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.

Keywords: Salmonella; bacteria; pathogens; platelets; thrombo-inflammation; thrombosis; virus.

Copyright © 2019 Beristain-Covarrubias, Perez-Toledo, Thomas, Henderson, Watson and Cunningham.

Figures

Figure 1

Examples of animal models available to study thrombosis during infection. A range of approaches has been employed to evaluate infection-induced thrombosis. Single microbial component-induced sepsis, or CLP models, mimic severe sepsis in humans, but most are usually only useable for a few days either because the infection is cleared or it is lethal. Some viral and bacterial infection models can induce longer-lasting infections and thrombotic complications may also be useful to study the resolution of thrombosis.

Figure 2

Thrombosis develops asynchronously in the spleen and liver after STm infection. Resident immune cells (monocytes/macrophages/neutrophils) are more abundant in the spleen compared to the liver. Although the mechanism is still under study, splenic phagocytic cells and neutrophils participate in the induction of white, platelet-rich, thrombi in the spleen 24 h after infection. Thrombi in the spleen resolve rapidly thereafter so that from day 7 onwards post-infection only “ghosts” of fibrin are observed. In the liver, thrombi are not detected until 7 days after infection, despite the liver and spleen having similarly high bacteria burdens in the first week post-infection. Thrombosis in the liver requires inflammatory cell recruitment and activation through TLR4, which promotes IFNγ production, the accumulation of monocytic cells and their upregulation of podoplanin. Inflammation is associated with perturbed endothelial integrity/endothelial damage making it possible for the interaction of podoplanin expressed on monocytic cells and CLEC-2 on platelets. Thrombosis in the liver persists for weeks and the resolution of thrombosis is observed from day 21 after infection. The mechanism(s) that underlie the resolution of thrombosis in these two different organs is still unknown. A strength of the STm infection model is that it offers an alternative tool to understand this process.

Figure 3

Current and potential molecules or pathways to target infection-associated thrombosis. Anticoagulants interfere with the activity of different clotting factors in the coagulation cascade that aims to rebalance hemostasis. Platelet GPVI and CLEC-2 are activated via SFK kinases and play a role in infection-mediated platelet activation. Neutrophil activation and the release of NETs together with associated factors (DNA/Histones) are also under study for developing strategies to limit their pro-thrombotic effects.