Abstract
The coagulation cascade and immune system are intricately linked, highly regulated and respond cooperatively in response to injury and infection. Increasingly, evidence of hyper-coagulation has been associated with autoimmune disorders, including multiple sclerosis (MS). The pathophysiology of MS includes immune cell activation and recruitment to the central nervous system (CNS) where they degrade myelin sheaths, leaving neuronal axons exposed to damaging inflammatory mediators. Breakdown of the blood-brain barrier (BBB) facilitates the entry of peripheral immune cells. Evidence of thrombin activity has been identified within the CNS of MS patients and studies using animal models of experimental autoimmune encephalomyelitis (EAE), suggest increased thrombin generation and activity may play a role in the pathogenesis of MS as well as inhibit remyelination processes. Thrombin is a serine protease capable of cleaving multiple substrates, including protease activated receptors (PARs), fibrinogen, and protein C. Cleavage of all three of these substrates represent pathways through which thrombin activity may exert immuno-regulatory effects and regulate permeability of the BBB during MS and EAE. In this review, we summarize evidence that thrombin activity directly, through PARs, and indirectly, through fibrin formation and activation of protein C influences neuro-immune responses associated with MS and EAE pathology.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
References
Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K (2007) The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 204:571–582. https://doi.org/10.1084/jem.20061931
Ahmed O, Geraldes R, DeLuca GC, Palace J (2019) Multiple sclerosis and the risk of systemic venous thrombosis: A systematic review. Mult Scler Relat Disord 27:424–430. https://doi.org/10.1016/j.msard.2018.10.008
Akassoglou K, Adams R.A., Bauer J., Mercado P., Tseveleki V., Lassmann H., Probert L., Strickland S. (2004) Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc Natl Acad Sci U S A 101:6698–6703. https://doi.org/10.1073/pnas.0303859101
Alabanza LM, Bynoe MS (2012) Thrombin induces an inflammatory phenotype in a human brain endothelial cell line. J Neuroimmunol 245:48–55. https://doi.org/10.1016/j.jneuroim.2012.02.004
Alabanza LM, Esmon NL, Esmon CT, Bynoe MS (2013) Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells. J Immunol 191:3764–3777. https://doi.org/10.4049/jimmunol.1202556
Bar-Or A et al (2008) Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 63:395–400. https://doi.org/10.1002/ana.21363
Bartha K, Dömötör E, Lanza F, Adam-Vizi V, Machovich R (2000) Identification of thrombin receptors in rat brain capillary endothelial cells. J Cereb Blood Flow Metab 20:175–182. https://doi.org/10.1097/00004647-200001000-00022
Baum CL, Arpey CJ (2005) Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatol Surg 31:674–686; discussion 686. https://doi.org/10.1111/j.1524-4725.2005.31612
Beilin O, Karussis DM, Korczyn AD, Gurwitz D, Aronovich R, Hantai D, Grigoriadis N, Mizrachi-Kol R, Chapman J (2005) Increased thrombin inhibition in experimental autoimmune encephalomyelitis. J Neurosci Res 79:351–359. https://doi.org/10.1002/jnr.20270
Berny MA, White TC, Tucker EI, Bush-Pelc LA, Di Cera E, Gruber A, McCarty OJ (2008) Thrombin mutant W215A/E217A acts as a platelet GPIb antagonist. Arterioscler Thromb Vasc Biol 28:329–334. https://doi.org/10.1161/ATVBAHA.107.156273
Berny-Lang MA et al (2011) Thrombin mutant W215A/E217A treatment improves neurological outcome and reduces cerebral infarct size in a mouse model of ischemic stroke. Stroke 42:1736–1741. https://doi.org/10.1161/STROKEAHA.110.603811
Boggio E et al (2016) Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo. J Immunol Res 2016:9345495. https://doi.org/10.1155/2016/9345495
Brailoiu E, Shipsky MM, Yan G, Abood ME, Brailoiu GC (2017) Mechanisms of modulation of brain microvascular endothelial cells function by thrombin. Brain Res 1657:167–175. https://doi.org/10.1016/j.brainres.2016.12.011
