Download PDF
Hamostaseologie 2024; 44(01): 021-030
DOI: 10.1055/a-2178-6491
Review Article

The Concept of Thromboinflammation

Waltraud C. Schrottmaier
1   Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
,
Alice Assinger
1   Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
› Author Affiliations Funding The study was funded by the National Institutes of Health (R01DK122813) and the Austrian Science Fund (FWF) P-32064 and P-34783.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Inflammation and thrombosis are intricate and closely interconnected biological processes that are not yet fully understood and lack effective targeted therapeutic approaches. Thrombosis initiated by inflammatory responses, known as immunothrombosis, can confer advantages to the host by constraining the spread of pathogens within the bloodstream. Conversely, platelets and the coagulation cascade can influence inflammatory responses through interactions with immune cells, endothelium, or complement system. These interactions can lead to a state of heightened inflammation resulting from thrombotic processes, termed as thromboinflammation. This review aims to comprehensively summarize the existing knowledge of thromboinflammation and addressing its significance as a challenging clinical issue.

Zusammenfassung

Entzündungen und Thrombosen sind komplizierte und eng miteinander verwobene biologische Prozesse, die noch nicht vollständig aufgeklärt sind und denen es an wirksamen gezielten Therapieansätzen mangelt. Eine durch Entzündungsreaktionen ausgelöste Thrombose, bekannt als Immunthrombose, kann Vorteile bringen, indem sie die Ausbreitung von Krankheitserregern im Blutkreislauf einschränkt. Umgekehrt können Thrombozyten und die Gerinnungskaskade durch Interaktionen mit Immunzellen, dem Endothel oder dem Komplementsystem Entzündungsreaktionen beeinflussen. Diese Wechselwirkungen können zu einem Zustand verstärkter Entzündung führen, der aus thrombotischen Prozessen resultiert und daher als Thromboinflammation bezeichnet wird. Dieser Übersichtsartikel zielt darauf ab, das vorhandene Wissen über Thromboinflammation umfassend zusammenzufassen und sich mit ihrer Bedeutung als anspruchsvolles klinisches Problem zu befassen, das noch nicht ausreichend verstanden und auch nicht therapeutisch behandelt wird.

Keywords

thromboinflammation - immunothrombosis - platelets - coagulation - leukocytes - complement

Schlüsselwörter

Thromboinflammation - Immunthrombose - Blutplättchen - Gerinnung - Leukozyten - Komplement


