Recent Advances in Immunothrombosis and Thromboinflammation

Abstract

Inflammation and thrombosis are traditionally considered two separate entities of acute host responses to barrier breaks. While inciting inflammatory responses is a prerequisite to fighting invading pathogens and subsequent restoration of tissue homeostasis, thrombus formation is a crucial step of the hemostatic response to prevent blood loss following vascular injury. Though originally designed to protect the host, excessive induction of either inflammatory signaling or thrombus formation and their reciprocal activation contribute to a plethora of disorders, including cardiovascular, autoimmune, and malignant diseases. In this state-of-the-art review, we summarize recent insights into the intricate interplay of inflammation and thrombosis. We focus on the protective aspects of immunothrombosis as well as evidence of detrimental sequelae of thromboinflammation, specifically regarding recent studies that elucidate its pathophysiology beyond coronavirus disease 2019 (COVID-19). We introduce recently identified molecular aspects of key cellular players like neutrophils, monocytes, and platelets that contribute to both immunothrombosis and thromboinflammation. Further, we describe the underlying mechanisms of activation involving circulating plasma proteins and immune complexes. We then illustrate how these factors skew the inflammatory state toward detrimental thromboinflammation across cardiovascular as well as septic and autoimmune inflammatory diseases. Finally, we discuss how the advent of new technologies and the integration with clinical data have been used to investigate the mechanisms and signaling cascades underlying immunothrombosis and thromboinflammation. This review highlights open questions that will need to be addressed by the field to translate our mechanistic understanding into clinically meaningful therapeutic targeting.

Keywords

inflammation - thrombosis - platelets - neutrophils - megakaryocytes

Authors' Contribution

R.K., C.G., and K.S. wrote the manuscript and designed the figures.

Publikationsverlauf

Eingereicht: 30. Dezember 2024

Angenommen: 22. Januar 2025

Artikel online veröffentlicht:
01. Mai 2025

• References

• 1 Stark K, Massberg S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Rev Cardiol 2021; 18 (09) 666-682
• 2 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359 (09) 938-949
• 3 Pisetsky DS. Pathogenesis of autoimmune disease. Nat Rev Nephrol 2023; 19 (08) 509-524
• 4 Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020; 383 (23) 2255-2273
• 5 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
• 6 Mackman N, Bergmeier W, Stouffer GA, Weitz JI. Therapeutic strategies for thrombosis: new targets and approaches. Nat Rev Drug Discov 2020; 19 (05) 333-352
• 7 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123 (18) 2768-2776
• 8 Stoll G, Nieswandt B. Thrombo-inflammation in acute ischaemic stroke - implications for treatment. Nat Rev Neurol 2019; 15 (08) 473-481
• 9 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
• 10 Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb Haemost 2011; 9 Suppl 1 (Suppl. 01) 182-188
• 11 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
• 12 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
• 13 Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133 (09) 906-918
• 14 Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers 2016; 2: 16045
• 15 Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers 2016; 2: 16037
• 16 Moore EE, Moore HB, Kornblith LZ. et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 2021; 7 (01) 30
• 17 Conway EM, Mackman N, Warren RQ. et al. Understanding COVID-19-associated coagulopathy. Nat Rev Immunol 2022; 22 (10) 639-649
• 18 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303 (5663) 1532-1535
• 19 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
• 20 Xu J, Zhang X, Pelayo R. et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15 (11) 1318-1321
