Inflammation and Coagulation in Neurologic and Psychiatric Disorders

Abstract

Coagulation factors are intrinsically expressed in various brain cells, including astrocytes and microglia. Their interaction with the inflammatory system is important for the well-being of the brain, but they are also crucial in the development of many diseases in the brain such as stroke and traumatic brain injury. The cellular effects of coagulation are mediated mainly by protease-activated receptors. In this review, we sum up the role of the coagulation cascade in the development of different diseases including psychiatric disorders. In inflammatory diseases such as multiple sclerosis, fibrinogen activates microglia and suppresses the differentiation of oligodendrocytes, leading to axonal damage and suppression of remyelination. In ischemic stroke, thrombin activity is associated with the size of infarction, and the inhibition of either thrombin- or protease-activated receptor 1 promotes neuronal survival and reduces the size of infarction. Patients suffering from Alzheimer's disease express higher levels of thrombin, which in turn damages the endothelium, increases blood–brain barrier permeability, and induces cell apoptosis. In major depressive disorder, a positive correlation is present between prothrombotic states and suicidality. Moreover, both protein S deficiency and antiphospholipid antibodies are associated with schizophrenia and there is an effect of warfarin on psychosis-free intervals. Studying the coagulation in the brain could open a new door in understanding and treating neurological and psychiatric disorders, and extensive research should be conducted in this field.

 

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Keywords

inflammation - coagulation - thrombin - psychiatric disorders

Neurocoagulation is closely linked to neuroinflammation, which is also important in many disease states. The crosstalk between the two systems is critical in the response of the body to injury.[1] While coagulation factors play a role in the development of inflammation,[2] [3] [4] the latter can activate coagulation as well.[5] This interplay is seen in many disease states, including sepsis[6] [7] and glioma.[8] Knowledge regarding the intrinsic coagulation system in the brain with its factors and receptors is a rapidly expanding field. In this review, we will focus on the coagulation system and its direct effects on the brain and its important role in neuroinflammation and disease ([Table 1]).

Table 1 Mechanisms involved in neuro-psychiatric disease states

	Cell types in brain	Coagulation factors	Ischemia/inflammation	Associated disease
Dementia	Astrocytes,[9] microglia[20] [23]	Thrombin [23] [43] [81] [82], FXII, FXI, prekallikrein[89] [90]	Complement system,[89] [90] Bim,[87] histones, ROS[94]	AD, vascular dementia
Depression	Neurons, glia?	TF, FVII, FX[97] [98] [99]	APS, ICAM-1, antiribosomal P antibodies[100]	SLE[100]
Psychosis	Neurons, glia	Low levels of tPA,[105] [106] protein S deficiency[106]	High cytokine levels, hyperhomocysteinemia[105]	SLE, APS[105]
MS	Microglia,[66] [67] [68] astrocytes[70]	Fibrinogen,[66] [67] thrombin[71]	ROS,[66] TF, protein C inhibitors, cytokines[70]

Abbreviations: AD, Alzheimer's disease; APS, antiphospholipid syndrome; Bim, B cell lymphoma 2-like protein; FVII, factor VII; FX, factor X; FXI, factor XI; FXII, factor XII; ICAM-1, intercellular adhesion molecule-1; MS, multiple sclerosis; ROS, reactive oxygen species; SLE, systemic lupus erythematosus; TF, tissue factor; tPA, tissue plasminogen activator.

Cell Types Involved in Brain Neuroinflammation and Coagulation

Astrocytes play a role in lipid metabolism through oxidative phosphorylation. Failing to do so leads to the build-up of fatty acids and lipid droplets within astrocytes, making them reactive through signal transducer and activator of transcription 3 (STAT3) activation. These cells eventually promote neurodegeneration and neuroinflammation, including Alzheimer's disease (AD).[9] Kim et al found that tumor necrosis factor activates astrocytes via STAT3 and serine protease inhibitor A3 expression. This elicits vascular inflammation and disrupts the blood–brain barrier (BBB).[10] The strategic location at the BBB makes astrocytes an important mediator and regulator in multiple sclerosis (MS) pathogenesis[11]; in response to pro-inflammatory stimuli such as lipopolysaccharides, interleukin-1β, and tumor necrosis factor-α,[12] they secrete monocyte chemoattractant protein-1 (CCL2) to the circulation,[13] which in turn not only attracts T cells, mast cells, and monocytes to the site of inflammation,[14] but also exerts autocrine properties that increase astrocyte migration and reduce apoptosis.[15] Moreover, thrombin was found to have a pro-inflammatory effect on astrocytes by inducing matrix metalloproteinase-9 expression and cell migration.[16]