Publication History

Received: 19 September 2023

Accepted: 21 November 2023

Article published online:
28 February 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
    CrossrefPubMedGoogle Scholar
  • 2 Gaertner F, Massberg S. Blood coagulation in immunothrombosis-at the frontline of intravascular immunity. Semin Immunol 2016; 28 (06) 561-569
    CrossrefPubMedGoogle Scholar
  • 3 Tanguay JF, Geoffroy P, Sirois MG. et al. Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions with recombinant P-selectin glycoprotein ligand-1. Thromb Haemost 2004; 91 (06) 1186-1193
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Blair P, Rex S, Vitseva O. et al. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res 2009; 104 (03) 346-354
    CrossrefPubMedGoogle Scholar
  • 5 Nieswandt B, Kleinschnitz C, Stoll G. Ischaemic stroke: a thrombo-inflammatory disease?. J Physiol 2011; 589 (17) 4115-4123
    CrossrefPubMedGoogle Scholar
  • 6 Dimitrov JD, Roumenina LT, Perrella G, Rayes J. Basic mechanisms of hemolysis-associated thrombo-inflammation and immune dysregulation. Arterioscler Thromb Vasc Biol 2023; 43 (08) 1349-1361
    CrossrefPubMedGoogle Scholar
  • 7 Conran N, De Paula EV. Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance. Haematologica 2020; 105 (10) 2380-2390
    CrossrefPubMedGoogle Scholar
  • 8 Palacios-Acedo AL, Mège D, Crescence L, Dignat-George F, Dubois C, Panicot-Dubois L. Platelets, thrombo-inflammation, and cancer: collaborating with the enemy. Front Immunol 2019; 10: 1805
    CrossrefPubMedGoogle Scholar
  • 9 Stoiber D, Assinger A. Platelet-leukocyte interplay in cancer development and progression. Cells 2020; 9 (04) 855
    CrossrefPubMedGoogle Scholar
  • 10 Olumuyiwa-Akeredolu OO, Page MJ, Soma P, Pretorius E. Platelets: emerging facilitators of cellular crosstalk in rheumatoid arthritis. Nat Rev Rheumatol 2019; 15 (04) 237-248
    CrossrefPubMedGoogle Scholar
  • 11 Müller-Calleja N, Hollerbach A, Royce J. et al. Lipid presentation by the protein C receptor links coagulation with autoimmunity. Science 2021; 371 (6534) eabc0956
    CrossrefPubMedGoogle Scholar
  • 12 Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood 2016; 128 (06) 753-762
    CrossrefPubMedGoogle Scholar
  • 13 Roth S, Cao J, Singh V. et al. Post-injury immunosuppression and secondary infections are caused by an AIM2 inflammasome-driven signaling cascade. Immunity 2021; 54 (04) 648-659.e8
    CrossrefPubMedGoogle Scholar
  • 14 Stark K, Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol 2021; 18 (09) 666-682
    CrossrefPubMedGoogle Scholar
  • 15 Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor antigen by immunostaining with monospecific, polyclonal anti-human tissue factor antibody. Thromb Res 1990; 59 (02) 421-437
    CrossrefPubMedGoogle Scholar
  • 16 Mackman N, Taubman MB. Does tissue factor expression by vascular smooth muscle cells provide a link between C-reactive protein and cardiovascular disease?. Arterioscler Thromb Vasc Biol 2008; 28 (04) 601-603
    CrossrefPubMedGoogle Scholar
  • 17 McDonald AG, Yang K, Roberts HR, Monroe DM, Hoffman M. Perivascular tissue factor is down-regulated following cutaneous wounding: implications for bleeding in hemophilia. Blood 2008; 111 (04) 2046-2048
    CrossrefPubMedGoogle Scholar
  • 18 Cirillo P, Golino P, Calabrò P. et al. C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc Res 2005; 68 (01) 47-55
    CrossrefPubMedGoogle Scholar
  • 19 Massberg S, Grahl L, von Bruehl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16 (08) 887-896
    CrossrefPubMedGoogle Scholar
  • 20 Schrottmaier WC, Mussbacher M, Salzmann M, Assinger A. Platelet-leukocyte interplay during vascular disease. Atherosclerosis 2020; 307: 109-120
    CrossrefPubMedGoogle Scholar
