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  • Review Article
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Thrombosis as an intravascular effector of innate immunity

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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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Figure 1: Mammalian haemostasis: a specialized process to prevent blood loss after injury.
Figure 2: Basic principles of immunothrombosis.
Figure 3: Retention of pathogens by immunothrombosis.
Figure 4: The thrombotic continuum — uncontrolled haemostasis and immunothrombosis trigger disease.

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References

  1. Roger, V. L. et al. Heart disease and stroke statistics — 2011 update: a report from the American Heart Association. Circulation 123, e18–e209 (2011).

    Article  PubMed  Google Scholar 

  2. Goldhaber, S. Z. & Bounameaux, H. Pulmonary embolism and deep vein thrombosis. Lancet 379, 1835–1846 (2012).

    Article  PubMed  Google Scholar 

  3. Sevitt, S. Thrombosis and embolism after injury. J. Clin. Pathol. Suppl. (R. Coll. Pathol.) 4, 86–101 (1970).

    Article  CAS  Google Scholar 

  4. Esmon, C. T. Basic mechanisms and pathogenesis of venous thrombosis. Blood Rev. 23, 225–229 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914–918 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Loof, T. G. et al. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood 118, 2589–2598 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Loof, T. G., Schmidt, O., Herwald, H. & Theopold, U. Coagulation systems of invertebrates and vertebrates and their roles in innate immunity: the same side of two coins? J. Innate Immun. 3, 34–40 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Dushay, M. S. Insect hemolymph clotting. Cell. Mol. Life Sci. 66, 2643–2650 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Li, D. et al. Insect hemolymph clotting: evidence for interaction between the coagulation system and the prophenoloxidase activating cascade. Insect Biochem. Mol. Biol. 32, 919–928 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Theopold, U., Li, D., Fabbri, M., Scherfer, C. & Schmidt, O. The coagulation of insect hemolymph. Cell. Mol. Life Sci. 59, 363–372 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Hickey, M. J. & Kubes, P. Intravascular immunity: the host–pathogen encounter in blood vessels. Nature Rev. Immunol. 9, 364–375 (2009).

    Article  CAS  Google Scholar 

  12. Furie, B. & Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Junt, T. et al. Dynamic visualization of thrombopoiesis within bone marrow. Science 317, 1767–1770 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Battinelli, E. M., Hartwig, J. H. & Italiano, J. E. Jr. Delivering new insight into the biology of megakaryopoiesis and thrombopoiesis. Curr. Opin. Hematol. 14, 419–426 (2007).

    Article  PubMed  Google Scholar 

  15. Massberg, S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J. Exp. Med. 197, 41–49 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gruner, S. et al. Multiple integrin–ligand interactions synergize in shear-resistant platelet adhesion at sites of arterial injury in vivo. Blood 102, 4021–4027 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Moog, S. et al. Platelet glycoprotein V binds to collagen and participates in platelet adhesion and aggregation. Blood 98, 1038–1046 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Bergmeier, W., Chauhan, A. K. & Wagner, D. D. Glycoprotein Ibα and von Willebrand factor in primary platelet adhesion and thrombus formation: lessons from mutant mice. Thromb. Haemost. 99, 264–270 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Wilcox, J. N., Smith, K. M., Schwartz, S. M. & Gordon, D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl Acad. Sci. USA 86, 2839–2843 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Esmon, C. T. The interactions between inflammation and coagulation. Br. J. Haematol. 131, 417–430 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Lentz, B. R. Exposure of platelet membrane phosphatidylserine regulates blood coagulation. Prog. Lipid Res. 42, 423–438 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Coughlin, S. R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3, 1800–1814 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Palabrica, T. et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 359, 848–851 (1992). An early study showing that leukocytes promote fibrin formation in a P-selectin-mediated manner in an arteriovenous shunt model of thrombus formation in vivo.

  24. Semple, J. W., Italiano, J. E. Jr & Freedman, J. Platelets and the immune continuum. Nature Rev. Immunol. 11, 264–274 (2011).