• 21 Perdomo J, Leung HHL, Ahmadi Z. et al. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat Commun 2019; 10 (01) 1322
• 22 Meyers S, Lox M, Kraisin S. et al. Neutrophils protect against Staphylococcus aureus endocarditis progression independent of extracellular trap release. Arterioscler Thromb Vasc Biol 2023; 43 (02) 267-285
• 23 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
• 24 Jung CJ, Yeh CY, Hsu RB, Lee CM, Shun CT, Chia JS. Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets. Circulation 2015; 131 (06) 571-581
• 25 Burn GL, Foti A, Marsman G, Patel DF, Zychlinsky A. The neutrophil. Immunity 2021; 54 (07) 1377-1391
• 26 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
• 27 Pircher J, Czermak T, Ehrlich A. et al. Cathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation. Nat Commun 2018; 9 (01) 1523
• 28 Su M, Chen C, Li S. et al. Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis. Nat Cardiovasc Res 2022; 1 (08) 732-747
• 29 Carminita E, Crescence L, Brouilly N, Altié A, Panicot-Dubois L, Dubois C. DNAse-dependent, NET-independent pathway of thrombus formation in vivo. Proc Natl Acad Sci U S A 2021; 118 (28) e2100561118
• 30 Darbousset R, Thomas GM, Mezouar S. et al. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood 2012; 120 (10) 2133-2143
• 31 Noubouossie DF, Whelihan MF, Yu YB. et al. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood 2017; 129 (08) 1021-1029
• 32 Jiao H, Jiang D, Hu X. et al. Mitocytosis, a migrasome-mediated mitochondrial quality-control process. Cell 2021; 184 (11) 2896-2910.e13
• 33 Jiang D, Jiao L, Li Q. et al. Neutrophil-derived migrasomes are an essential part of the coagulation system. Nat Cell Biol 2024; 26 (07) 1110-1123
• 34 Whitefoot-Keliin KM, Benaske CC, Allen ER. et al. In response to bacteria, neutrophils release extracellular vesicles capable of initiating thrombin generation through DNA-dependent and independent pathways. J Leukoc Biol 2024; 116 (06) 1223-1236
• 35 Dhanesha N, Nayak MK, Doddapattar P. et al. Targeting myeloid-cell specific integrin α9β1 inhibits arterial thrombosis in mice. Blood 2020; 135 (11) 857-861
• 36 Nayak L, Sweet DR, Thomas A. et al. A targetable pathway in neutrophils mitigates both arterial and venous thrombosis. Sci Transl Med 2022; 14 (660) eabj7465
• 37 Abu-Fanne R, Stepanova V, Litvinov RI. et al. Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability. Blood 2019; 133 (05) 481-493
• 38 Novotny J, Oberdieck P, Titova A. et al. Thrombus NET content is associated with clinical outcome in stroke and myocardial infarction. Neurology 2020; 94 (22) e2346-e2360
• 39 Denorme F, Portier I, Rustad JL. et al. Neutrophil extracellular traps regulate ischemic stroke brain injury. J Clin Invest 2022; 132 (10) e154225
• 40 Cao J, Roth S, Zhang S. et al; DEMDAS Study Group. DNA-sensing inflammasomes cause recurrent atherosclerotic stroke. Nature 2024; 633 (8029) 433-441
• 41 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
• 42 Silvestre-Roig C, Braster Q, Wichapong K. et al. Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death. Nature 2019; 569 (7755) 236-240
• 43 Pekayvaz K, Kilani B, Joppich M. et al. Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis and correlate with thrombus resolution. Immunity 2025; (e-pub ahead of print)
• 44 Ahamed J, Versteeg HH, Kerver M. et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A 2006; 103 (38) 13932-13937
• 45 Disse J, Petersen HH, Larsen KS. et al. The endothelial protein C receptor supports tissue factor ternary coagulation initiation complex signaling through protease-activated receptors. J Biol Chem 2011; 286 (07) 5756-5767
• 46 Liang HP, Kerschen EJ, Hernandez I. et al. EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice. Blood 2015; 125 (18) 2845-2854
• 47 Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296 (5574) 1880-1882
• 48 Riewald M, Ruf W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc Natl Acad Sci U S A 2001; 98 (14) 7742-7747
