Adaptive Immunity in Immunothrombosis

David Noone; Roger J.S. Preston; Gemma Leon

doi:10.1055/a-2722-7189

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost
DOI: 10.1055/a-2722-7189

Review Article

Adaptive Immunity in Immunothrombosis

Authors

David Noone

¹Irish Centre of Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Roger J.S. Preston

¹Irish Centre of Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
Gemma Leon

¹Irish Centre of Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland

Abstract

Thrombosis is a comorbidity associated with autoimmune, allergic, and infectious conditions; however, the mechanistic basis for this elevated risk is poorly understood. The simultaneous activation of the immune and coagulation systems to assist in response to injury and efficient pathogen clearance, termed immunothrombosis, is typically described as a bidirectional interaction between the innate immune and coagulation systems. More recently, however, data have emerged highlighting the involvement of adaptive immune cells in this process. In this review, we discuss the role of adaptive immune cells in clot formation and resolution, and explore how the adaptive immune system modulates procoagulant activity in autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus, and graft versus host disease; allergic disorders, such as dermatitis and asthma; infectious diseases, such as coronavirus disease 2019 (COVID-19) and human immunodeficiency virus (HIV); and ischemic conditions such as myocardial infarction and stroke.

Keywords

immunothrombosis - thromboinflammation - coagulation - fibrinolysis - adaptive immunity - T cells - B cells - lymphocytes

