Journal Article

Histological comparison of arterial thrombi in mice and men and the influence of Cl-amidine on thrombus formation

Legate, Kyle R., Novotny, Julia, Pircher, Joachim, Titova, Anna, Oberdieck, Paul, Lorenz, Michael, von Brühl, Marie-Luise, Hoti, Qendresa, Chandraratne, Sue, Pelisek, Jaroslav, Schulz, Christian, Urtz, Nicole, Konrad, Ildiko, Weinberger, Tobias, Ehrlich, Andreas, Massberg, Steffen, Stark, Konstantin, Philippi, Vanessa, Schubert, Irene

2018

Overview

Medical 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). In 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. Neutrophils 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amidines / Analysis / Animal models / Arginine / Arginine deiminase / Biology and Life Sciences / Bleeding / Blood clots / Blood platelets / Carotid artery / Coagulation / Coagulation factors / Comparative analysis / Complications / Deoxyribonucleic acid / DNA / Drug therapy / Ferric chloride / Heart / Heart attack / Heart attacks / Immune system / Influence / Injury prevention / Iron chlorides / Leukocytes (neutrophilic) / Medical treatment / Medicine / Medicine and Health Sciences / Mice / Mitochondrial DNA / Myocardial infarction / Neutrophils / Pathogens / Patients / Pharmacology / Platelets / Research and Analysis Methods / Thromboembolism / Thrombosis