• 49 Kral-Pointner JB, Haider P, Szabo PL. et al. Reduced monocyte and neutrophil infiltration and activation by P-Selectin/CD62P inhibition enhances thrombus resolution in mice. Arterioscler Thromb Vasc Biol 2024; 44 (04) 954-968
• 50 Rayes J, Brill A. Hot under the clot: venous thrombogenesis is an inflammatory process. Blood 2024; 144 (05) 477-489
• 51 Hottz ED, Azevedo-Quintanilha IG, Palhinha L. et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136 (11) 1330-1341
• 52 Rolling CC, Sowa MA, Wang TT. et al. P2Y12 inhibition suppresses proinflammatory platelet-monocyte interactions. Thromb Haemost 2023; 123 (02) 231-244
• 53 Tutwiler V, Madeeva D, Ahn HS. et al. Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia. Blood 2016; 127 (04) 464-472
• 54 Li C, Ture SK, Nieves-Lopez B. et al. Thrombocytopenia independently leads to changes in monocyte immune function. Circ Res 2024; 134 (08) 970-986
• 55 Marx C, Novotny J, Salbeck D. et al. Eosinophil-platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps. Blood 2019; 134 (21) 1859-1872
• 56 Uderhardt S, Ackermann JA, Fillep T. et al. Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. J Exp Med 2017; 214 (07) 2121-2138
• 57 Mueller TT, Pilartz M, Thakur M. et al. Mutual regulation of CD4⁺ T cells and intravascular fibrin in infections. Haematologica 2024; 109 (08) 2487-2499
• 58 Dou HWR, Tavallaie M, Xiao T. et al. Hematopoietic and eosinophil-specific LNK(SH2B3) deficiency promote eosinophilia and arterial thrombosis. Blood 2024; 143 (17) 1758-1772
• 59 Rothmeier AS, Marchese P, Petrich BG. et al. Caspase-1-mediated pathway promotes generation of thromboinflammatory microparticles. J Clin Invest 2015; 125 (04) 1471-1484
• 60 Gaertner F, Ishikawa-Ankerhold H, Stutte S. et al. Plasmacytoid dendritic cells control homeostasis of megakaryopoiesis. Nature 2024; 631 (8021) 645-653
• 61 Lan W, Li J, Ye Z. et al. A subset of megakaryocytes regulates development of hematopoietic stem cell precursors. EMBO J 2024; 43 (09) 1722-1739
• 62 Bruns I, Lucas D, Pinho S. et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 2014; 20 (11) 1315-1320
• 63 Koupenova M, Livada AC, Morrell CN. Platelet and megakaryocyte roles in innate and adaptive immunity. Circ Res 2022; 130 (02) 288-308
• 64 Nicolai L, Pekayvaz K, Massberg S. Platelets: Orchestrators of immunity in host defense and beyond. Immunity 2024; 57 (05) 957-972
• 65 Kaiser R, Anjum A, Kammerer L. et al. Mechanosensing via a GpIIb/Src/14-3-3ζ axis critically regulates platelet migration in vascular inflammation. Blood 2023; 141 (24) 2973-2992
• 66 Nicolai L, Kaiser R, Escaig R. et al. Single platelet and megakaryocyte morpho-dynamics uncovered by multicolor reporter mouse strains in vitro and in vivo. . Haematologica 2022; 107 (07) 1669-1680
• 67 Nicolai L, Schiefelbein K, Lipsky S. et al. Vascular surveillance by haptotactic blood platelets in inflammation and infection. Nat Commun 2020; 11 (01) 5778
• 68 Gaertner F, Ahmad Z, Rosenberger G. et al. Migrating platelets are mechano-scavengers that collect and bundle bacteria. Cell 2017; 171 (06) 1368-1382.e23
• 69 Nagy Z, Vögtle T, Geer MJ. et al. The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions. Blood 2019; 133 (04) 331-343
• 70 Chandraratne S, von Bruehl ML, Pagel JI. et al. Critical role of platelet glycoprotein ibα in arterial remodeling. Arterioscler Thromb Vasc Biol 2015; 35 (03) 589-597
• 71 Petzold T, Ruppert R, Pandey D. et al. β1 integrin-mediated signals are required for platelet granule secretion and hemostasis in mouse. Blood 2013; 122 (15) 2723-2731
• 72 Massberg S, Schürzinger K, Lorenz M. et al. Platelet adhesion via glycoprotein IIb integrin is critical for atheroprogression and focal cerebral ischemia: an in vivo study in mice lacking glycoprotein IIb. Circulation 2005; 112 (08) 1180-1188
• 73 Massberg S, Gawaz M, Grüner S. et al. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo. J Exp Med 2003; 197 (01) 41-49
• 74 Massberg S, Brand K, Grüner S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196 (07) 887-896
