a main cause of death worldwide, making it a major health-care challenge. Platelets and the coagulation cascade are effectively targeted by antithrombotic approaches, which carry an inherent risk of bleeding. Moreover, antithrombotics cannot completely prevent thrombotic events, implicating a therapeutic gap due to a third, not yet adequately addressed mechanism, namely inflammation. In this Review, we discuss how the synergy between inflammation and thrombosis drives thrombotic diseases. We focus on the huge potential of anti-inflammatory strategies to target cardiovascular pathologies. Findings in the past decade have uncovered a sophisticated connection between innate immunity, platelet activation and coagulation, termed immunothrombosis. Immunothrombosis is an important host defence mechanism to limit systemic spreading of pathogens through the bloodstream. However, the aberrant activation of immunothrombosis in cardiovascular diseases causes myocardial infarction, stroke and venous thromboembolism. The clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is supported by the increased risk of cardiovascular events in patients with inflammatory diseases but also during infections, including in COVID-19. Clinical trials in the past 4 years have confirmed the anti-ischaemic effects of anti-inflammatory strategies, backing the concept of a prothrombotic function of inflammation. Targeting inflammation to prevent thrombosis leaves haemostasis mainly unaffected, circumventing the risk of bleeding associated with current approaches. Considering the growing number of anti-inflammatory therapies, it is crucial to appreciate their potential in covering therapeutic gaps in cardiovascular diseases.

Role of SARS-CoV-2 -induced cytokines and growth factors in coagulopathy and thromboembolism

“…Patients with COVID19 manifest with thromboembolic complications as a result of inflammation, platelet activation and hypercoagulation [102] , [121] . It is identified that the activated platelets play an important role in SARS-CoV-2 associated thrombus formation as platelets coordinate between inflammation and thrombosis which lead to thromboinflammation [122] .…”

Cardiovascular implications of the COVID-19 pandemic

“…However, it quickly became evident that the infection has far-reaching effects on other parts of the body as well. Since then, both basic and clinical researchers have re-explored the close connection between the immune system and the cardiovascular system [12] .…”

“…vWF plays a role in adhesion and aggregation of platelets and contributes to thrombosis [25] . In addition, neutrophils, which also express ACE2 receptors, are activated by the virus and release neutrophil extracellular traps (NETs) [12] . NETs are key mediators of immunothrombosis that activate factor XII and trigger the coagulation cascade [26] .…”

Thrombo-Inflammation: A Focus on NTPDase1/CD39

“…The endothelium is the first site where haemostasis and inflammation communicate, through several connecting points. When the endothelium is intact, under physiological conditions, the balance between its pro-and anti-thrombotic features is preserved; on the contrary, when the endothelium is activated, such as during inflammation, it loses these properties and becomes a suitable surface where inflammatory events build up a prothrombotic environment [1,2,4,5]. The knowledge of cellular and molecular events interfacing inflammation and haemostasis is required to identify novel therapeutic strategies.…”