Full Text

References

References
1 Klavina PA, Leon G, Curtis AM, Preston RJS. Dysregulated haemostasis in thrombo-inflammatory disease. Clin Sci (Lond) 2022; 136 (24) 1809-1829
2 Scridon A. Platelets and their role in hemostasis and thrombosis-from physiology to pathophysiology and therapeutic implications. Int J Mol Sci 2022; 23 (21) 12772
3 Heestermans M, Naudin C, Mailer RK. et al. Identification of the factor XII contact activation site enables sensitive coagulation diagnostics. Nat Commun 2021; 12 (01) 5596
4 Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol 2019; 39 (03) 331-338
5 Morrissey JH, Choi SH, Smith SA. Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation. Blood 2012; 119 (25) 5972-5979
6 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139 (06) 1143-1156
7 Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler Thromb Vasc Biol 2008; 28 (03) 387-391
8 Frick IM, Akesson P, Herwald H. et al. The contact system–a novel branch of innate immunity generating antibacterial peptides. EMBO J 2006; 25 (23) 5569-5578
9 Herwald H, Mörgelin M, Björck L. Contact activation by pathogenic bacteria: a virulence mechanism contributing to the pathophysiology of sepsis. Scand J Infect Dis 2003; 35 (09) 604-607
10 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13 (01) 34-45
11 Aristizábal B, González Á. Innate immune system. In: Autoimmunity: From Bench to Bedside [Internet]. El Rosario University Press; 2013. . Accessed September 8, 2025 at: https://www.ncbi.nlm.nih.gov/books/NBK459455/
12 Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol 2015; 16 (04) 343-353
13 Janeway Jr CA, Travers P, Walport M. et al. Immunobiology: The Immune System in Health and Disease. 5th edn.. Garland Sciences; 2001. . Accessed October 23, 2025 at: https://www.ncbi.nlm.nih.gov/books/NBK10757/
14 Orita Y, Sato Y, Kimura N. et al. Characteristic ultrasound features of mucosa-associated lymphoid tissue lymphoma of the salivary and thyroid gland. Acta Otolaryngol 2013; 134: 93-99 . Accessed September 18, 2024 at: https://www.tandfonline.com/doi/full/10.3109/00016489.2013.831994
15 Ruddle NH, Akirav EM. Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J Immunol 2009; 183 (04) 2205-2212
16 Cupedo T, Jansen W, Kraal G, Mebius RE. Induction of secondary and tertiary lymphoid structures in the skin. Immunity 2004; 21 (05) 655-667
17 Schuh JCL. Mucosa-associated lymphoid tissue and tertiary lymphoid structures of the eye and ear in laboratory animals. Toxicol Pathol 2021; 49: 472-482 . Accessed September 17, 2024 at: https://pubmed.ncbi.nlm.nih.gov/33252012/#
18 Knop E, Knop N, Pleyer U. Clinical aspects of MALT. In: Krieglstein GK, Weinreb RN, Pleyer U, Mondino B. eds. Uveitis and Immunological Disorders. Springer; 2005: 67-89
19 Chatzileontiadou DSM, Sloane H, Nguyen AT, Gras S, Grant EJ. The many faces of CD4⁺ T cells: Immunological and structural characteristics. Int J Mol Sci 2020; 22 (01) 73
20 Appay V, Zaunders JJ, Papagno L. et al. Characterization of CD4(+) CTLs ex vivo. J Immunol 2002; 168 (11) 5954-5958
21 Xie Y, Akpinarli A, Maris C. et al. Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med 2010; 207 (03) 651-667
22 Poncette L, Bluhm J, Blankenstein T. The role of CD4 T cells in rejection of solid tumors. Curr Opin Immunol 2022; 74: 18-24
23 Quezada SA, Simpson TR, Peggs KS. et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 2010; 207 (03) 637-650
24 Peeters LM, Vanheusden M, Somers V. et al. Cytotoxic CD4+ T cells drive multiple sclerosis progression. Front Immunol 2017; 8: 1160
25 Raveney BJE, Sato W, Takewaki D. et al. Involvement of cytotoxic Eomes-expressing CD4+ T cells in secondary progressive multiple sclerosis. Proc Natl Acad Sci U S A 2021; 118: e2021818118 . Accessed January 28, 2025 at: https://pubmed.ncbi.nlm.nih.gov/33836594/
26 Zhu Y, Feng Y, Liu H. et al. CD4+CD29+T cells are blamed for the persistent inflammatory response in ulcerative colitis. Int J Clin Exp Pathol 2015; 8 (03) 2627-2637
27 Yang D, Tian Z, Zhang M. et al. NKG2D⁺CD4⁺ T cells kill regulatory T cells in a NKG2D-NKG2D ligand-dependent manner in systemic lupus erythematosus. Sci Rep 2017; 7 (01) 1288
28 Namekawa T, Wagner UG, Goronzy JJ, Weyand CM. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum 1998; 41 (12) 2108-2116
29 Duftner C, Goldberger C, Falkenbach A. et al. Prevalence, clinical relevance and characterization of circulating cytotoxic CD4+CD28- T cells in ankylosing spondylitis. Arthritis Res Ther 2003; 5 (05) R292-R300
30 Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. B Cells and Antibodies. In: Molecular Biology of the Cell. NCBI Bookshelf; . Accessed March 20, 2025 at: https://www.ncbi.nlm.nih.gov/books/NBK26884/