• 75 Massberg S, Enders G, Matos FC. et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood 1999; 94 (11) 3829-3838
• 76 Mayer K, Hein-Rothweiler R, Schüpke S. et al. Efficacy and safety of Revacept, a novel lesion-directed competitive antagonist to platelet glycoprotein VI, in patients undergoing elective percutaneous coronary intervention for stable ischemic heart disease: the randomized, double-blind, placebo-controlled ISAR-PLASTER phase 2 trial. JAMA Cardiol 2021; 6 (07) 753-761
• 77 Sung PS, Huang TF, Hsieh SL. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nat Commun 2019; 10 (01) 2402
• 78 Yakovenko O, Nunez J, Bensing B. et al. Serine-rich repeat adhesins mediate shear-enhanced streptococcal binding to platelets. Infect Immun 2018; 86 (06) e00160-18
• 79 Miajlovic H, Zapotoczna M, Geoghegan JA, Kerrigan SW, Speziale P, Foster TJ. Direct interaction of iron-regulated surface determinant IsdB of Staphylococcus aureus with the GPIIb/IIIa receptor on platelets. Microbiology (Reading) 2010; 156 (Pt 3): 920-928
• 80 Chaipan C, Soilleux EJ, Simpson P. et al. DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J Virol 2006; 80 (18) 8951-8960
• 81 Koupenova M, Corkrey HA, Vitseva O. et al. The role of platelets in mediating a response to human influenza infection. Nat Commun 2019; 10 (01) 1780
• 82 Boilard E, Paré G, Rousseau M. et al. Influenza virus H1N1 activates platelets through FcγRIIA signaling and thrombin generation. Blood 2014; 123 (18) 2854-2863
• 83 Cloutier N, Allaeys I, Marcoux G. et al. Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. Proc Natl Acad Sci U S A 2018; 115 (07) E1550-E1559
• 84 Palankar R, Kohler TP, Krauel K, Wesche J, Hammerschmidt S, Greinacher A. Platelets kill bacteria by bridging innate and adaptive immunity via platelet factor 4 and FcγRIIA. J Thromb Haemost 2018; 16 (06) 1187-1197
• 85 Koupenova M, Corkrey HA, Vitseva O. et al. SARS-CoV-2 initiates programmed cell death in platelets. Circ Res 2021; 129 (06) 631-646
• 86 Liesenborghs L, Meyers S, Lox M. et al. Staphylococcus aureus endocarditis: distinct mechanisms of bacterial adhesion to damaged and inflamed heart valves. Eur Heart J 2019; 40 (39) 3248-3259
• 87 Oury C, Meyers S, Jacques N. et al. Protective effect of ticagrelor against infective endocarditis induced by virulent Staphylococcus aureus in mice. JACC Basic Transl Sci 2023; 8 (11) 1439-1453
• 88 Claushuis TAM, de Vos AF, Nieswandt B. et al. Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria. Blood 2018; 131 (08) 864-876
• 89 Rayes J, Watson SP, Nieswandt B. Functional significance of the platelet immune receptors GPVI and CLEC-2. J Clin Invest 2019; 129 (01) 12-23
• 90 Rayes J, Jadoui S, Lax S. et al. The contribution of platelet glycoprotein receptors to inflammatory bleeding prevention is stimulus and organ dependent. Haematologica 2018; 103 (06) e256-e258
• 91 Kaiser R, Escaig R, Erber J, Nicolai L. Neutrophil-platelet interactions as novel treatment targets in cardiovascular disease. Front Cardiovasc Med 2022; 8: 824112
• 92 Sreeramkumar V, Adrover JM, Ballesteros I. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 2014; 346 (6214) 1234-1238
• 93 Mauler M, Herr N, Schoenichen C. et al. Platelet serotonin aggravates myocardial ischemia/reperfusion injury via neutrophil degranulation. Circulation 2019; 139 (07) 918-931
• 94 De Giovanni M, Tam H, Valet C, Xu Y, Looney MR, Cyster JG. GPR35 promotes neutrophil recruitment in response to serotonin metabolite 5-HIAA. Cell 2022; 185 (05) 815-830.e19
• 95 De Giovanni M, Dang EV, Chen KY, An J, Madhani HD, Cyster JG. Platelets and mast cells promote pathogenic eosinophil recruitment during invasive fungal infection via the 5-HIAA-GPR35 ligand-receptor system. Immunity 2023; 56 (07) 1548-1560.e5
• 96 Poli V, Di Gioia M, Sola-Visner M. et al. Inhibition of transcription factor NFAT activity in activated platelets enhances their aggregation and exacerbates gram-negative bacterial septicemia. Immunity 2022; 55 (02) 224-236.e5