  • 21 Shi C, Yang L, Braun A, Anders HJ. Extracellular DNA-a Danger signal triggering immunothrombosis. Front Immunol 2020; 11: 568513
    CrossrefPubMedGoogle Scholar
  • 22 Trejo J. Protease-activated receptors: new concepts in regulation of G protein-coupled receptor signaling and trafficking. J Pharmacol Exp Ther 2003; 307 (02) 437-442
    CrossrefPubMedGoogle Scholar
  • 23 Gur-Cohen S, Itkin T, Chakrabarty S. et al. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat Med 2015; 21 (11) 1307-1317
    CrossrefPubMedGoogle Scholar
  • 24 Chandrabalan A, Ramachandran R. Molecular mechanisms regulating proteinase-activated receptors (PARs). FEBS J 2021; 288 (08) 2697-2726
    CrossrefPubMedGoogle Scholar
  • 25 Minami T, Sugiyama A, Wu SQ, Abid R, Kodama T, Aird WC. Thrombin and phenotypic modulation of the endothelium. Arterioscler Thromb Vasc Biol 2004; 24 (01) 41-53
    CrossrefPubMedGoogle Scholar
  • 26 Clark SR, Ma AC, Tavener SA. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13 (04) 463-469
    CrossrefPubMedGoogle Scholar
  • 27 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
    CrossrefPubMedGoogle Scholar
  • 28 McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12 (03) 324-333
    CrossrefPubMedGoogle Scholar
  • 29 von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209 (04) 819-835
    CrossrefPubMedGoogle Scholar
  • 30 Rangaswamy C, Englert H, Deppermann C, Renné T. Polyanions in coagulation and thrombosis: focus on polyphosphate and neutrophils extracellular traps. Thromb Haemost 2021; 121 (08) 1021-1030
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Kenny EF, Herzig A, Krüger R. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife 2017; 6: x
    CrossrefPubMedGoogle Scholar
  • 32 Lewis HD, Liddle J, Coote JE. et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol 2015; 11 (03) 189-191
    CrossrefPubMedGoogle Scholar
  • 33 Sollberger G, Tilley DO, Zychlinsky A. Neutrophil extracellular traps: the biology of chromatin externalization. Dev Cell 2018; 44 (05) 542-553
    CrossrefPubMedGoogle Scholar
  • 34 Silvestre-Roig C, Hidalgo A, Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood 2016; 127 (18) 2173-2181
    CrossrefPubMedGoogle Scholar
  • 35 Uhl B, Vadlau Y, Zuchtriegel G. et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood 2016; 128 (19) 2327-2337
    CrossrefPubMedGoogle Scholar
  • 36 Zhang D, Chen G, Manwani D. et al. Neutrophil ageing is regulated by the microbiome. Nature 2015; 525 (7570) 528-532
    CrossrefPubMedGoogle Scholar
  • 37 Meyers S, Crescente M, Verhamme P, Martinod K. Staphylococcus aureus and neutrophil extracellular traps: the master manipulator meets its match in immunothrombosis. Arterioscler Thromb Vasc Biol 2022; 42 (03) 261-276
    CrossrefPubMedGoogle Scholar
  • 38 Mailer RK, Rangaswamy C, Konrath S, Emsley J, Renné T. An update on factor XII-driven vascular inflammation. Biochim Biophys Acta Mol Cell Res 2022; 1869 (01) 119166
    CrossrefPubMedGoogle Scholar
  • 39 Jansen PM, Pixley RA, Brouwer M. et al. Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase. Blood 1996; 87 (06) 2337-2344
    CrossrefPubMedGoogle Scholar
  • 40 Madjene C, Boutigny A, Bouton MC, Arocas V, Richard B. Protease Nexin-1 in the cardiovascular system: wherefore art thou?. Front Cardiovasc Med 2021; 8: 652852
    CrossrefPubMedGoogle Scholar
  • 41 Boulaftali Y, Adam F, Venisse L. et al. Anticoagulant and antithrombotic properties of platelet protease nexin-1. Blood 2010; 115 (01) 97-106
    CrossrefPubMedGoogle Scholar
  • 42 Lim JH, Woo CH, Li JD. Critical role of type 1 plasminogen activator inhibitor (PAI-1) in early host defense against nontypeable Haemophilus influenzae (NTHi) infection. Biochem Biophys Res Commun 2011; 414 (01) 67-72
    CrossrefPubMedGoogle Scholar