Microglia are considered the primary immune cells in the central nervous system (CNS); they eliminate microbes and damaged brain cells. Also, they release proinflammatory cytokines, making them a crucial player in neuroinflammation and neurodegeneration as well.[17] Coagulation factors such as thrombin induce the release of interleukin-1β in BV2-microglial cells.[18] Various studies have highlighted the role of thrombin in inducing proinflammatory phenotypes of microglia, which in turn release nitric oxide, reactive oxygen species (ROS), and other cytokines.[19] [20] [21] [22] Therefore, thrombin-targeted therapy is suggested as a potential treatment for AD.[23]

 

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Coagulation Factors Intrinsic to the Nervous System

The nervous system intrinsically expresses most components of the coagulation pathways. The coagulation factor thrombin promotes epileptic seizures, has deleterious effects on nerve conduction, and participates in the progression of glioblastoma multiforme.[24] Kant et al examined the potentially protective effect of activated protein C (aPC) on experimental autoimmune encephalomyelitis (EAE), and found a decrease in microglial activity, manifested by the attenuated expression of matrix metalloproteinase-9.[25] Another study that addressed white matter stroke in middle-aged mice concluded that 3K3A-aPC, a recombinant analog of the blood protease aPC, diminishes both microglial and astrocyte responses, thus protecting white matter and oligodendrocytes from ischemia, via activation of protease-activated receptor (PAR) 1 and 3. This could open a new horizon in the treatment of white matter stroke, the second most common cause of dementia.[26]

Many coagulation factors are intrinsically expressed in the CNS, including prothrombin, which is expressed in multiple brain cells and regions, such as astroglial cell lines, cortex, and cerebellum.[27] [28] [29] The extrinsic coagulation cascade starts with tissue factor building a complex with activated factor VII (FVIIa). In the process, factor Xa cleaves prothrombin to thrombin within the prothrombinase complex, which consists of factors Va and Xa, Ca²⁺, and phospholipids.[30] Other than its role in the coagulation cascade, thrombin has a dose-dependent effect on astrocytes; at low doses, it reverses astrocyte–stellate morphology[31] and promotes proliferation and inflammatory cytokine release.[32]

 

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The Cellular Effects of Coagulation Are Mediated Mainly by Protease Activated Receptors

The interaction between neurocoagulation and neuroinflammation is largely centered on the PARs. PARs are a family of G-protein-coupled receptors. These receptors, PAR1, -2, -3, and -4,[33] [34] [35] [36] are differentially expressed in brain cells, including neurons and glial cells,[37] [38] [39] [40] platelets, endothelial cells, smooth muscles, and immune and inflammatory cells.[41] [42] Once activated, they play a pivotal role in brain development and mitogenesis, and exert both neuroprotective and neurodegenerative effects.[41] [43] [44] [45] [46] [47] PAR1 activation via thrombin causes platelet aggregation in the setting of clot formation.[48] In the peripheral nervous system, PAR1 is expressed on Schwann cell microvilli at the node of Ranvier; its activation by thrombin leads to nerve conduction block.[49] In addition, PAR1 at the neuromuscular junction plays a role in synaptic reduction and transmission, namely through phosphorylation of the Discs large protein[50]—the protein that maintains the Drosophila epithelial polarity.[51] Accumulating evidence shows that PAR1 activation by thrombin and granzyme A (secreted by T lymphocytes) results in morphological neuronal changes and neurite retraction.[52] [53] Continuous PAR1 activation by thrombin leads to neuronal apoptosis.[52] PAR2 was found to induce neurogenic inflammation via neutrophil infiltrations, calcitonin gene-related peptide, and substance P secretion.[54] [55] In MS, while activation of PAR1 through granzyme B and interleukin-1β results in cytotoxicity and neuroinflammation,[56] PAR2 was found to contribute to demyelination and axonal injury, through T lymphocyte infiltration and microglial activation.[57] Multiple proteases including thrombin, aPC, and FVIIa drive PAR1 activation.[58] Interestingly, different levels of thrombin lead to different PAR1-related outcomes; while lower levels induce neuroprotection through astrocyte modulation,[59] high concentrations of thrombin seen in minimal traumatic brain injuries[60] and stroke[61] have devastating effects on the brain. In contrast, aPC builds a complex with its receptor, the endothelial protein C receptor (EPCR). This aPC–EPCR complex activates PAR1,[62] leading to neurogenesis in the setting of ischemia,[63] and reduced BBB permeability via nuclear factor kappa B inhibition.[64] Golderman et al synthesized several molecules and gave them the name FEAM (Factor VIIa, EPCR, aPC Modulators). These molecules show promising results in preventing neuroinflammation, without affecting coagulation.[65]