• 97 Chen Z, Luo J, Li J. et al. Intestinal IL-33 promotes platelet activity for neutrophil recruitment during acute inflammation. Blood 2022; 139 (12) 1878-1891
• 98 Althaus K, Marini I, Zlamal J. et al. Antibody-induced procoagulant platelets in severe COVID-19 infection. Blood 2021; 137 (08) 1061-1071
• 99 Nicolai L, Leunig A, Pekayvaz K. et al. Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration. Blood 2022; 140 (05) 478-490
• 100 Greinacher A, Selleng K, Palankar R. et al. Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. Blood 2021; 138 (22) 2256-2268
• 101 Guo L, Shen S, Rowley JW. et al. Platelet MHC class I mediates CD8+ T-cell suppression during sepsis. Blood 2021; 138 (05) 401-416
• 102 Schuhmann MK, Stoll G, Bieber M. et al. CD84 links T cell and platelet activity in cerebral thrombo-inflammation in acute stroke. Circ Res 2020; 127 (08) 1023-1035
• 103 Colicchia M, Schrottmaier WC, Perrella G. et al. S100A8/A9 drives the formation of procoagulant platelets through GPIbα. Blood 2022; 140 (24) 2626-2643
• 104 Leung HHL, Perdomo J, Ahmadi Z. et al. NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia. Nat Commun 2022; 13 (01) 5206
• 105 Denorme F, Manne BK, Portier I. et al. Platelet necrosis mediates ischemic stroke outcome in mice. Blood 2020; 135 (06) 429-440
• 106 Middleton EA, He XY, Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020; 136 (10) 1169-1179
• 107 Nicolai L, Leunig A, Brambs S. et al. Immunothrombotic dysregulation in covid-19 pneumonia is associated with respiratory failure and coagulopathy. Circulation 2020; 142 (12) 1176-1189
• 108 Yang M, Jiang H, Ding C. et al. STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion. Immunity 2023; 56 (05) 1013-1026.e6
• 109 Pelzl L, Singh A, Funk J. et al. Antibody-mediated procoagulant platelet formation in COVID-19 is AKT dependent. J Thromb Haemost 2021; 20: 387-398
• 110 Althaus K, Möller P, Uzun G. et al. Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia. Haematologica 2021; 106 (08) 2170-2179
• 111 Baig AA, Haining EJ, Geuss E. et al. TMEM16F-mediated platelet membrane phospholipid scrambling is critical for hemostasis and thrombosis but not thromboinflammation in mice-brief report. Arterioscler Thromb Vasc Biol 2016; 36 (11) 2152-2157
• 112 Hua VM, Abeynaike L, Glaros E. et al. Necrotic platelets provide a procoagulant surface during thrombosis. Blood 2015; 126 (26) 2852-2862
• 113 Jobe SM, Wilson KM, Leo L. et al. Critical role for the mitochondrial permeability transition pore and cyclophilin D in platelet activation and thrombosis. Blood 2008; 111 (03) 1257-1265
• 114 Kaiser R, Dewender R, Mulkers M. et al. Procoagulant platelet activation promotes venous thrombosis. Blood 2024; 144 (24) 2546-2553
• 115 Schaubaecher JB, Smiljanov B, Haring F. et al. Procoagulant platelets promote immune evasion in triple-negative breast cancer. Blood 2024; 144 (02) 216-226
• 116 Kaiser R, Escaig R, Kranich J. et al. Procoagulant platelet sentinels prevent inflammatory bleeding through GPIIBIIIA and GPVI. Blood 2022; 140 (02) 121-139
• 117 Duerschmied D, Suidan GL, Demers M. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013; 121 (06) 1008-1015
• 118 Brill A, Fuchs TA, Chauhan AK. et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 2011; 117 (04) 1400-1407
• 119 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
• 120 Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson SP. Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation. Blood 2011; 117 (19) 5198-5206
• 121 Riedl J, Flynn KC, Raducanu A. et al. Lifeact mice for studying F-actin dynamics. Nat Methods 2010; 7 (03) 168-169
• 122 Stark K, Kilani B, Stockhausen S. et al. Antibodies and complement are key drivers of thrombosis. Immunity 2024; 57 (09) 2140-2156.e10
• 123 Khandelwal S, Barnes A, Rauova L. et al. Complement mediates binding and procoagulant effects of ultralarge HIT immune complexes. Blood 2021; 138 (21) 2106-2116