    Article  CAS  Google Scholar 

  25. von Bruhl, M. L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Downing, L. J. et al. Anti-P-selectin antibody decreases inflammation and thrombus formation in venous thrombosis. J. Vasc. Surg. 25, 816–827 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Wakefield, T. W., Myers, D. D. & Henke, P. K. Mechanisms of venous thrombosis and resolution. Arterioscler. Thromb. Vasc. Biol. 28, 387–391 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  29. Brill, A. et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 117, 1400–1407 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Niessen, F. et al. Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation. Nature 452, 654–658 (2008). This study provides evidence for the activation of dendritic cells by coagulation via a PAR1–sphingosine-1-phosphate receptor 3 axis, which in turn induces a massive inflammatory response.

    Article  CAS  PubMed  Google Scholar 

  31. Haselmayer, P., Grosse-Hovest, L., von Landenberg, P., Schild, H. & Radsak, M. P. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood 110, 1029–1035 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nature Med. 17, 1410–1422 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Yeaman, M. R. Platelets in defense against bacterial pathogens. Cell. Mol. Life Sci. 67, 525–544 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Nieswandt, B. et al. Long-term antithrombotic protection by in vivo depletion of platelet glycoprotein VI in mice. J. Exp. Med. 193, 459–469 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Angelillo-Scherrer, A. et al. Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis. Nature Med. 7, 215–221 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Jackson, S. P. Arterial thrombosis — insidious, unpredictable and deadly. Nature Med. 17, 1423–1436 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Rivers, R. P., Hathaway, W. E. & Weston, W. L. The endotoxin-induced coagulant activity of human monocytes. Br. J. Haematol. 30, 311–316 (1975).

    Article  CAS  PubMed  Google Scholar 

  38. Muller, I. et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J. 17, 476–478 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Giesen, P. L. et al. Blood-borne tissue factor: another view of thrombosis. Proc. Natl Acad. Sci. USA 96, 2311–2315 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Darbousset, R. et al. Tissue factor positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 120, 2133–2143 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Maugeri, N. et al. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J. Thromb. Haemost. 4, 1323–1330 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Moosbauer, C. et al. Eosinophils are a major intravascular location for tissue factor storage and exposure. Blood 109, 995–1002 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Zillmann, A. et al. Platelet-associated tissue factor contributes to the collagen-triggered activation of blood coagulation. Biochem. Biophys. Res. Commun. 281, 603–609 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Reinhardt, C. et al. Protein disulfide isomerase acts as an injury response signal that enhances fibrin generation via tissue factor activation. J. Clin. Invest. 118, 1110–1122 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Jasuja, R. et al. Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents. J. Clin. Invest. 122, 2104–2113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cho, J., Furie, B. C., Coughlin, S. R. & Furie, B. A critical role for extracellular protein disulfide isomerase during thrombus formation in mice. J. Clin. Invest. 118, 1123–1131 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Jaillon, S. et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J. Exp. Med. 204, 793–804 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cho, J. H. et al. Human peptidoglycan recognition protein S is an effector of neutrophil-mediated innate immunity. Blood 106, 2551–2558 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dziarski, R., Platt, K. A., Gelius, E., Steiner, H. & Gupta, D. Defect in neutrophil killing and increased susceptibility to infection with nonpathogenic Gram-positive bacteria in peptidoglycan recognition protein-S (PGRP-S)-deficient mice. Blood 102, 689–697 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nature Med. 16, 887–896 (2010). This study identifies thrombosis as a physiological mechanism of immune defence during infections. It characterizes molecular and cellular mediators supporting the physiological formation of thrombosis in microvessels, which include neutrophils and externalized nucleosomes, and shows that arterial thrombosis shares these mediators with physiological thrombosis.