  • 43 Renckens R, Pater JM, van der Poll T. Plasminogen activator inhibitor type-1-deficient mice have an enhanced IFN-gamma response to lipopolysaccharide and staphylococcal enterotoxin B. J Immunol 2006; 177 (11) 8171-8176
    CrossrefPubMedGoogle Scholar
  • 44 Whyte CS. All tangled up: interactions of the fibrinolytic and innate immune systems. Front Med (Lausanne) 2023; 10: 1212201
    CrossrefPubMedGoogle Scholar
  • 45 Uhl B, Zuchtriegel G, Puhr-Westerheide D. et al. Tissue plasminogen activator promotes postischemic neutrophil recruitment via its proteolytic and nonproteolytic properties. Arterioscler Thromb Vasc Biol 2014; 34 (07) 1495-1504
    CrossrefPubMedGoogle Scholar
  • 46 Medcalf RL, Keragala CB. Fibrinolysis: a primordial system linked to the immune response. Int J Mol Sci 2021; 22 (07) 3406
    CrossrefPubMedGoogle Scholar
  • 47 Borg RJ, Samson AL, Au AE. et al. Dendritic cell-mediated phagocytosis but not immune activation is enhanced by plasmin. PLoS One 2015; 10 (07) e0131216
    CrossrefPubMedGoogle Scholar
  • 48 Plug T, Meijers JC. Structure-function relationships in thrombin-activatable fibrinolysis inhibitor. J Thromb Haemost 2016; 14 (04) 633-644
    CrossrefPubMedGoogle Scholar
  • 49 Renckens R, Roelofs JJ, ter Horst SA. et al. Absence of thrombin-activatable fibrinolysis inhibitor protects against sepsis-induced liver injury in mice. J Immunol 2005; 175 (10) 6764-6771
    CrossrefPubMedGoogle Scholar
  • 50 Schrottmaier WC, Kral JB, Badrnya S, Assinger A. Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes. Thromb Haemost 2015; 114 (03) 478-489
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Mussbacher M, Pirabe A, Brunnthaler L, Schrottmaier WC, Assinger A. Horizontal microRNA transfer by platelets - evidence and implications. Front Physiol 2021; 12: 678362
    CrossrefPubMedGoogle Scholar
  • 52 Kral JB, Schrottmaier WC, Salzmann M, Assinger A. Platelet interaction with innate immune cells. Transfus Med Hemother 2016; 43 (02) 78-88
    CrossrefPubMedGoogle Scholar
  • 53 Senchenkova EY, Ansari J, Becker F. et al. Novel role for the AnxA1-Fpr2/ALX signaling axis as a key regulator of platelet function to promote resolution of inflammation. Circulation 2019; 140 (04) 319-335
    CrossrefPubMedGoogle Scholar
  • 54 Nishimura S, Nagasaki M, Kunishima S. et al. IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs. J Cell Biol 2015; 209 (03) 453-466
    CrossrefPubMedGoogle Scholar
  • 55 Petzold T, Zhang Z, Ballesteros I. et al. Neutrophil “plucking” on megakaryocytes drives platelet production and boosts cardiovascular disease. Immunity 2022; 55 (12) 2285-2299.e7
    CrossrefPubMedGoogle Scholar
  • 56 Hamad OA, Nilsson PH, Wouters D, Lambris JD, Ekdahl KN, Nilsson B. Complement component C3 binds to activated normal platelets without preceding proteolytic activation and promotes binding to complement receptor 1. J Immunol 2010; 184 (05) 2686-2692
    CrossrefPubMedGoogle Scholar
  • 57 Peerschke EI, Ghebrehiwet B. Platelet receptors for the complement component C1q: implications for hemostasis and thrombosis. Immunobiology 1998; 199 (02) 239-249
    CrossrefPubMedGoogle Scholar
  • 58 Arbesu I, Bucsaiova M, Fischer MB, Mannhalter C. Platelet-borne complement proteins and their role in platelet-bacteria interactions. J Thromb Haemost 2016; 14 (11) 2241-2252
    CrossrefPubMedGoogle Scholar
  • 59 Rawish E, Sauter M, Sauter R, Nording H, Langer HF. Complement, inflammation and thrombosis. Br J Pharmacol 2021; 178 (14) 2892-2904
    CrossrefPubMedGoogle Scholar
  • 60 Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD. Interactions between coagulation and complement–their role in inflammation. Semin Immunopathol 2012; 34 (01) 151-165
    CrossrefPubMedGoogle Scholar
