Abstract
AimsMedical treatment of arterial thrombosis is mainly directed against platelets and coagulation factors, and can lead to bleeding complications. Novel antithrombotic therapies targeting immune cells and neutrophil extracellular traps (NETs) are currently being investigated in animals. We addressed whether immune cell composition of arterial thrombi induced in mouse models of thrombosis resemble those of human patients with acute myocardial infarction (AMI).Methods and resultsIn a prospective cohort study of patients suffering from AMI, 81 human arterial thrombi were harvested during percutaneous coronary intervention and subjected to detailed histological analysis. In mice, arterial thrombi were induced using two distinct experimental models, ferric chloride (FeCl3) and wire injury of the carotid artery. We found that murine arterial thrombi induced by FeCl3 were highly concordant with human coronary thrombi regarding their immune cell composition, with neutrophils being the most abundant cell type, as well as the presence of NETs and coagulation factors. Pharmacological treatment of mice with the protein arginine deiminase (PAD)-inhibitor Cl-amidine abrogated NET formation, reduced arterial thrombosis and limited injury in a model of myocardial infarction.ConclusionsNeutrophils are a hallmark of arterial thrombi in patients suffering from acute myocardial infarction and in mouse models of arterial thrombosis. Inhibition of PAD could represent an interesting strategy for the treatment of arterial thrombosis to reduce neutrophil-associated tissue damage and improve functional outcome.
Highlights
Ischemic heart diseases account for 7.0 million deaths per year worldwide [1]
In a prospective cohort study of patients suffering from acute myocardial infarction (AMI), 81 human arterial thrombi were harvested during percutaneous coronary intervention and subjected to detailed histological analysis
We found that murine arterial thrombi induced by FeCl3 were highly concordant with human coronary thrombi regarding their immune cell composition, with neutrophils being the most abundant cell type, as well as the presence of neutrophils provide extracellular traps (NETs) and coagulation factors
Summary
Ischemic heart diseases account for 7.0 million deaths per year worldwide [1]. In AMI patients, arterial thrombosis is typically triggered by rupture of an atherosclerotic plaque within coronary arteries [2]. Platelets support the local recruitment of immune cells to nascent thrombi at the site of plaque rupture. The subsequent crosstalk between platelets and recruited immune effectors results in activation of blood coagulation [5], which propagates thrombus formation and growth in a process termed immunothrombosis [6]. The latter represents a physiological process supported by immune cells and specific thrombosis-related molecules generating an intravascular scaffold that facilitates the recognition, containment and destruction of pathogens, thereby protecting host integrity. Neutrophils provide extracellular traps (NETs), DNA matrices that act as strong procoagulant surfaces propagating local coagulation [6,7,8]
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