31 LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008; 112: 1570-1580 . Accessed March 20, 2025 at: https://ashpublications.org/blood/article/112/5/1570/25424/B-lymphocytes-how-they-develop-and-function
32 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
33 Luther N, Shahneh F, Brähler M. et al. Innate effector-memory T-cell activation regulates post-thrombotic vein wall inflammation and thrombus resolution. Circ Res 2016; 119 (12) 1286-1295
34 Nosaka M, Ishida Y, Kimura A. et al. Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice. J Clin Invest 2011; 121 (07) 2911-2920
35 Senchenkova EY, Russell J, Yildirim A, Granger DN, Gavins FNE. Novel role of T cells and IL-6 (interleukin-6) in angiotensin II-induced microvascular dysfunction. Hypertension 2019; 73 (04) 829-838
36 Senchenkova EY, Russell J, Kurmaeva E, Ostanin D, Granger DN. Role of T lymphocytes in angiotensin II-mediated microvascular thrombosis. Hypertension 2011; 58 (05) 959-965
37 Ou Q, Power R, Griffin MD. Revisiting regulatory T cells as modulators of innate immune response and inflammatory diseases. Front Immunol 2023; 14: 1287465
38 Shahneh F, Grill A, Klein M. et al. Specialized regulatory T cells control venous blood clot resolution through SPARC. Blood 2021; 137 (11) 1517-1526
39 Risk of Venous and Arterial Thromboembolic Events in Patients Receiving Targeted Anti-cancer Therapy – A Nationwide Cohort Study. ISTH Congress Abstracts. Accessed November 2, 2022 at: https://abstracts.isth.org/abstract/risk-of-venous-and-arterial-thromboembolic-events-in-patients-receiving-targeted-anti-cancer-therapy-a-nationwide-cohort-study/
40 Wang TF, Khorana AA, Carrier M. Thrombotic complications associated with immune checkpoint inhibitors. Cancers (Basel) 2021; 13 (18) 4606
41 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112 (09) 682-698
42 Nossent JC, Keen HI, Preen DB, Inderjeeth CA. Long-term incidence, risk factors and complications for venous thromboembolism in patients with systemic lupus erythematosus. Lupus 2024; 33 (08) 787-796
43 Amoroso A, Mitterhofer AP, Del Porto F. et al. Antibodies to anionic phospholipids and anti-beta2-GPI: association with thrombosis and thrombocytopenia in systemic lupus erythematosus. Hum Immunol 2003; 64 (02) 265-273
44 Kappelman MD, Horvath-Puho E, Sandler RS. et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011; 60 (07) 937-943
45 Grainge MJ, West J, Card TR. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet 2010; 375 (9715): 657-663
46 Gerber DE, Segal JB, Levy MY, Kane J, Jones RJ, Streiff MB. The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: Implications for VTE prevention. Blood 2008; 112 (03) 504-510
47 Kekre N, Kim HT, Ho VT. et al. Venous thromboembolism is associated with graft-versus-host disease and increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Haematologica 2017; 102 (07) 1185-1191
48 de Lima M, Anagnostopoulos A, Munsell M. et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: Dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood 2004; 104 (03) 865-872
49 Russell JA, Duan Q, Chaudhry MA. et al. Transplantation from matched siblings using once-daily intravenous busulfan/fludarabine with thymoglobulin: a myeloablative regimen with low nonrelapse mortality in all but older patients with high-risk disease. Biol Blood Marrow Transplant 2008; 14 (08) 888-895
50 Maris MB, Sandmaier BM, Storer BE. et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant 2006; 12 (04) 454-465
51 Gonsalves A, Carrier M, Wells PS, McDiarmid SA, Huebsch LB, Allan DS. Incidence of symptomatic venous thromboembolism following hematopoietic stem cell transplantation. J Thromb Haemost 2008; 6 (09) 1468-1473
52 Azık F, Gökçebay DG, Tavil B, Işık P, Tunç B, Uçkan D. Venous thromboembolism after allogeneic pediatric hematopoietic stem cell transplantation: A single-center study. Turk J Haematol 2015; 32 (03) 228-233
53 Labrador J, González-Rivero J, Monroy R. et al. Management patterns and outcomes in symptomatic venous thromboembolism following allogeneic hematopoietic stem cell transplantation. A 15-years experience at a single center. Thromb Res 2016; 142: 52-56
54 Mukhopadhyay S, Gabre J, Chabasse C, Bromberg JS, Antalis TM, Sarkar R. Depletion of CD4 and CD8 positive T cells impairs venous thrombus resolution in mice. Int J Mol Sci 2020; 21 (05) 1650
55 Tormey VJ, Faul J, Leonard C, Burke CM, Dilmec A, Poulter LW. T-cell cytokines may control the balance of functionally distinct macrophage populations. Immunology 1997; 90 (04) 463-469
56 Hasselwander S, Xia N, Mimmler M. et al. B lymphocyte-deficiency in mice promotes venous thrombosis. Heliyon 2022; 8 (11) e11740
57 Stark K, Kilani B, Stockhausen S. et al. Antibodies and complement are key drivers of thrombosis. Immunity 2024; 57 (09) 2140-2156.e10
58 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