  • 61 Ekdahl KN, Rönnblom L, Sturfelt G, Nilsson B. Increased phosphate content in complement component C3, fibrinogen, vitronectin, and other plasma proteins in systemic lupus erythematosus: covariation with platelet activation and possible association with thrombosis. Arthritis Rheum 1997; 40 (12) 2178-2186
    CrossrefPubMedGoogle Scholar
  • 62 Verschoor A, Langer HF. Crosstalk between platelets and the complement system in immune protection and disease. Thromb Haemost 2013; 110 (05) 910-919
    PubMedGoogle Scholar
  • 63 Amara U, Rittirsch D, Flierl M. et al. Interaction between the coagulation and complement system. Adv Exp Med Biol 2008; 632: 71-79
    PubMedGoogle Scholar
  • 64 Wojta J, Huber K, Valent P. New aspects in thrombotic research: complement induced switch in mast cells from a profibrinolytic to a prothrombotic phenotype. Pathophysiol Haemost Thromb 2003; 33 (5-6): 438-441
    CrossrefPubMedGoogle Scholar
  • 65 Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res 2016; 118 (09) 1392-1408
    CrossrefPubMedGoogle Scholar
  • 66 Wojta J, Kaun C, Zorn G. et al. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood 2002; 100 (02) 517-523
    CrossrefPubMedGoogle Scholar
  • 67 Langer F, Spath B, Fischer C. et al. Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase. Blood 2013; 121 (12) 2324-2335
    CrossrefPubMedGoogle Scholar
  • 68 Thomson AH. Human recombinant DNase in cystic fibrosis. J R Soc Med 1995; 88 (Suppl 25, Suppl 25): 24-29
    PubMedGoogle Scholar
  • 69 Holliday ZM, Earhart AP, Alnijoumi MM, Krvavac A, Allen LH, Schrum AG. Non-randomized trial of dornase alfa for acute respiratory distress syndrome secondary to Covid-19. Front Immunol 2021; 12: 714833
    CrossrefPubMedGoogle Scholar
  • 70 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107 (36) 15880-15885
    CrossrefPubMedGoogle Scholar
  • 71 Neeli I, Dwivedi N, Khan S, Radic M. Regulation of extracellular chromatin release from neutrophils. J Innate Immun 2009; 1 (03) 194-201
    CrossrefPubMedGoogle Scholar
  • 72 Huang H, Tohme S, Al-Khafaji AB. et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 2015; 62 (02) 600-614
    CrossrefPubMedGoogle Scholar
  • 73 Zheng W, Warner R, Ruggeri R. et al. PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis. J Pharmacol Exp Ther 2015; 353 (02) 288-298
    CrossrefPubMedGoogle Scholar
  • 74 Knight JS, Zhao W, Luo W. et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J Clin Invest 2013; 123 (07) 2981-2993
    CrossrefPubMedGoogle Scholar
  • 75 Prasannan N, Scully M. Novel antiplatelet strategies targeting VWF and GPIb. Platelets 2021; 32 (01) 42-46
    CrossrefPubMedGoogle Scholar
  • 76 Vilahur G, Gutiérrez M, Arzanauskaite M, Mendieta G, Ben-Aicha S, Badimon L. Intracellular platelet signalling as a target for drug development. Vascul Pharmacol 2018; 111: 22-25
    CrossrefPubMedGoogle Scholar
  • 77 McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol 2018; 15 (03) 181-191
    CrossrefPubMedGoogle Scholar
  • 78 Schrottmaier WC, Kral-Pointner JB, Salzmann M. et al. Platelet p110β mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia. Cell Rep 2022; 41 (06) 111614
    CrossrefPubMedGoogle Scholar
  • 79 Verhamme P, Yi BA, Segers A. et al; ANT-005 TKA Investigators. Abelacimab for prevention of venous thromboembolism. N Engl J Med 2021; 385 (07) 609-617
    CrossrefPubMedGoogle Scholar
  • 80 Labberton L, Kenne E, Long AT. et al. Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 2016; 7: 12616
    CrossrefPubMedGoogle Scholar
  • 81 Miller SE, Warach SJ. Evolving thrombolytics: from alteplase to tenecteplase. Neurotherapeutics 2023; 20 (03) 664-678
    CrossrefPubMedGoogle Scholar
  • 82 Hernández-Jiménez M, Abad-Santos F, Cotgreave I. et al. Safety and efficacy of ApTOLL in patients with ischemic stroke undergoing endovascular treatment: a phase 1/2 randomized clinical trial. JAMA Neurol 2023; 80 (08) 779-788
    CrossrefPubMedGoogle Scholar