Key Points
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Thrombosis involves the pathological occlusion of blood vessels, which inhibits the blood supply to organs. It is the most frequent cause of mortality worldwide, as it directly causes myocardial infarction, stroke, pulmonary embolism, thrombotic microangiopathies and complications during sepsis as well as other diseases.
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Thrombosis is traditionally seen as a pathological form of blood vessel repair via haemostasis. Indeed, both thrombosis and haemostasis are induced by two core processes: blood coagulation, which leads to fibrin formation; and platelet activation. However, thrombosis is also supported by cellular mediators (for example, neutrophils) and molecular mediators (for example, intravascular tissue factor) that are largely irrelevant for haemostasis.
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Immune cells and thrombosis-specific molecular mediators induce a physiological type of thrombosis in microvessels (such as sinusoids in the liver and spleen). This form of thrombosis has been designated here as immunothrombosis.
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Immunothrombosis involves a local platform consisting of fibrin, monocytes, neutrophils and platelets, which together contribute to pathogen recognition. This process helps to suppress the tissue invasion and dissemination of pathogens and to reduce their survival. The local nature of immunothrombosis and its occurrence in only a restricted number of microvessels probably ensures that immunothrombosis does not seriously perturb overall organ perfusion.
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Together, these properties characterize immunothrombosis as an independent process of innate immunity that is specifically activated by blood-borne microorganisms and by circulating altered-self components.
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Pathological thrombosis in large veins and microvessels (such as venous thromboembolism and thrombotic macroangiopathies) shares similar triggers (namely, pathogens and altered-self components), the same evolutionary origin and identical molecular and cellular mediators with immunothrombosis. This suggests that together with haemostasis, immunothrombosis is the most relevant biological process underlying pathological thrombosis.
Abstract
Thrombosis is the most frequent cause of mortality worldwide and is closely linked to haemostasis, which is the biological mechanism that stops bleeding after the injury of blood vessels. Indeed, both processes share the core pathways of blood coagulation and platelet activation. Here, we summarize recent work suggesting that thrombosis under certain circumstances has a major physiological role in immune defence, and we introduce the term immunothrombosis to describe this process. Immunothrombosis designates an innate immune response induced by the formation of thrombi inside blood vessels, in particular in microvessels. Immunothrombosis is supported by immune cells and by specific thrombosis-related molecules and generates an intravascular scaffold that facilitates the recognition, containment and destruction of pathogens, thereby protecting host integrity without inducing major collateral damage to the host. However, if uncontrolled, immunothrombosis is a major biological process fostering the pathologies associated with thrombosis.
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Acknowledgements
The authors thank all previous and present members of both laboratories who have contributed to the work mentioned in this Review. In addition, we thank M.-L. von Brühl, S. Pfeiler, K. Stark, F. Gärtner, R. Byrne and S. Haidari for their help in preparing the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) through Sonderforschungsbereich 914 (S.M.) and the DFG grants EN 178/11-1, 178/13-1 and 178/14-1 (B.E.), as well as by grants from the Deutsche Krebshilfe (to B.E.), the EU FP7 programme (PRESTIGE) (to S.M.), the Wilhelm Sander Stiftung (to B.E.) and the Munich Heart Alliance (a member of the Deutsches Zentrum für Herz-Kreislauf-Forschung) (to S.M.).
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Supplementary information S1 (movie)
Intravital two-photon microscopy reveals the recruitment of LysM-eGFP+ neutrophils (green) and platelets (yellow) to the vessel wall (red) during the onset of deep vein thrombosis in a mouse model. (MOV 1771 kb)
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Glossary
- Thrombosis
-
The formation of a thrombus (clot) inside blood vessels, resulting in partial or complete vessel occlusion.
- Myocardial infarction
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An episode of acute cardiac ischaemia that leads to the death of heart-muscle cells. It is usually caused by the rupture of an atherosclerotic plaque leading to clot formation.
- Atherothrombosis
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Following the rupture of unstable atherosclerotic plaques, thrombogenic material becomes exposed or released and triggers thrombus formation and eventually the occlusion of an artery.
- Haemostasis
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A biological process that repairs perforations in blood vessels via the formation of a thrombus consisting of aggregating platelets and fibrin in the vessel wall.
- Disseminated intravascular coagulation
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(DIC; also known as consumptive coagulopathy). A pathological process in which the blood begins to coagulate throughout the entire body. During this process, platelets and coagulation factors are depleted, resulting in a paradoxical situation in which there is a high risk of simultaneous fatal thrombosis and large-scale haemorrhage. DIC often occurs in critically ill patients with overwhelming infection, fulminant sepsis, extensive tissue damage or malignancy.
- Microparticles
-
(Also known as microvesicles). Cell-derived membrane vesicles that originate from the plasma membrane via shedding. Microparticles have to be distinguished from exosomes, which are cell-derived membrane vesicles derived from multivesicular bodies, which are compartments of the endosomal system.
- Intravascular tissue factor
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Tissue factor that is expressed on cells in the blood and on the microparticles that they release.
- Neutrophil extracellular traps
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(NETs). Sets of extracellular fibres produced mostly by activated neutrophils to ensnare invading microorganisms. NETs enhance neutrophil-mediated killing of extracellular pathogens but cause minimal damage to host cells.
- Extracellular nucleosomes
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Extracellular lattices consisting of DNA and histones that can originate from neutrophils, in particular in the form of NETs.
- Extrinsic pathway of coagulation
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A process supporting blood coagulation that is traditionally assumed to be initiated outside the blood vessel lumen.
- Contact pathway of coagulation
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A process that supports blood coagulation initiated by blood-borne factor XII, which is activated following contact with pathogens, damaged cells and foreign surfaces such as glass.
- Sepsis
-
A systemic response to severe infection or tissue damage that leads to a hyperactive and unbalanced network of pro-inflammatory mediators. Vascular permeability, cardiac function and metabolic balance are affected, resulting in tissue necrosis, multi-organ failure and death.
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Engelmann, B., Massberg, S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 13, 34–45 (2013). https://doi.org/10.1038/nri3345
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DOI: https://doi.org/10.1038/nri3345
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