59 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
60 Aggarwal R, Charles-Schoeman C, Schessl J. et al; ProDERM Trial Group. Trial of intravenous immune globulin in dermatomyositis. N Engl J Med 2022; 387 (14) 1264-1278
61 Ammann EM, Jones MP, Link BK. et al. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Blood 2016; 127 (02) 200-207
62 Daniel GW, Menis M, Sridhar G. et al. Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion 2012; 52 (10) 2113-2121
63 Menis M, Sridhar G, Selvam N. et al. Hyperimmune globulins and same-day thrombotic adverse events as recorded in a large healthcare database during 2008-2011. Am J Hematol 2013; 88 (12) 1035-1040
64 Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol 2012; 23 (07) 1672-1679
65 Marcoux G, Laroche A, Espinoza Romero J, Boilard E. Role of platelets and megakaryocytes in adaptive immunity. Platelets 2021; 32 (03) 340-351
66 Gray D, Siepmann K, Wohlleben G. CD40 ligation in B cell activation, isotype switching and memory development. Semin Immunol 1994; 6 (05) 303-310
67 Renshaw BR, Fanslow III WC, Armitage RJ. et al. Humoral immune responses in CD40 ligand-deficient mice. J Exp Med 1994; 180 (05) 1889-1900
68 Elzey BD, Tian J, Jensen RJ. et al. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 2003; 19 (01) 9-19
69 Hasegawa S, Pawankar R, Suzuki K. et al. Functional expression of the high affinity receptor for IgE (FcepsilonRI) in human platelets and its' intracellular expression in human megakaryocytes. Blood 1999; 93 (08) 2543-2551
70 Capron M, Jouault T, Prin L. et al. Functional study of a monoclonal antibody to IgE Fc receptor (Fc epsilon R2) of eosinophils, platelets, and macrophages. J Exp Med 1986; 164 (01) 72-89
71 Joseph M, Gounni AS, Kusnierz JP. et al. Expression and functions of the high-affinity IgE receptor on human platelets and megakaryocyte precursors. Eur J Immunol 1997; 27 (09) 2212-2218
72 Qian K, Xie F, Gibson AW, Edberg JC, Kimberly RP, Wu J. Functional expression of IgA receptor FcalphaRI on human platelets. J Leukoc Biol 2008; 84 (06) 1492-1500
73 Karas SP, Rosse WF, Kurlander RJ. Characterization of the IgG-Fc receptor on human platelets. Blood 1982; 60 (06) 1277-1282
74 Arman M, Krauel K. Human platelet IgG Fc receptor FcγRIIA in immunity and thrombosis. J Thromb Haemost 2015; 13 (06) 893-908
75 Czapiga M, Kirk AD, Lekstrom-Himes J. Platelets deliver costimulatory signals to antigen-presenting cells: a potential bridge between injury and immune activation. Exp Hematol 2004; 32 (02) 135-139
76 Silva-Cardoso SC, Affandi AJ, Spel L. et al. CXCL4 exposure potentiates TLR-driven polarization of human monocyte-derived dendritic cells and increases stimulation of T cells. J Immunol 2017; 199 (01) 253-262
77 Han P, Hanlon D, Arshad N. et al. Platelet P-selectin initiates cross-presentation and dendritic cell differentiation in blood monocytes. Sci Adv 2020; 6 (11) eaaz1580
78 Katoh N, Soga F, Nara T. et al. Effect of serotonin on the differentiation of human monocytes into dendritic cells. Clin Exp Immunol 2006; 146 (02) 354-361
79 Spectre G, Zhu L, Ersoy M. et al. Platelets selectively enhance lymphocyte adhesion on subendothelial matrix under arterial flow conditions. Thromb Haemost 2012; 108 (02) 328-337
80 Pitchford SC, Momi S, Giannini S. et al. Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood 2005; 105 (05) 2074-2081
81 Scherlinger M, Guillotin V, Douchet I. et al. Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis. Sci Transl Med 2021; 13 (600) eabi4994
82 Gerdes N, Zhu L, Ersoy M. et al. Platelets regulate CD4⁺ T-cell differentiation via multiple chemokines in humans. Thromb Haemost 2011; 106 (02) 353-362
83 Song Y, Li J, Wu Y. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct Target Ther 2024; 9 (01) 263
84 El Jurdi N, Elhusseini H, Beckman J. et al. High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group. Blood Cancer J 2021; 11 (05) 96
85 Leon G, Klavina PA, Rehill AM. et al. Tissue factor-dependent colitogenic CD4⁺ T cell thrombogenicity is regulated by activated protein C signalling. Nat Commun 2025; 16 (01) 1677
86 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
87 Dieudonné Y, Guffroy A, Poindron V. et al. B cells in primary antiphospholipid syndrome: Review and remaining challenges. Autoimmun Rev 2021; 20 (05) 102798
88 Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018; 16 (01) 26-42
89 IFFCA. What is IBD? | efcca.org. European Federation of Crohns & Ulcerative Colitis Associations. April 4, 2024. Accessed February 14, 2024 at: https://efcca.org/content/what-ibd
90 Solem CA, Loftus EVJ, Tremaine WJ, Sandborn WJ. Venous thromboembolism in inflammatory bowel disease. Am J Gastroenterol 2004; 99 (01) 97-101
91 Novacek G, Weltermann A, Sobala A. et al. Inflammatory bowel disease is a risk factor for recurrent venous thromboembolism. Gastroenterology 2010; 139 (03) 779-787 , 787.e1