Brueckmann M et al (2004) Activated protein C inhibits the release of macrophage inflammatory protein-1-alpha from THP-1 cells and from human monocytes. Cytokine 26:106–113. https://doi.org/10.1016/j.cyto.2004.01.004
Burda JE, Radulovic M, Yoon H, Scarisbrick IA (2013) Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. Glia 61:1456–1470. https://doi.org/10.1002/glia.22534
Burzynski LC et al (2019) The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin. Immunity 50:1033–1042.e1036. https://doi.org/10.1016/j.immuni.2019.03.003
Cantwell AM, Di Cera E (2000) Rational design of a potent anticoagulant thrombin. J Biol Chem 275:39827–39830. https://doi.org/10.1074/jbc.C000751200
Chang A, Nishiyama A, Peterson J, Prineas J, Trapp BD (2000) NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J Neurosci 20:6404–6412
Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173. https://doi.org/10.1056/NEJMoa010994
Choi SH, Lee DY, Kim SU, Jin BK (2005) Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: role of microglial NADPH oxidase. J Neurosci 25:4082–4090. https://doi.org/10.1523/JNEUROSCI.4306-04.2005
Choi CI, Yoon H, Drucker KL, Langley MR, Kleppe L, Scarisbrick IA (2018) The Thrombin Receptor Restricts Subventricular Zone Neural Stem Cell Expansion and Differentiation. Sci Rep 8:9360. https://doi.org/10.1038/s41598-018-27613-9
Chu AJ (2011) Tissue factor, blood coagulation, and beyond: an overview. Int J Inflamm 2011:367284. https://doi.org/10.4061/2011/367284
Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264. https://doi.org/10.1038/35025229
Courville CB (1959) The effects of heparin in acute exacerbations of multiple sclerosis. Observations and deductions. Bull Los Angel Neurol Soc 24:187–196
Culpepper WJ et al (2019) Validation of an algorithm for identifying MS cases in administrative health claims datasets. Neurology 92:e1016–e1028. https://doi.org/10.1212/WNL.0000000000007043
Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ (2010) The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 115:1121–1130. https://doi.org/10.1182/blood-2009-09-201616
Davalos D, Akassoglou K (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34:43–62. https://doi.org/10.1007/s00281-011-0290-8
Davalos D et al (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 3:1227. https://doi.org/10.1038/ncomms2230
Davalos D et al (2014) Early detection of thrombin activity in neuroinflammatory disease. Ann Neurol 75:303–308. https://doi.org/10.1002/ana.24078
De Luca C, Virtuoso A, Maggio N, Papa M (2017) Neuro-Coagulopathy: Blood Coagulation Factors in Central Nervous System Diseases. Int J Mol Sci 18. https://doi.org/10.3390/ijms18102128
Drake TA, Morrissey JH, Edgington TS (1989) Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 134:1087–1097
Duperray A et al (1997) Molecular identification of a novel fibrinogen binding site on the first domain of ICAM-1 regulating leukocyte-endothelium bridging. J Biol Chem 272:435–441. https://doi.org/10.1074/jbc.272.1.435
Eddleston M, de la Torre JC, Oldstone MB, Loskutoff DJ, Edgington TS, Mackman N (1993) Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis. J Clin Invest 92:349–358. https://doi.org/10.1172/JCI116573
Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105:3178–3184. https://doi.org/10.1182/blood-2004-10-3985
Feistritzer C, Schuepbach RA, Mosnier LO, Bush LA, Di Cera E, Griffin JH, Riewald M (2006) Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem 281:20077–20084. https://doi.org/10.1074/jbc.M600506200
Festoff BW, Li C, Woodhams B, Lynch S (2012) Soluble thrombomodulin levels in plasma of multiple sclerosis patients and their implication. J Neurol Sci 323:61–65. https://doi.org/10.1016/j.jns.2012.08.008
Festoff BW, Sajja RK, van Dreden P, Cucullo L (2016) HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease. J Neuroinflammation 13:194. https://doi.org/10.1186/s12974-016-0670-z
Flick MJ, Du X, Degen JL (2004) Fibrin(ogen)-alpha M beta 2 interactions regulate leukocyte function and innate immunity in vivo. Exp Biol Med (Maywood) 229:1105–1110. https://doi.org/10.1177/153537020422901104