• 124 Weckbach LT, Schweizer L, Kraechan A. et al; EMB Study Group. Association of complement and MAPK activation with SARS-CoV-2-associated myocardial inflammation. JAMA Cardiol 2022; 7 (03) 286-297
• 125 Skendros P, Mitsios A, Chrysanthopoulou A. et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis. J Clin Invest 2020; 130 (11) 6151-6157
• 126 Høiland II, Liang RA, Braekkan SK. et al. Complement activation assessed by the plasma terminal complement complex and future risk of venous thromboembolism. J Thromb Haemost 2019; 17 (06) 934-943
• 127 Sauter RJ, Sauter M, Reis ES. et al. Functional relevance of the anaphylatoxin receptor c3ar for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis. Circulation 2018; 138 (16) 1720-1735
• 128 Ponomaryov T, Payne H, Fabritz L, Wagner DD, Brill A. Mast cells granular contents are crucial for deep vein thrombosis in mice. Circ Res 2017; 121 (08) 941-950
• 129 Thienel M, Müller-Reif JB, Zhang Z. et al. Immobility-associated thromboprotection is conserved across mammalian species from bear to human. Science 2023; 380 (6641) 178-187
• 130 Bourne JH, Colicchia M, Di Y. et al. Heme induces human and mouse platelet activation through C-type-lectin-like receptor-2. Haematologica 2021; 106 (02) 626-629
• 131 Bourne JH, Perrella G, El-Awaisi J. et al. Hydroxychloroquine inhibits hemolysis-induced arterial thrombosis ex vivo and improves lung perfusion in hemin-treated mice. J Thromb Haemost 2024; 22 (07) 2018-2026
• 132 El-Awaisi J, Perrella G, Mayor N. et al. Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice. bioRxiv 2024; 2024 .2005.2004.592537
• 133 Yong J, Toh CH. Rethinking coagulation: from enzymatic cascade and cell-based reactions to a convergent model involving innate immune activation. Blood 2023; 142 (25) 2133-2145
• 134 Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010; 115 (06) 1121-1130
• 135 Garlapati V, Molitor M, Michna T. et al. Targeting myeloid cell coagulation signaling blocks MAP kinase/TGF-β1-driven fibrotic remodeling in ischemic heart failure. J Clin Invest 2023; 133 (04) e156436
• 136 Simats A, Zhang S, Messerer D. et al. Innate immune memory after brain injury drives inflammatory cardiac dysfunction. Cell 2024; 187 (17) 4637-4655.e26
• 137 Silva LM, Doyle AD, Greenwell-Wild T. et al. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier. Science 2021; 374 (6575) eabl5450
• 138 Ryu JK, Yan Z, Montano M. et al. Fibrin drives thromboinflammation and neuropathology in COVID-19. Nature 2024; 633 (8031) 905-913
• 139 Beck S, Öftering P, Li R. et al. Platelet glycoprotein V spatio-temporally controls fibrin formation. Nat Cardiovasc Res 2023; 2 (04) 368-382
• 140 Alard J-E, Ortega-Gomez A, Wichapong K. et al. Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5. Sci Transl Med 2015; 7 (317) 317ra196
• 141 Vajen T, Koenen RR, Werner I. et al. Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis. Sci Rep 2018; 8 (01) 10647
• 142 Grommes J, Alard JE, Drechsler M. et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med 2012; 185 (06) 628-636
• 143 Garcia-Romo GS, Caielli S, Vega B. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med 2011; 3 (73) 73ra20
• 144 Leffler J, Martin M, Gullstrand B. et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol 2012; 188 (07) 3522-3531
• 145 Lood C, Blanco LP, Purmalek MM. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 2016; 22 (02) 146-153
• 146 Müller-Calleja N, Grunz K, Nguyen TS. et al. Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development. Blood 2024; 143 (12) 1167-1180
• 147 Manoharan J, Rana R, Kuenze G. et al. Tissue factor binds to and inhibits interferon-α receptor 1 signaling. Immunity 2024; 57 (01) 68-85.e11
• 148 McDonald B, Davis RP, Kim SJ. et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 2017; 129 (10) 1357-1367
• 149 de Stoppelaar SF, van't Veer C, Claushuis TA, Albersen BJ, Roelofs JJ, van der Poll T. Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice. Blood 2014; 124 (25) 3781-3790
• 150 Dhanesha N, Jain M, Doddapattar P, Undas A, Chauhan AK. Cellular fibronectin promotes deep vein thrombosis in diet-induced obese mice. J Thromb Haemost 2021; 19 (03) 814-821