92 Alkim H, Ayaz S, Alkim C, Ulker A, Sahin B. Continuous active state of coagulation system in patients with nonthrombotic inflammatory bowel disease. Clin Appl Thromb Hemost 2011; 17 (06) 600-604
93 Anthoni C, Russell J, Wood KC. et al. Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis. J Exp Med 2007; 204 (07) 1595-1601
94 Kondreddy V, Keshava S, Esmon CT, Pendurthi UR, Rao LVM. A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis. Sci Rep 2020; 10 (01) 20569
95 Vetrano S, Ploplis VA, Sala E. et al. Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation. Proc Natl Acad Sci U S A 2011; 108 (49) 19830-19835
96 Scaldaferri F, Sans M, Vetrano S. et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 2007; 117 (07) 1951-1960
97 Wang Y, Luo L, Braun OÖ. et al. Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Sci Rep 2018; 8 (01) 4020
98 Moschonas I, Tselepis A. Platelet-derived microparticles induce the formation of neutrophil extracellular traps. Atherosclerosis 2018; 275: e106
99 Deutschmann A, Schlagenhauf A, Leschnik B, Hoffmann KM, Hauer A, Muntean W. Increased procoagulant function of microparticles in pediatric inflammatory bowel disease: role in increased thrombin generation. J Pediatr Gastroenterol Nutr 2013; 56 (04) 401-407
100 Palkovits J, Novacek G, Kollars M. et al. Tissue factor exposing microparticles in inflammatory bowel disease. J Crohns Colitis 2013; 7 (03) 222-229
101 Castro-Dopico T, Colombel JF, Mehandru S. Targeting B cells for inflammatory bowel disease treatment: back to the future. Curr Opin Pharmacol 2020; 55: 90-98
102 Martin JC, Chang C, Boschetti G. et al. Single-cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 2019; 178 (06) 1493-1508.e20
103 Quinton JF, Sendid B, Reumaux D. et al. Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 1998; 42 (06) 788-791
104 Choung RS, Princen F, Stockfisch TP. et al; PREDICTS Study Team. Serologic microbial associated markers can predict Crohn's disease behaviour years before disease diagnosis. Aliment Pharmacol Ther 2016; 43 (12) 1300-1310
105 Adams RJ, Heazlewood SP, Gilshenan KS, O'Brien M, McGuckin MA, Florin THJ. IgG antibodies against common gut bacteria are more diagnostic for Crohn's disease than IgG against mannan or flagellin. Am J Gastroenterol 2008; 103 (02) 386
106 Uo M, Hisamtasu T, Miyoshi J. et al. Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation. Gut 2013; 62: 1734-1744 . Accessed March 21, 2025 at: https://gut.bmj.com/content/62/12/1734.short?casa_token=aYFY-a2SRuIAAAAA:BK47Q3CiVhUVL21ZUIuLj82c_SuzUSqOO4QYJYV5rzkOZgW8e6Y-zqwBTLs2sTrSe2TiP1z2jfaF
107 Lagrange J, Lacolley P, Wahl D, Peyrin-Biroulet L, Regnault V. Shedding light on hemostasis in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 2021; 19 (06) 1088-1097.e6
108 Aichbichler BW, Petritsch W, Reicht GA. et al. Anti-cardiolipin antibodies in patients with inflammatory bowel disease. Dig Dis Sci 1999; 44 (04) 852-856
109 Sipeki N, Davida L, Palyu E. et al. Prevalence, significance and predictive value of antiphospholipid antibodies in Crohn's disease. World J Gastroenterol 2015; 21 (22) 6952-6964
110 Zeng L, Yan Z, Ding S, Xu K, Wang L. Endothelial injury, an intriguing effect of methotrexate and cyclophosphamide during hematopoietic stem cell transplantation in mice. Transplant Proc 2008; 40 (08) 2670-2673
111 Swystun LL, Mukherjee S, Levine M, Liaw PC. The chemotherapy metabolite acrolein upregulates thrombin generation and impairs the protein C anticoagulant pathway in animal-based and cell-based models. J Thromb Haemost 2011; 9 (04) 767-775
112 Yu J, May L, Milsom C. et al. Contribution of host-derived tissue factor to tumor neovascularization. Arterioscler Thromb Vasc Biol 2008; 28 (11) 1975-1981
113 Johannesdottir SA, Horváth-Puhó E, Dekkers OM. et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013; 173 (09) 743-752
114 Sinha RK, Flynn R, Zaiken M. et al. Activated protein C ameliorates chronic graft-versus-host disease by PAR1-dependent biased cell signaling on T cells. Blood 2019; 134 (09) 776-781
115 Ranjan S, Goihl A, Kohli S. et al. Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. Nat Commun 2017; 8 (01) 311
116 Rachakonda SP, Penack O, Dietrich S. et al. Single-nucleotide polymorphisms within the thrombomodulin gene (THBD) predict mortality in patients with graft-versus-host disease. J Clin Oncol 2014; 32 (30) 3421-3427
117 Luft T, Dietrich S, Falk C. et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood 2011; 118 (06) 1685-1692
118 Andrulis M, Dietrich S, Longerich T. et al. Loss of endothelial thrombomodulin predicts response to steroid therapy and survival in acute intestinal graft-versus-host disease. Haematologica 2012; 97 (11) 1674-1677