    Article  CAS  PubMed  Google Scholar 

  53. Engelmann, B., Luther, T. & Muller, I. Intravascular tissue factor pathway — a model for rapid initiation of coagulation within the blood vessel. Thromb. Haemost. 89, 3–8 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Takano, S., Kimura, S., Ohdama, S. & Aoki, N. Plasma thrombomodulin in health and diseases. Blood 76, 2024–2029 (1990).

    CAS  PubMed  Google Scholar 

  55. Glaser, C. B. et al. Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation. J. Clin. Invest. 90, 2565–2573 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xu, J., Zhang, X., Monestier, M., Esmon, N. L. & Esmon, C. T. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J. Immunol. 187, 2626–2631 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nature Med. 15, 1318–1321 (2009). This work shows that extracellular histones induce death during sepsis in vivo , which is preceded by endothelial damage, haemorrhage and thrombosis.

    Article  CAS  PubMed  Google Scholar 

  58. Semeraro, F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118, 1952–1961 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. van der Poll, T., de Boer, J. D. & Levi, M. The effect of inflammation on coagulation and vice versa. Curr. Opin. Infect. Dis. 24, 273–278 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Zinsser, H. H. & Pryde, A. W. Experimental study of physical factors, including fibrin formation, influencing the spread of fluids and small particles within and from the peritoneal cavity of the dog. Ann. Surg. 136, 818–827 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Johnson, L. L., Berggren, K. N., Szaba, F. M., Chen, W. & Smiley, S. T. Fibrin-mediated protection against infection-stimulated immunopathology. J. Exp. Med. 197, 801–806 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Szaba, F. M. & Smiley, S. T. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood 99, 1053–1059 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Flick, M. J. et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo. J. Clin. Invest. 113, 1596–1606 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Degen, J. L., Bugge, T. H. & Goguen, J. D. Fibrin and fibrinolysis in infection and host defense. J. Thromb. Haemost. 5 (Suppl. 1), 24–31 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Delvaeye, M. & Conway, E. M. Coagulation and innate immune responses: can we view them separately? Blood 114, 2367–2374 (2009). References 64 and 65 comprehensively summarize previous findings on the relationship of blood coagulation with inflammation and innate immunity in general.

    Article  CAS  PubMed  Google Scholar 

  66. Hippenstiel, S. & Suttorp, N. Interaction of pathogens with the endothelium. Thromb. Haemost. 89, 18–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Luo, D. et al. Protective roles for fibrin, tissue factor, plasminogen activator inhibitor-1, and thrombin activatable fibrinolysis inhibitor, but not factor XI, during defense against the Gram-negative bacterium Yersinia enterocolitica. J. Immunol. 187, 1866–1876 (2011). In this study, several molecules that are crucial for blood coagulation are demonstrated to protect hosts from bacterial infection in vivo . This is probably mediated by intravascular mechanisms that support immunothrombosis, which helps to prevent the spreading of intravascular bacteria.

    Article  CAS  PubMed  Google Scholar 

  68. Guha, M. & Mackman, N. LPS induction of gene expression in human monocytes. Cell Signal. 13, 85–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Wolberg, A. S., Monroe, D. M., Roberts, H. R. & Hoffman, M. R. Tissue factor de-encryption: ionophore treatment induces changes in tissue factor activity by phosphatidylserine-dependent and -independent mechanisms. Blood Coagul. Fibrinolysis 10, 201–210 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Morrison, D. C. & Cochrane, C. G. Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J. Exp. Med. 140, 797–811 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kannemeier, C. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc. Natl Acad. Sci. USA 104, 6388–6393 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ammollo, C. T., Semeraro, F., Xu, J., Esmon, N. L. & Esmon, C. T. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J. Thromb. Haemost. 9, 1795–1803 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Med. 13, 463–469 (2007). The authors show that the recognition of pathogens by TLR4 on platelets is linked to neutrophil activation and the release of NETs, which contributes to the capture of microorganisms during systemic infection. Accordingly, platelets contribute to pathogen recognition and to the inhibition of pathogen spreading in vivo.