• 151 Schattner M. Platelet TLR4 at the crossroads of thrombosis and the innate immune response. J Leukoc Biol 2019; 105 (05) 873-880
• 152 Modin D, Claggett B, Sindet-Pedersen C. et al. Acute COVID-19 and the incidence of ischemic stroke and acute myocardial infarction. Circulation 2020; 142 (21) 2080-2082
• 153 Al-Ani F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID-19 infection. A scoping review. Thromb Res 2020; 192: 152-160
• 154 Nicolai L, Leunig A, Brambs S. et al. Vascular neutrophilic inflammation and immunothrombosis distinguish severe COVID-19 from influenza pneumonia. J Thromb Haemost 2020; 19: 574-581
• 155 Ackermann M, Verleden SE, Kuehnel M. et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020; 383 (02) 120-128
• 156 Kaiser R, Leunig A, Pekayvaz K. et al. Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19. JCI Insight 2021; 6 (18) e150862
• 157 Ahamed J, Laurence J. Long COVID endotheliopathy: hypothesized mechanisms and potential therapeutic approaches. J Clin Invest 2022; 132 (15) e161167
• 158 Fogarty H, Ward SE, Townsend L. et al; Irish COVID-19 Vasculopathy Study (iCVS) Investigators. Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. J Thromb Haemost 2022; 20 (10) 2429-2438
• 159 Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med 2022; 28 (03) 583-590
• 160 Stanger L, Yamaguchi A, Holinstat M. Antiplatelet strategies: past, present, and future. J Thromb Haemost 2023; 21 (12) 3317-3328
• 161 Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021; 384 (22) 2092-2101
• 162 von Hundelshausen P, Lorenz R, Siess W, Weber C. Vaccine-induced immune thrombotic thrombocytopenia (VITT): targeting pathomechanisms with Bruton tyrosine kinase inhibitors. Thromb Haemost 2021; 121 (11) 1395-1399
• 163 Weber C, von Hundelshausen P, Siess W. VITT after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021; 385 (23) 2203-2204
• 164 Goldmann L, Duan R, Kragh T. et al. Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?. Blood Adv 2019; 3 (23) 4021-4033
• 165 Pekayvaz K, Leunig A, Kaiser R. et al. Protective immune trajectories in early viral containment of non-pneumonic SARS-CoV-2 infection. Nat Commun 2022; 13 (01) 1018
• 166 Mishra A, Malik R, Hachiya T. et al; COMPASS Consortium, INVENT Consortium, Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, Estonian Biobank, PRECISE4Q Consortium, FinnGen Consortium, NINDS Stroke Genetics Network (SiGN), MEGASTROKE Consortium, SIREN Consortium, China Kadoorie Biobank Collaborative Group, VA Million Veteran Program, International Stroke Genetics Consortium (ISGC), Biobank Japan, CHARGE Consortium, GIGASTROKE Consortium. Stroke genetics informs drug discovery and risk prediction across ancestries. Nature 2022; 611 (7934) 115-123
• 167 Combes AJ, Courau T, Kuhn NF. et al; UCSF COMET Consortium. Global absence and targeting of protective immune states in severe COVID-19. Nature 2021; 591 (7848) 124-130
• 168 Kaiser R, Leunig A, Pekayvaz K. et al. Self-sustaining interleukin-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19. JCI Insight 2021; 6: e150862
• 169 Pekayvaz K, Losert C, Knottenberg V. et al. Multiomic analyses uncover immunological signatures in acute and chronic coronary syndromes. Nat Med 2024; 30 (06) 1696-1710
• 170 Schulte-Schrepping J, Reusch N, Paclik D. et al; Deutsche COVID-19 OMICS Initiative (DeCOI). Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 2020; 182 (06) 1419-1440.e23
• 171 Tiedt S, Prestel M, Malik R. et al. RNA-Seq identifies circulating miR-125a-5p, miR-125b-5p, and miR-143-3p as potential biomarkers for acute ischemic stroke. Circ Res 2017; 121 (08) 970-980
• 172 Koyama S, Ito K, Terao C. et al. Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat Genet 2020; 52 (11) 1169-1177
• 173 Kathiresan S, Voight BF, Purcell S. et al; Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009; 41 (03) 334-341
• 174 Fuster JJ, MacLauchlan S, Zuriaga MA. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017; 355 (6327) 842-847