Flick MJ et al (2011) The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A. Blood 117:6326–6337. https://doi.org/10.1182/blood-2010-08-304915
Frigerio S, Ariano C, Bernardi G, Ciusani E, Massa G, La Mantia L, Salmaggi A (1998) Cerebrospinal fluid thrombomodulin and sVCAM-1 in different clinical stages of multiple sclerosis patients. J Neuroimmunol 87:88–93. https://doi.org/10.1016/s0165-5728(98)00045-9
Funes SC, Rios M, Escobar-Vera J, Kalergis AM (2018) Implications of macrophage polarization in autoimmunity. Immunology 154:186–195. https://doi.org/10.1111/imm.12910
Gadepalli R, Kotla S, Heckle MR, Verma SK, Singh NK, Rao GN (2013) Novel role for p21-activated kinase 2 in thrombin-induced monocyte migration. J Biol Chem 288:30815–30831. https://doi.org/10.1074/jbc.M113.463414
Gandhi R, Laroni A, Weiner HL (2010) Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol 221:7–14. https://doi.org/10.1016/j.jneuroim.2009.10.015
Garg N, Smith TW (2015) An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav 5:e00362. https://doi.org/10.1002/brb3.362
Gay FW, Drye TJ, Dick GW, Esiri MM (1997) The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 120(Pt 8):1461–1483. https://doi.org/10.1093/brain/120.8.1461
Göbel K et al (2016a) Prothrombin and factor X are elevated in multiple sclerosis patients. Ann Neurol 80:946–951. https://doi.org/10.1002/ana.24807
Göbel K et al (2016b) Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat Commun 7:11626. https://doi.org/10.1038/ncomms11626
Griffin JH, Zlokovic BV, Mosnier LO (2015) Activated protein C: biased for translation. Blood 125:2898–2907. https://doi.org/10.1182/blood-2015-02-355974
Griffin JH, Zlokovic BV, Mosnier LO (2018) Activated protein C, protease activated receptor 1, and neuroprotection. Blood 132:159–169. https://doi.org/10.1182/blood-2018-02-769026
Gruber A, Cantwell AM, Di Cera E, Hanson SR (2002) The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo. J Biol Chem 277:27581–27584. https://doi.org/10.1074/jbc.C200237200
Gruber A, Fernández JA, Bush L, Marzec U, Griffin JH, Hanson SR, DI Cera E (2006) Limited generation of activated protein C during infusion of the protein C activator thrombin analog W215A/E217A in primates. J Thromb Haemost 4:392–397. https://doi.org/10.1111/j.1538-7836.2006.01760.x
Guan JX, Sun SG, Cao XB, Chen ZB, Tong ET (2004) Effect of thrombin on blood brain barrier permeability and its mechanism. Chin Med J 117:1677–1681
Han MH et al (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451:1076–1081. https://doi.org/10.1038/nature06559
Hauser SL et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688. https://doi.org/10.1056/NEJMoa0706383
Healy LD et al (2017) Activated protein C inhibits neutrophil extracellular trap formation. J Biol Chem 292:8616–8629. https://doi.org/10.1074/jbc.M116.768309
Healy LD, Rigg RA, Griffin JH, McCarty OJT (2018) Regulation of immune cell signaling by activated protein C. J Leukoc Biol. https://doi.org/10.1002/JLB.3MIR0817-338R
Heuberger DM, Schuepbach RA (2019) Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thromb J 17:4. https://doi.org/10.1186/s12959-019-0194-8
Houston G, Cuthbertson BH (2009) Activated protein C for the treatment of severe sepsis. Clin Microbiol Infect 15:319–324. https://doi.org/10.1111/j.1469-0691.2009.02751.x
Hsieh JY, Smith TD, Meli VS, Tran TN, Botvinick EL, Liu WF (2017) Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen. Acta Biomater 47:14–24. https://doi.org/10.1016/j.actbio.2016.09.024
Hu X, Leak RK, Shi Y, Suenaga J, Gao Y, Zheng P, Chen J (2015) Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 11:56–64. https://doi.org/10.1038/nrneurol.2014.207
Huang C, Ma R, Sun S, Wei G, Fang Y, Liu R, Li G (2008) JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. J Neuroimmunol 204:118–125. https://doi.org/10.1016/j.jneuroim.2008.07.004
Hunter SF (2016) Overview and diagnosis of multiple sclerosis. Am J Manag Care 22:s141–s150
Hurley A et al (2013) Enhanced effector function of CD8(+) T cells from healthy controls and HIV-infected patients occurs through thrombin activation of protease-activated receptor 1. J Infect Dis 207:638–650. https://doi.org/10.1093/infdis/jis730