119 Dietrich S, Falk CS, Benner A. et al. Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment. Biol Blood Marrow Transplant 2013; 19 (01) 22-27
120 Wang J, Boerma M, Fu Q, Hauer-Jensen M. Significance of endothelial dysfunction in the pathogenesis of early and delayed radiation enteropathy. World J Gastroenterol 2007; 13 (22) 3047-3055
121 ClinicalTrials.gov. Study Details | Safety Evaluation of 3K3A-APC in Ischemic Stroke. Accessed March 22, 2025 at: https://clinicaltrials.gov/study/NCT02222714?term=3K3A-APC&rank=2
122 ClinicalTrials.gov. Study Details | Efficacy and Safety Evaluation of 3K3A-APC in Ischemic Stroke. Accessed March 22, 2025 at: https://clinicaltrials.gov/study/NCT05484154?term=3K3A-APC&rank=1
123 ClinicalTrials.gov. Study Details | 3K3A-APC for Treatment of Amyotrophic Lateral Sclerosis (ALS). Accessed March 22, 2025 at: https://clinicaltrials.gov/study/NCT05039268?term=NCT05039268&rank=1
124 Biedermann BC, Sahner S, Gregor M. et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet 2002; 359 (9323): 2078-2083
125 Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, von Bergwelt-Baildon MS. The role of B cells in the pathogenesis of graft-versus-host disease. Blood 2009; 114 (24) 4919-4927
126 Zhang C, Todorov I, Zhang Z. et al. Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood 2006; 107 (07) 2993-3001
127 Patriarca F, Skert C, Sperotto A. et al. The development of autoantibodies after allogeneic stem cell transplantation is related with chronic graft-vs-host disease and immune recovery. Exp Hematol 2006; 34 (03) 389-396
128 Siegel CH, Sammaritano LR. Systemic lupus erythematosus: A review. JAMA 2024; 331 (17) 1480-1491
129 Gustafsson J, Gunnarsson I, Börjesson O. et al. Predictors of the first cardiovascular event in patients with systemic lupus erythematosus - a prospective cohort study. Arthritis Res Ther 2009; 11 (06) R186
130 Ohl K, Tenbrock K. Inflammatory cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2011; 2011: 432595
131 Rauch J, Salem D, Subang R, Kuwana M, Levine JS. β2- I-reactive T cells in autoimmune disease. Front Immunol 2018; 9: 2836
132 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
133 Sisó A, Ramos-Casals M, Bové A. et al. Previous antimalarial therapy in patients diagnosed with lupus nephritis: influence on outcomes and survival. Lupus 2008; 17 (04) 281-288
134 Petri M, Konig MF, Li J, Goldman DW. Association of higher hydroxychloroquine blood levels with reduced thrombosis risk in systemic lupus erythematosus. Arthritis Rheumatol 2021; 73 (06) 997-1004
135 Wallace DJ. Does hydroxychloroquine sulfate prevent clot formation in systemic lupus erythematosus?. Arthritis Rheum 1987; 30 (12) 1435-1436
136 Kaiser R, Cleveland CM, Criswell LA. Risk and protective factors for thrombosis in systemic lupus erythematosus: results from a large, multi-ethnic cohort. Ann Rheum Dis 2009; 68 (02) 238-241
137 Jung H, Bobba R, Su J. et al. The protective effect of antimalarial drugs on thrombovascular events in systemic lupus erythematosus. Arthritis Rheum 2010; 62 (03) 863-868
138 Hsu CY, Lin YS, Su YJ. et al. Effect of long-term hydroxychloroquine on vascular events in patients with systemic lupus erythematosus: a database prospective cohort study. Rheumatology (Oxford) 2017; 56 (12) 2212-2221
139 Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis 2022; 14: 17 59720X211073001
140 Chung WS, Lin CL, Ho FM. et al. Asthma increases pulmonary thromboembolism risk: a nationwide population cohort study. Eur Respir J 2014; 43 (03) 801-807
141 Schouten M, VAN DE Pol MA, Levi M, VAN DER Poll T, VAN DER Zee JS. Early activation of coagulation after allergen challenge in patients with allergic asthma. J Thromb Haemost 2009; 7 (09) 1592-1594
142 Mitchel JA, Antoniak S, Lee JH. et al. IL-13 augments compressive stress-induced tissue factor expression in human airway epithelial cells. Am J Respir Cell Mol Biol 2016; 54 (04) 524-531
143 Asayama K, Kobayashi T, D'Alessandro-Gabazza CN. et al. Protein S protects against allergic bronchial asthma by modulating Th1/Th2 balance. Allergy 2020; 75 (09) 2267-2278
144 Yuda H, Adachi Y, Taguchi O. et al. Activated protein C inhibits bronchial hyperresponsiveness and Th2 cytokine expression in mice. Blood 2004; 103 (06) 2196-2204
145 Matsumoto T, Matsushima Y, Toda M. et al. Activated protein C modulates the proinflammatory activity of dendritic cells. J Asthma Allergy 2015; 8: 29-37
146 Xue M, Lin H, Zhao R, Fryer C, March L, Jackson CJ. Activated protein C protects against murine contact dermatitis by suppressing protease-activated receptor 2. Int J Mol Sci 2022; 23 (01) 516
147 Filuta AL, Amezcua P, Ruff BP. et al. The key roles of thrombin and fibrinogen in human infant and mice atopic dermatitis models. Allergy 2024; 79 (01) 239-242