    Article  CAS  PubMed  Google Scholar 

  74. Kraemer, B. F. et al. Novel anti-bacterial activities of β-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog. 7, e1002355 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cox, D., Kerrigan, S. W. & Watson, S. P. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J. Thromb. Haemost. 9, 1097–1107 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Aslam, R. et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo. Blood 107, 637–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Semple, J. W., Aslam, R., Kim, M., Speck, E. R. & Freedman, J. Platelet-bound lipopolysaccharide enhances Fc receptor-mediated phagocytosis of IgG-opsonized platelets. Blood 109, 4803–4805 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Patrignani, P. et al. Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo. Blood 107, 3572–3574 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Stahl, A. L. et al. Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108, 167–176 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhang, G. et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J. Immunol. 182, 7997–8004 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Verschoor, A. et al. A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3. Nature Immunol. 12, 1194–1201 (2011).

    Article  CAS  Google Scholar 

  82. Silasi-Mansat, R. et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116, 1002–1010 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Markiewski, M. M., Nilsson, B., Ekdahl, K. N., Mollnes, T. E. & Lambris, J. D. Complement and coagulation: strangers or partners in crime? Trends Immunol. 28, 184–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Hamad, O. A., Back, J., Nilsson, P. H., Nilsson, B. & Ekdahl, K. N. Platelets, complement, and contact activation: partners in inflammation and thrombosis. Adv. Exp. Med. Biol. 946, 185–205 (2012).

    Article  CAS  PubMed  Google Scholar 

  85. Frick, I. M. et al. The contact system--a novel branch of innate immunity generating antibacterial peptides. EMBO J. 25, 5569–5578 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bianchi, M. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 114, 2619–2622 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Beutler, B. Innate immunity: an overview. Mol. Immunol. 40, 845–859 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Bergmann, S. & Hammerschmidt, S. Fibrinolysis and host response in bacterial infections. Thromb. Haemost. 98, 512–520 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Sun, H. et al. Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science 305, 1283–1286 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Buchanan, J. T. et al. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 16, 396–400 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Beiter, K. et al. An endonuclease allows Streptococcus pneumoniae to escape from neutrophil extracellular traps. Curr. Biol. 16, 401–407 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Cheng, A. G. et al. Contribution of coagulases towards Staphylococcus aureus disease and protective immunity. PLoS Pathog. 6, e1001036 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Guggenberger, C., Wolz, C., Morrissey, J. A. & Heesemann, J. Two distinct coagulase-dependent barriers protect Staphylococcus aureus from neutrophils in a three dimensional in vitro infection model. PLoS Pathog. 8, e1002434 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pawlinski, R. et al. Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood 116, 806–814 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ma, A. C. & Kubes, P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J. Thromb. Haemost. 6, 415–420 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Tsukamoto, T., Chanthaphavong, R. S. & Pape, H. C. Current theories on the pathophysiology of multiple organ failure after trauma. Injury 41, 21–26 (2010).

    Article  PubMed  Google Scholar 

  97. Muller, F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139, 1143–1156 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chou, J. et al. Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation. Blood 104, 3190–3197 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Falati, S. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J. Exp. Med. 197, 1585–1598 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kleinschnitz, C. et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J. Exp. Med. 203, 513–518 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Renne, T. et al. Defective thrombus formation in mice lacking coagulation factor XII. J. Exp. Med. 202, 271–281 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hakkim, A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813–9818 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Dorner, T. SLE in 2011: deciphering the role of NETs and networks in SLE. Nature Rev. Rheumatol. 8, 68–70 (2012).

    Article  CAS  Google Scholar 

Download references

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

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

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

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

(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

Tissue factor that is expressed on cells in the blood and on the microparticles that they release.

Neutrophil extracellular traps

(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

Extracellular lattices consisting of DNA and histones that can originate from neutrophils, in particular in the form of NETs.

Extrinsic pathway of coagulation

A process supporting blood coagulation that is traditionally assumed to be initiated outside the blood vessel lumen.

Contact pathway of coagulation

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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