Iezzi G, Scotet E, Scheidegger D, Lanzavecchia A (1999) The interplay between the duration of TCR and cytokine signaling determines T cell polarization. Eur J Immunol 29:4092–4101. https://doi.org/10.1002/(SICI)1521-4141(199912)29:12<4092::AID-IMMU4092>3.0.CO;2-A
Inaba Y et al (2001) Plasma thrombin-antithrombin III complex is associated with the severity of experimental autoimmune encephalomyelitis. J Neurol Sci 185:89–93. https://doi.org/10.1016/s0022-510x(01)00468-3
Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR (1999) Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 103:879–887. https://doi.org/10.1172/JCI6042
Kalashnyk O et al (2013) Expression, function and cooperating partners of protease-activated receptor type 3 in vascular endothelial cells and B lymphocytes studied with specific monoclonal antibody. Mol Immunol 54:319–326. https://doi.org/10.1016/j.molimm.2012.12.021
Kant R, Halder SK, Fernández JA, Griffin JH, Milner R (2020) Activated Protein C Attenuates Experimental Autoimmune Encephalomyelitis Progression by Enhancing Vascular Integrity and Suppressing Microglial Activation. Front Neurosci 14:333. https://doi.org/10.3389/fnins.2020.00333
Kaplan ZS et al (2015) Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4. Nat Commun 6:7835. https://doi.org/10.1038/ncomms8835
Kim YV, Di Cello F, Hillaire CS, Kim KS (2004) Differential Ca2+ signaling by thrombin and protease-activated receptor-1-activating peptide in human brain microvascular endothelial cells. Am J Phys Cell Physiol 286:C31–C42. https://doi.org/10.1152/ajpcell.00157.2003
Koh CS, Gausas J, Paterson PY (1992) Concordance and localization of maximal vascular permeability change and fibrin deposition in the central neuraxis of Lewis rats with cell-transferred experimental allergic encephalomyelitis. J Neuroimmunol 38:85–93. https://doi.org/10.1016/0165-5728(92)90093-z
Kotter MR, Stadelmann C, Hartung HP (2011) Enhancing remyelination in disease--can we wrap it up? Brain 134:1882–1900. https://doi.org/10.1093/brain/awr014
Koudriavtseva T (2014) Thrombotic processes in multiple sclerosis as manifestation of innate immune activation. Front Neurol 5:119. https://doi.org/10.3389/fneur.2014.00119
Koupenova M, Clancy L, Corkrey HA, Freedman JE (2018) Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis. Circ Res 122:337–351. https://doi.org/10.1161/CIRCRESAHA.117.310795
Kremer D, Aktas O, Hartung HP, Küry P (2011) The complex world of oligodendroglial differentiation inhibitors. Ann Neurol 69:602–618. https://doi.org/10.1002/ana.22415
Langer HF et al (2012) Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 110:1202–1210. https://doi.org/10.1161/CIRCRESAHA.111.256370
Languino LR, Plescia J, Duperray A, Brian AA, Plow EF, Geltosky JE, Altieri DC (1993) Fibrinogen mediates leukocyte adhesion to vascular endothelium through an ICAM-1-dependent pathway. Cell 73:1423–1434. https://doi.org/10.1016/0092-8674(93)90367-y
Languino LR, Duperray A, Joganic KJ, Fornaro M, Thornton GB, Altieri DC (1995) Regulation of leukocyte-endothelium interaction and leukocyte transendothelial migration by intercellular adhesion molecule 1-fibrinogen recognition. Proc Natl Acad Sci U S A 92:1505–1509. https://doi.org/10.1073/pnas.92.5.1505
Laurens N, Koolwijk P, de Maat MP (2006) Fibrin structure and wound healing. J Thromb Haemost 4:932–939. https://doi.org/10.1111/j.1538-7836.2006.01861.x
Lee DM, Weinblatt ME (2001) Rheumatoid arthritis. Lancet 358:903–911. https://doi.org/10.1016/S0140-6736(01)06075-5
Lee DY, Oh YJ, Jin BK (2005) Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. Glia 51:98–110. https://doi.org/10.1002/glia.20190
Lee PW, Severin ME, Lovett-Racke AE (2017) TGF-β regulation of encephalitogenic and regulatory T cells in multiple sclerosis. Eur J Immunol 47:446–453. https://doi.org/10.1002/eji.201646716
Li R, Patterson KR, Bar-Or A (2018) Reassessing B cell contributions in multiple sclerosis. Nat Immunol 19:696–707. https://doi.org/10.1038/s41590-018-0135-x