148 Fleischer MI, Röhrig N, Raker VK. et al. Protease- and cell type-specific activation of protease-activated receptor 2 in cutaneous inflammation. J Thromb Haemost 2022; 20 (12) 2823-2836
149 Rad F, Dabbagh A, Dorgalaleh A, Biswas A. The relationship between inflammatory cytokines and coagulopathy in patients with COVID-19. J Clin Med 2021; 10 (09) 2020
150 Eljilany I, Elzouki AN. D-Dimer, fibrinogen, and IL-6 in COVID-19 patients with suspected venous thromboembolism: a narrative review. Vasc Health Risk Manag 2020; 16: 455-462
151 Mukhopadhyay S, Sinha S, Mohapatra SK. Analysis of transcriptomic data sets supports the role of IL-6 in NETosis and immunothrombosis in severe COVID-19. BMC Genom Data 2021; 22 (01) 49
152 Nguyen N, Nguyen H, Ukoha C. et al. Relation of interleukin-6 levels in COVID-19 patients with major adverse cardiac events. Proc Bayl Univ Med Cent 2021; 35 (01) 6-9
153 Dechamps M, De Poortere J, Martin M. et al. Inflammation-induced coagulopathy substantially differs between COVID-19 and septic shock: a prospective observational study. Front Med (Lausanne) 2022; 8: 780750
154 Liu H, Guo N, Zheng Q. et al. Association of interleukin-6, ferritin, and lactate dehydrogenase with venous thromboembolism in COVID-19: a systematic review and meta-analysis. BMC Infect Dis 2024; 24 (01) 324
155 Agrawal A, Bajaj S, Bhagat U. et al. Incidence, predictors, and outcomes of venous and arterial thrombosis in COVID-19: A nationwide inpatient analysis. Heart Lung Circ 2024; 33 (11) 1563-1573
156 Piazza G, Campia U, Hurwitz S. et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol 2020; 76 (18) 2060-2072
157 Hill JB, Garcia D, Crowther M. et al. Frequency of venous thromboembolism in 6513 patients with COVID-19: a retrospective study. Blood Adv 2020; 4 (21) 5373-5377
158 Langnau C, Rohlfing AK, Gekeler S. et al. Platelet activation and plasma levels of furin are associated with prognosis of patients with coronary artery disease and COVID-19. Arterioscler Thromb Vasc Biol 2021; 41 (06) 2080-2096
159 Liu H, Hu T, Zhang C. et al. Mechanisms of COVID-19 thrombosis in an inflammatory environment and new anticoagulant targets. Am J Transl Res 2021; 13 (05) 3925-3941
160 Zuo Y, Yalavarthi S, Shi H. et al. Neutrophil extracellular traps in COVID-19. JCI Insight 2020; 5 (11) e138999
161 Rohlfing AK, Rath D, Geisler T, Gawaz M. Platelets and COVID-19. Hamostaseologie 2021; 41 (05) 379-385
162 Bergamaschi L, Mescia F, Turner L. et al; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity 2021; 54 (06) 1257-1275.e8
163 Paletta A, Di Diego García F, Varese A. et al. Platelets modulate CD4⁺ T-cell function in COVID-19 through a PD-L1 dependent mechanism. Br J Haematol 2022; 197 (03) 283-292
164 Santa Cruz A, Mendes-Frias A, Azarias-da-Silva M. et al. Post-acute sequelae of COVID-19 is characterized by diminished peripheral CD8⁺β7 integrin⁺ T cells and anti-SARS-CoV-2 IgA response. Nat Commun 2023; 14 (01) 1772
165 Peluso MJ, Lu S, Tang AF. et al. Markers of immune activation and inflammation in individuals with postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection. J Infect Dis 2021; 224 (11) 1839-1848
166 Yin K, Peluso MJ, Luo X. et al. Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to SARS-CoV-2. Nat Immunol 2024; 25 (02) 218-225
167 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
168 Perkins MV, Joseph SB, Dittmer DP, Mackman N. cardiovascular disease and thrombosis in HIV infection. Arterioscler Thromb Vasc Biol 2023; 43 (02) 175-191
169 Green SA, Smith M, Hasley RB. et al. Activated platelet-T-cell conjugates in peripheral blood of patients with HIV infection: coupling coagulation/inflammation and T cells. AIDS 2015; 29 (11) 1297-1308
170 Dai XP, Wu FY, Cui C. et al. Increased platelet-CD4⁺ T cell aggregates are correlated with HIV-1 permissiveness and CD4⁺ T cell loss. Front Immunol 2021; 12: 799124
171 Schirone L, Forte M, D'Ambrosio L. et al. An overview of the molecular mechanisms associated with myocardial ischemic injury: State of the art and translational perspectives. Cells 2022; 11 (07) 1165
172 Liu Y, Li L, Wang Z, Zhang J, Zhou Z. Myocardial ischemia-reperfusion injury; Molecular mechanisms and prevention. Microvasc Res 2023; 149: 104565
173 Silvis MJM, Kaffka Genaamd Dengler SE, Odille CA. et al. Damage-associated molecular patterns in myocardial infarction and heart transplantation: The road to translational success. Front Immunol 2020; 11: 599511
174 Hausenloy DJ, Botker HE, Engstrom T. et al. Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: Trials and tribulations. Eur Heart J 2017; 38 (13) 935-941
175 Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Invest 2013; 123 (01) 92-100
176 Planas AM. Role of immune cells migrating to the ischemic brain. Stroke 2018; 49 (09) 2261-2267