• 175 Jaiswal S, Natarajan P, Silver AJ. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017; 377 (02) 111-121
• 176 Liu W, Pircher J, Schuermans A. et al. Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk. Blood 2024; 143 (15) 1539-1550
• 177 Liu W, Hardaway BD, Kim E. et al. Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice. J Clin Invest 2024; 135 (01) e182939
• 178 Dou H, Kotini A, Liu W. et al. Oxidized phospholipids promote NETosis and arterial thrombosis in LNK(SH2B3) deficiency. Circulation 2021; 144 (24) 1940-1954
• 179 Kaiser R, Leunig A, Pekayvaz K. et al. Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19. JCI Insight 2021; 6 (18) e150862
• 180 Schuermans A, Pournamdari AB, Lee J. et al. Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction. Nat Cardiovasc Res 2024; 3 (12) 1516-1530
• 181 Thibord F, Klarin D, Brody JA. et al; Global Biobank Meta-Analysis Initiative; Estonian Biobank Research Team; 23andMe Research Team; Biobank Japan; CHARGE Hemostasis Working Group. Cross-ancestry investigation of venous thromboembolism genomic predictors. Circulation 2022; 146 (16) 1225-1242 W
• 182 Gottschlich A, Thomas M, Grünmeier R. et al. Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia. Nat Biotechnol 2023; 41 (11) 1618-1632
• 183 Kaiser R, Gold C, Joppich M. et al. Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment. Sci Adv 2024; 10 (12) eadl1710
• 184 Cruz MA, Bohinc D, Andraska EA. et al. Nanomedicine platform for targeting activated neutrophils and neutrophil-platelet complexes using an α₁-antitrypsin-derived peptide motif. Nat Nanotechnol 2022; 17 (09) 1004-1014
• 185 Kim C, Kim H, Sim WS. et al. Spatiotemporal control of neutrophil fate to tune inflammation and repair for myocardial infarction therapy. Nat Commun 2024; 15 (01) 8481
• 186 Sekhon UDS, Swingle K, Girish A. et al. Platelet-mimicking procoagulant nanoparticles augment hemostasis in animal models of bleeding. Sci Transl Med 2022; 14 (629) eabb8975
• 187 Girish A, Jolly K, Alsaadi N. et al. Platelet-inspired intravenous nanomedicine for injury-targeted direct delivery of thrombin to augment hemostasis in coagulopathies. ACS Nano 2022; 16 (10) 16292-16313
• 188 Raghunathan S, Rayes J, Sen Gupta A. Platelet-inspired nanomedicine in hemostasis thrombosis and thromboinflammation. J Thromb Haemost 2022; 20 (07) 1535-1549
• 189 Leberzammer J, Agten SM, Blanchet X. et al. Targeting platelet-derived CXCL12 impedes arterial thrombosis. Blood 2022; 139 (17) 2691-2705
• 190 Momin N, Pabel S, Rudra A. et al. Therapeutic Spp1 silencing in TREM2⁺ cardiac macrophages suppresses atrial fibrillation. bioRxiv 2024; 2024 .2008.2010.607461
• 191 Beck C, Ramanujam D, Vaccarello P. et al. Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage. Nat Commun 2023; 14 (01) 4564
• 192 Ridker PM, Everett BM, Thuren T. et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
• 193 Mazighi M, Köhrmann M, Lemmens R. et al; ACTIMIS Study Group. Safety and efficacy of platelet glycoprotein VI inhibition in acute ischaemic stroke (ACTIMIS): a randomised, double-blind, placebo-controlled, phase 1b/2a trial. Lancet Neurol 2024; 23 (02) 157-167
• 194 Navarro S, Talucci I, Göb V. et al. The humanized platelet glycoprotein VI Fab inhibitor EMA601 protects from arterial thrombosis and ischaemic stroke in mice. Eur Heart J 2024; 45 (43) 4582-4597
• 195 van Eeuwijk JM, Stegner D, Lamb DJ. et al. The novel oral Syk inhibitor, Bl1002494, protects mice from arterial thrombosis and thromboinflammatory brain infarction. Arterioscler Thromb Vasc Biol 2016; 36 (06) 1247-1253
• 196 Tardif JC, Kouz S, Waters DD. et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019; 381 (26) 2497-2505
• 197 Gullotta GS, De Feo D, Friebel E. et al. Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology. Nat Immunol 2023; 24 (06) 925-940
• 198 Cervia-Hasler C, Brüningk SC, Hoch T. et al. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science 2024; 383 (6680) eadg7942