Lider O, Baharav E, Mekori YA, Miller T, Naparstek Y, Vlodavsky I, Cohen IR (1989) Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins. J Clin Invest 83:752–756. https://doi.org/10.1172/JCI113953
Lin C, Rezaee F, Waasdorp M, Shi K, van der Poll T, Borensztajn K, Spek CA (2015) Protease activated receptor-1 regulates macrophage-mediated cellular senescence: a risk for idiopathic pulmonary fibrosis. Oncotarget 6:35304–35314. https://doi.org/10.18632/oncotarget.6095
Loike JD et al (1991) CD11c/CD18 on neutrophils recognizes a domain at the N terminus of the A alpha chain of fibrinogen. Proc Natl Acad Sci U S A 88:1044–1048. https://doi.org/10.1073/pnas.88.3.1044
López ML, Soriano-Sarabia N, Bruges G, Marquez ME, Preissner KT, Schmitz ML, Hackstein H (2014) Expression pattern of protease activated receptors in lymphoid cells. Cell Immunol 288:47–52. https://doi.org/10.1016/j.cellimm.2014.02.004
López-Zambrano M, Rodriguez-Montesinos J, Crespo-Avilan GE, Muñoz-Vega M, Preissner KT (2020) Thrombin Promotes Macrophage Polarization into M1-Like Phenotype to Induce Inflammatory Responses. Thromb Haemost 120:658–670. https://doi.org/10.1055/s-0040-1703007
Lu W, Bhasin M, Tsirka SE (2002) Involvement of tissue plasminogen activator in onset and effector phases of experimental allergic encephalomyelitis. J Neurosci 22:10781–10789
Lund SA, Giachelli CM, Scatena M (2009) The role of osteopontin in inflammatory processes. J Cell Commun Signal 3:311–322. https://doi.org/10.1007/s12079-009-0068-0
Luo D et al (2013) Fibrin facilitates both innate and T cell-mediated defense against Yersinia pestis. J Immunol 190:4149–4161. https://doi.org/10.4049/jimmunol.1203253
Lyden P et al (2019) Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke. Ann Neurol 85:125–136. https://doi.org/10.1002/ana.25383
Machida T et al (2015) Brain pericytes are the most thrombin-sensitive matrix metalloproteinase-9-releasing cell type constituting the blood-brain barrier in vitro. Neurosci Lett 599:109–114. https://doi.org/10.1016/j.neulet.2015.05.028
Machida T et al (2017a) Role of thrombin-PAR1-PKCθ/δ axis in brain pericytes in thrombin-induced MMP-9 production and blood-brain barrier dysfunction in vitro. Neuroscience 350:146–157. https://doi.org/10.1016/j.neuroscience.2017.03.026
Machida T et al (2017b) Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model. PLoS One 12:e0177447. https://doi.org/10.1371/journal.pone.0177447
Maeda Y, Solanky M, Menonna J, Chapin J, Li W, Dowling P (2001) Platelet-derived growth factor-alpha receptor-positive oligodendroglia are frequent in multiple sclerosis lesions. Ann Neurol 49:776–785. https://doi.org/10.1002/ana.1015
Mari B et al (1994) Thrombin and thrombin receptor agonist peptide induce early events of T cell activation and synergize with TCR cross-linking for CD69 expression and interleukin 2 production. J Biol Chem 269:8517–8523
Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815. https://doi.org/10.1093/brain/awm236
Marty I, Péclat V, Kirdaite G, Salvi R, So A, Busso N (2001) Amelioration of collagen-induced arthritis by thrombin inhibition. J Clin Invest 107:631–640. https://doi.org/10.1172/JCI11064
Maschmeyer J, Shearer R, Lonser E, Spindle DK (1961) Heparin potassium in the treatment of chronic multiple sclerosis. Bull Los Angel Neurol Soc 26:165–171
Matsumoto T et al (2015) Activated protein C modulates the proinflammatory activity of dendritic cells. J Asthma Allergy 8:29–37. https://doi.org/10.2147/JAA.S75261
McCarty OJ, Tien N, Bochner BS, Konstantopoulos K (2003) Exogenous eosinophil activation converts PSGL-1-dependent binding to CD18-dependent stable adhesion to platelets in shear flow. Am J Phys Cell Physiol 284:C1223–C1234. https://doi.org/10.1152/ajpcell.00403.2002
Möller T, Hanisch UK, Ransom BR (2000) Thrombin-induced activation of cultured rodent microglia. J Neurochem 75:1539–1547. https://doi.org/10.1046/j.1471-4159.2000.0751539.x
Morel A, Bijak M, Miller E, Rywaniak J, Miller S, Saluk J (2015) Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage. Oxidative Med Cell Longev 2015:240918. https://doi.org/10.1155/2015/240918
Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH (2012) Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood 120:5237–5246. https://doi.org/10.1182/blood-2012-08-452169
Muradashvili N, Tyagi N, Tyagi R, Munjal C, Lominadze D (2011) Fibrinogen alters mouse brain endothelial cell layer integrity affecting vascular endothelial cadherin. Biochem Biophys Res Commun 413:509–514. https://doi.org/10.1016/j.bbrc.2011.07.133
Muradashvili N et al (2012) Fibrinogen-induced increased pial venular permeability in mice. J Cereb Blood Flow Metab 32:150–163. https://doi.org/10.1038/jcbfm.2011.144
Naldini A, Bernini C, Pucci A, Carraro F (2005) Thrombin-mediated IL-10 up-regulation involves protease-activated receptor (PAR)-1 expression in human mononuclear leukocytes. J Leukoc Biol 78:736–744. https://doi.org/10.1189/jlb.0205082
Nasirzade J, Kargarpour Z, Hasannia S, Strauss FJ, Gruber R (2020) Platelet-rich fibrin elicits an anti-inflammatory response in macrophages in vitro. J Periodontol 91:244–252. https://doi.org/10.1002/JPER.19-0216
Nelson LM et al (2019) A new way to estimate neurologic disease prevalence in the United States: Illustrated with MS. Neurology 92:469–480. https://doi.org/10.1212/WNL.0000000000007044
Nham SU (1999) Characteristics of fibrinogen binding to the domain of CD11c, an alpha subunit of p150,95. Biochem Biophys Res Commun 264:630–634. https://doi.org/10.1006/bbrc.1999.1564
Noorbakhsh F, Vergnolle N, Hollenberg MD, Power C (2003) Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 4:981–990. https://doi.org/10.1038/nrn1255
Ohkuma K, Matsuda K, Kariya R, Goto H, Kamei S, Hamamoto T, Okada S (2015) Anti-inflammatory effects of activated protein C on human dendritic cells. Microbiol Immunol 59:381–388. https://doi.org/10.1111/1348-0421.12262
Panek WK et al (2019) Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model. Mol Neurobiol 56:5032–5040. https://doi.org/10.1007/s12035-018-1430-0
Parsons ME et al (2017) Thrombin generation correlates with disease duration in multiple sclerosis (MS): Novel insights into the MS-associated prothrombotic state. Mult Scler J Exp Transl Clin 3:2055217317747624. https://doi.org/10.1177/2055217317747624
Paterson PY (1976) Experimental allergic encephalomyelitis: role of fibrin deposition in immunopathogenesis of inflammation in rats. Fed Proc 35:2428–2434
Patibandla PK, Tyagi N, Dean WL, Tyagi SC, Roberts AM, Lominadze D (2009) Fibrinogen induces alterations of endothelial cell tight junction proteins. J Cell Physiol 221:195–203. https://doi.org/10.1002/jcp.21845
Patrikios P et al (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172. https://doi.org/10.1093/brain/awl217
Peeters PJ, Bazelier MT, Uitdehaag BM, Leufkens HG, De Bruin ML, de Vries F (2014) The risk of venous thromboembolism in patients with multiple sclerosis: the Clinical Practice Research Datalink. J Thromb Haemost 12:444–451. https://doi.org/10.1111/jth.12523
Puy C, Rigg RA, McCarty OJ (2016) The hemostatic role of factor XI. Thromb Res 141(Suppl 2):S8–S11. https://doi.org/10.1016/S0049-3848(16)30354-1
Ranjan S et al (2017) Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. Nat Commun 8:311. https://doi.org/10.1038/s41467-017-00169-4
Rigg RA et al (2019) Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions. Platelets 30:126–135. https://doi.org/10.1080/09537104.2017.1406076
Rodrigues SF, Granger DN (2015) Blood cells and endothelial barrier function. Tissue Barriers 3:e978720. https://doi.org/10.4161/21688370.2014.978720
Ryu J, Pyo H, Jou I, Joe E (2000) Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-kappa B. J Biol Chem 275:29955–29959. https://doi.org/10.1074/jbc.M001220200
Ryu JK et al (2015) Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 6:8164. https://doi.org/10.1038/ncomms9164
Ryu JK et al (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 19:1212–1223. https://doi.org/10.1038/s41590-018-0232-x
Schuepbach RA, Feistritzer C, Fernández JA, Griffin JH, Riewald M (2009) Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1. Thromb Haemost 101:724–733. https://doi.org/10.1160/th08-10-0632