177 Francisco J, Del Re DP. Inflammation in myocardial ischemia/reperfusion injury: underlying mechanisms and therapeutic potential. Antioxidants 2023; 12 (11) 1944
178 Kleinschnitz C, Schwab N, Kraft P. et al. Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 2010; 115 (18) 3835-3842
179 Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and interferon-γ in ischemic stroke. Circulation 2006; 113 (17) 2105-2112
180 Yang Z, Day YJ, Toufektsian MC. et al. Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation 2006; 114 (19) 2056-2064
181 Ren X, Akiyoshi K, Dziennis S. et al. Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke. J Neurosci 2011; 31 (23) 8556-8563
182 Liesz A, Suri-Payer E, Veltkamp C. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15 (02) 192-199
183 Ren X, Akiyoshi K, Vandenbark AA, Hurn PD, Offner H. CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke. Metab Brain Dis 2011; 26 (01) 87-90
184 Schuhmann MK, Kraft P, Stoll G. et al. CD28 superagonist-mediated boost of regulatory T cells increases thrombo-inflammation and ischemic neurodegeneration during the acute phase of experimental stroke. J Cereb Blood Flow Metab 2015; 35 (01) 6-10
185 Weirather J, Hofmann UDW, Beyersdorf N. et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 2014; 115 (01) 55-67
186 Saxena A, Dobaczewski M, Rai V. et al. Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am J Physiol Heart Circ Physiol 2014; 307 (08) H1233-H1242
187 Zacchigna S, Martinelli V, Moimas S. et al. Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction. Nat Commun 2018; 9 (01) 2432
188 Rieckmann M, Delgobo M, Gaal C. et al. Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses. J Clin Invest 2019; 129 (11) 4922-4936
189 Thachil J, Toh CH, Levi M, Watson HG. The withdrawal of Activated Protein C from the use in patients with severe sepsis and DIC [Amendment to the BCSH guideline on disseminated intravascular coagulation]. Br J Haematol 2012; 157 (04) 493-494
190 Mosnier LO, Gale AJ, Yegneswaran S, Griffin JH. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 2004; 104 (06) 1740-1744
191 Han MH, Hwang SI, Roy DB. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008; 451 (7182): 1076-1081
192 Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory effects of heparin and its derivatives: a systematic review. Adv Pharmacol Sci 2015; 2015: 507151
193 Kashiwakura Y, Kojima H, Kanno Y, Hashiguchi M, Kobata T. Heparin affects the induction of regulatory T cells independent of anti-coagulant activity and suppresses allogeneic immune responses. Clin Exp Immunol 2020; 202 (01) 119-135
194 Lider O, Baharav E, Mekori YA. et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins. J Clin Invest 1989; 83 (03) 752-756
195 Hecht I, Hershkoviz R, Shivtiel S. et al. Heparin-disaccharide affects T cells: inhibition of NF-kappaB activation, cell migration, and modulation of intracellular signaling. J Leukoc Biol 2004; 75 (06) 1139-1146
196 Mondal S, Jana M, Dasarathi S, Roy A, Pahan K. Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11-mediated protection of regulatory T cells. Sci Signal 2018; 11 (558) eaar8278
197 Rudick RA, Sandrock A. Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother 2004; 4 (04) 571-580
198 Guagnozzi D, Caprilli R. Natalizumab in the treatment of Crohn's disease. Biologics 2008; 2 (02) 275-284
199 Becker K, Kindrick D, Relton J, Harlan J, Winn R. Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 2001; 32 (01) 206-211
200 Relton JK, Sloan KE, Frew EM, Whalley ET, Adams SP, Lobb RR. Inhibition of alpha4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats. Stroke 2001; 32 (01) 199-205
201 Llovera G, Hofmann K, Roth S. et al. Results of a preclinical randomized controlled multicenter trial (pRCT): Anti-CD49d treatment for acute brain ischemia. Sci Transl Med 2015; 7 (299) 299ra121
202 Langhauser F, Kraft P, Göb E. et al. Blocking of α4 integrin does not protect from acute ischemic stroke in mice. Stroke 2014; 45 (06) 1799-1806
203 Elkins J, Veltkamp R, Montaner J. et al. Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 2017; 16 (03) 217-226
204 Kraft P, Göb E, Schuhmann MK. et al. FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection. Stroke 2013; 44 (11) 3202-3210
205 Shichita T, Sugiyama Y, Ooboshi H. et al. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat Med 2009; 15 (08) 946-950
206 Fu Y, Zhang N, Ren L. et al. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc Natl Acad Sci U S A 2014; 111 (51) 18315-18320
207 Zhu Z, Fu Y, Tian D. et al. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 2015; 132 (12) 1104-1112
208 Tian DC, Shi K, Zhu Z. et al. Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke by promoting anterograde reperfusion and retrograde collateral flow. Ann Neurol 2018; 84 (05) 717-728