Understanding Infection-Induced Thrombosis: Lessons Learned From Animal Models

Abstract

Thrombosis is a common consequence of infection that is associated with poor patient outcome. Nevertheless, the mechanisms by which infection-associated thrombosis is induced, maintained and resolved are poorly understood, as is the contribution thrombosis makes to host control of infection and pathogen spread. The key difference between infection-associated thrombosis and thrombosis in other circumstances is a stronger inflammation-mediated component caused by the presence of the pathogen and its products. This inflammation triggers the activation of platelets, which may accompany damage to the endothelium, resulting in fibrin deposition and thrombus formation. This process is often referred to as thrombo-inflammation. Strikingly, despite its clinical importance and despite thrombi being induced to many different pathogens, it is still unclear whether the mechanisms underlying this process are conserved and how we can best understand this process. This review summarizes thrombosis in a variety of models, including single antigen models such as LPS, and infection models using viruses and bacteria. We provide a specific focus on Salmonella Typhimurium infection as a useful model to address all stages of thrombosis during infection. We highlight how this model has helped us identify how thrombosis can appear in different organs at different times and thrombi be detected for weeks after infection in one site, yet largely be resolved within 24 h in another. Furthermore, we discuss the observation that thrombi induced to Salmonella Typhimurium are largely devoid of bacteria. Finally, we discuss the value of different therapeutic approaches to target thrombosis, the potential importance of timing in their administration and the necessity to maintain normal hemostasis after treatment. Improvements in our understanding of these processes can be used to better target infection-mediated mechanisms of thrombosis.

<p>Microbial Modulation of Coagulation Disorders in Venous Thromboembolism</p>

“…Many bacteria such as Helicobacter pylori, Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli increase the risk associated with the stroke. 5 It has also been reported that various cardiovascular diseases may be associated with bacterial involvement as shown on the example of infective endocarditis. 108 Relationships between pneumonia due to Haemophilus influenzae and infection with other bacteria and myocardial infarction have been confirmed.…”

“…17 It is believed that systemic infections increase the risk of deep vein thrombosis/pulmonary embolism about 2-20 times. 5 An additional risk factor for VTE is the age of the patients, the presence of malignant tumors, and hereditary features. 3 It is also known that the formation of blood clots in vessels occurs during sepsis, which indicates the participation of bacteria in this process.…”

“…Thrombosis initiated by pathogens is associated with the release of inflammatory agents activating platelets, which may be accompanied by damage to the endothelium, leading to fibrin deposition and the consequence of thrombus formation. 5 There are many wellknown bacteria that cause infections and increase the risk of thrombotic complications, including ischemic stroke and myocardial infarction. 103,104 This group includes Helicobacter pylori, Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Epstein-Bar virus, herpesvirus and cytomegalovirus.…”

“…Pathogens that promote sepsis and are involved in the development of thrombosis include both gram-positive (Staphylococcus aureus, Streptococcus pyogenes) and gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Chlamydia pneumoniae, Helicobacter pylori, Haemophilus influenzae). 5 The result of sepsis caused by gram-negative bacteria is endotoxemia, ie the appearance of released lipopolysaccharide (LPS, endotoxin) in the host's blood. The consequence of endotoxemia is the septic shock, one key element of which is intravascular coagulation.…”

COVID-19 and Thrombosis Predisposition

“…Moreover, this and other animal models showed histological evidence of fibrin deposits in multiple organs such as the spleen, liver, lungs, and kidneys. 16,17 These fibrin deposits could be associated with activated macrophages, which in turn are attracted by infected cells, demonstrating the interplay between inflammatory cells and the advent of systemic coagulopathy. In another experiment, mice infected with influenza virus showed platelet aggregation, pulmonary microvascular thrombosis, endothelial dysfunction, and hyperinflammatory cytokine responses.…”