Scolding N, Franklin R, Stevens S, Heldin CH, Compston A, Newcombe J (1998) Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121(Pt 12):2221–2228. https://doi.org/10.1093/brain/121.12.2221
Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A (2008) Evidence of platelet activation in multiple sclerosis. J Neuroinflammation 5:27. https://doi.org/10.1186/1742-2094-5-27
Simmons J, Pittet JF (2015) The coagulopathy of acute sepsis. Curr Opin Anaesthesiol 28:227–236. https://doi.org/10.1097/ACO.0000000000000163
Sinha RK et al (2018) PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke. Blood 131:1163–1171. https://doi.org/10.1182/blood-2017-10-810895
Sorensen PS et al. (2014) Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 82:573–581 .https://doi.org/10.1212/WNL.0000000000000125
Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL, Esmon CT (1996) The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci U S A 93:10212–10216. https://doi.org/10.1073/pnas.93.19.10212
Stolz L, Derouiche A, Devraj K, Weber F, Brunkhorst R, Foerch C (2017) Anticoagulation with warfarin and rivaroxaban ameliorates experimental autoimmune encephalomyelitis. J Neuroinflammation 14:152. https://doi.org/10.1186/s12974-017-0926-2
Sturn DH, Kaneider NC, Feistritzer C, Djanani A, Fukudome K, Wiedermann CJ (2003) Expression and function of the endothelial protein C receptor in human neutrophils. Blood 102:1499–1505. https://doi.org/10.1182/blood-2002-12-3880
Sugama Y, Tiruppathi C, offakidevi K, Andersen TT, Fenton JW, Malik AB (1992) Thrombin-induced expression of endothelial P-selectin and intercellular adhesion molecule-1: a mechanism for stabilizing neutrophil adhesion. J Cell Biol 119:935–944. https://doi.org/10.1083/jcb.119.4.935
Suo Z et al (2002) Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J Neurochem 80:655–666. https://doi.org/10.1046/j.0022-3042.2001.00745.x
Suo Z, Wu M, Citron BA, Gao C, Festoff BW (2003) Persistent protease-activated receptor 4 signaling mediates thrombin-induced microglial activation. J Biol Chem 278:31177–31183. https://doi.org/10.1074/jbc.M302137200
Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133–150. https://doi.org/10.1038/nrneurol.2017.188
Szaba FM, Smiley ST (2002) Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo. Blood 99:1053–1059. https://doi.org/10.1182/blood.v99.3.1053
Takada Y et al (2010) A T cell-binding fragment of fibrinogen can prevent autoimmunity. J Autoimmun 34:453–459. https://doi.org/10.1016/j.jaut.2009.11.017
Tay TL, Savage JC, Hui CW, Bisht K, Tremblay M (2017) Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J Physiol 595:1929–1945. https://doi.org/10.1113/JP272134
Tucker EI et al (2020) The protein C activator AB002 rapidly interrupts thrombus development in baboons. Blood 135:689–699. https://doi.org/10.1182/blood.2019002771
Tyagi N, Roberts AM, Dean WL, Tyagi SC, Lominadze D (2008) Fibrinogen induces endothelial cell permeability. Mol Cell Biochem 307:13–22. https://doi.org/10.1007/s11010-007-9579-2
Ugarova TP et al (2003) Sequence gamma 377–395(P2), but not gamma 190–202(P1), is the binding site for the alpha MI-domain of integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry 42:9365–9373. https://doi.org/10.1021/bi034057k
Van Kaer L, Postoak JL, Wang C, Yang G, Wu L (2019) Innate, innate-like and adaptive lymphocytes in the pathogenesis of MS and EAE. Cell Mol Immunol 16:531–539. https://doi.org/10.1038/s41423-019-0221-5
Varisco PA, Péclat V, van Ness K, Bischof-Delaloye A, So A, Busso N (2000) Effect of thrombin inhibition on synovial inflammation in antigen induced arthritis. Ann Rheum Dis 59:781–787. https://doi.org/10.1136/ard.59.10.781
Vaughn CB, Jakimovski D, Kavak KS, Ramanathan M, Benedict RHB, Zivadinov R, Weinstock-Guttman B (2019) Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol 15:329–342. https://doi.org/10.1038/s41582-019-0183-3
Verbout NG et al (2015) Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis. Metab Brain Dis 30:57–65. https://doi.org/10.1007/s11011-014-9558-8
Vicente CP, Weiler H, Di Cera E, Tollefsen DM (2012) Thrombomodulin is required for the antithrombotic activity of thrombin mutant W215A/E217A in a mouse model of arterial thrombosis. Thromb Res 130:646–648. https://doi.org/10.1016/j.thromres.2011.11.026
Vos CM et al (2005) Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis. Neurobiol Dis 20:953–960. https://doi.org/10.1016/j.nbd.2005.06.012
Wakefield AJ, More LJ, Difford J, McLaughlin JE (1994) Immunohistochemical study of vascular injury in acute multiple sclerosis. J Clin Pathol 47:129–133. https://doi.org/10.1136/jcp.47.2.129
Wallin MT et al (2019) The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology 92:e1029–e1040. https://doi.org/10.1212/WNL.0000000000007035
Wang Y, Richter-Landsberg C, Reiser G (2004) Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling. Neuroscience 126:69–82. https://doi.org/10.1016/j.neuroscience.2004.03.024
Wang L et al (2010) Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity 32:518–530. https://doi.org/10.1016/j.immuni.2010.03.014
White TC et al (2008) Protein C supports platelet binding and activation under flow: role of glycoprotein Ib and apolipoprotein E receptor 2. J Thromb Haemost 6:995–1002. https://doi.org/10.1111/j.1538-7836.2008.02979.x
Wolswijk G (1998) Oligodendrocyte regeneration in the adult rodent CNS and the failure of this process in multiple sclerosis. Prog Brain Res 117:233–247. https://doi.org/10.1016/s0079-6123(08)64019-4
Wolter J et al (2016) Thrombomodulin-dependent protein C activation is required for mitochondrial function and myelination in the central nervous system. J Thromb Haemost 14:2212–2226. https://doi.org/10.1111/jth.13494
Xue M, Dervish S, Harrison LC, Fulcher G, Jackson CJ (2012) Activated protein C inhibits pancreatic islet inflammation, stimulates T regulatory cells, and prevents diabetes in non-obese diabetic (NOD) mice. J Biol Chem 287:16356–16364. https://doi.org/10.1074/jbc.M111.325951
Yanagita M, Kobayashi R, Kashiwagi Y, Shimabukuro Y, Murakami S (2007) Thrombin regulates the function of human blood dendritic cells. Biochem Biophys Res Commun 364:318–324. https://doi.org/10.1016/j.bbrc.2007.10.002
Yang Y, Tian SJ, Wu L, Huang DH, Wu WP (2011) Fibrinogen depleting agent batroxobin has a beneficial effect on experimental autoimmune encephalomyelitis. Cell Mol Neurobiol 31:437–448. https://doi.org/10.1007/s10571-010-9637-2
Yoon H, Choi C-I, Triplet EM, Langley MR, Kleppe LS, Kim HN, Simon WL, Scarisbrick IA (2020) Blocking the thrombin receptor promotes repair of demyelinated lesions in the adult brain. J Neurosci 40 (7):1483–1500
Yoon H, Radulovic M, Drucker KL, Wu J, Scarisbrick IA (2015) The thrombin receptor is a critical extracellular switch controlling myelination. Glia 63:846–859. https://doi.org/10.1002/glia.22788
Ziliotto N et al (2020) Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis. Eur J Neurol 27:235–243. https://doi.org/10.1111/ene.1405
Funding
This work was supported by grants from the National Institutes of Health (R01HL101972, R01HL151367, R21CA223461, R24NS104161, and R44HL117589).
Author information
Authors and Affiliations
Contributions
KRJ, IP, AG, JJS, PP, LSS, OJTM and NV wrote and approved the final version of manuscript.
Corresponding author
Ethics declarations
Conflict of interest
N. Verbout and A. Gruber are employees of Aronora, Inc., and they as well as OHSU may have a financial interest in the results of this study. N. Verbout and O. McCarty are inventors on a patent for METHODS AND COMPOSITIONS USED IN TREATING INFLAMMATORY AND AUTOIMMUNE DISEASES (US Patent 10,137,177) which has been licensed by Aronora, Inc. J.J. Shatzel reports receiving consulting fees from Aronora, Inc. The other authors state that they have no conflicts of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Jordan, K.R., Parra-Izquierdo, I., Gruber, A. et al. Thrombin generation and activity in multiple sclerosis. Metab Brain Dis 36, 407–420 (2021). https://doi.org/10.1007/s11011-020-00652-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-020-00652-w