 

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How Neurocoagulation Plays a Role in Neuroinflammation in Nervous System Disease, Multiples Sclerosis, Stroke, Dementia, and Psychiatric Disease

Several studies in mice, namely EAE models, have highlighted the role of neurocoagulation in MS. In MS, the breakdown of BBB results in fibrinogen entry into the CNS. Once inside, fibrinogen activates microglia via CD11b⁺/CD18 integrin receptor binding, leading to ROS release. Subsequently, this leads to axonal damage.[66] Both pharmacological and genetic disruptions of fibrin–microglia interaction are found to attenuate microglial activation and suppress relapsing paralysis.[66] [67] Fibrinogen is also found to suppress the differentiation of oligodendrocyte progenitor cells, and so prevent remyelination.[68] Furthermore, treatment of EAE models with recombinant thrombin reduces CD11b⁺ activation in microglia, demyelination, and fibrinogen build-up in the brain.[69] Aberrant regulation of the coagulation cascade is associated with the accumulation of tissue factor and protein C inhibitors within chronic active plaques. The administration of hirudin or recombinant aPC has proven to attenuate both the extent of EAE and cytokine release from astrocytes and other immune cells.[70] Interestingly, protease nexin 1 levels increase early in EAE, consequently inhibiting thrombin activity. This finding unveils a new treatment approach in MS and EAE via thrombin inhibition.[71]

Neurocoagulation induces an inflammatory response in stroke through different mechanisms. First, stagnation of blood following vessel occlusion in stroke increases shearing stress on both platelets and endothelial cells, which in turn secretes P-selectins that attract leukocytes to the area and contribute to cluster formation of leukocytes, leading to further occlusion.[72] Other adhesion molecules play a role in leukocytes chemotaxis, adhesion, and transmigration.[73] Moreover, thrombin induces further inflammation through both neutrophil and monocyte chemotaxis, and increased expression of other adhesion molecules on endothelial cells—specifically through PARs and nuclear factor kappa B.[74] Thrombin also activates C3 and C5 components of the complement system—causing further endothelial disruption.[75] The loss of thrombomodulin, a molecule that builds a strong anticoagulant and anti-inflammatory complex in conjugation with aPC, protein S, and EPCR, leads to the activation of complement system and monocytes, and induces inflammation.[76] In the setting of ischemic stroke, the increase in thrombin activity correlates with infarct size[77] and also impairs synaptic function upon restoration of blood flow.[78] This is supported by a later study that highlights the role of apixaban, a factor Xa inhibitor, in reducing thrombin activity and infarct size.[79] Upon oxygen and glucose deprivation, thrombin activates N-methyl-D-aspartate receptors via PAR1. This alters synaptic plasticity by inducing ischemic long-term potentiation. It is known that the inhibition of either thrombin or PAR1 has positive effects on synaptic activity as well as on neuronal survival.[80]

Studies show an increased activity of thrombin and its receptor PAR1 in AD.[43] [81] Thrombin is also largely expressed in micro-vessels of AD patients.[82] In brain endothelial cells, thrombin induces inflammation, leading to elevation of intracellular adhesion molecule-1, vascular cell adhesion molecule, and CXC chemokines,[83] and damages endothelial cells through nitric oxide, ROS, and inflammatory cytokines.[84] It also increases BBB permeability via microtubule disassembly[85] and proto-oncogene c (Src) kinase.[86] Equally important is the impact of thrombin on neuronal apoptosis, namely via upregulation of the pro-apoptotic protein Bcl-2-interacting mediator of cell death,[87] and by rapid calcium influx into neurons.[88] These findings altogether underline the importance of the multifaceted thrombin in the development and progression of neurodegeneration, including AD.[81] In vascular dementia, there is a strong correlation between the coagulation system and the complement system. Coagulation factors, including factor (F) XII, FXI, and prekallikrein can initiate both the classic and the alternative pathways.[89] [90] FXa, plasmin, thrombin, FIXa, and FXIa cleave C3 to C3a and C5 to C5a.[91] [92] Finally, various lines of evidence demonstrate that C3a can induce atherosclerosis,[93] while C5a is proven to promote the release of histones and ROS, leading to inflammation, and thus contributing to the pathogenesis of vascular dementia.[94]

The association between major depressive disorder (MDD) and suicidality is well-established,[95] with a lifetime mortality of 3.4%.[96] Interestingly, MDD is associated with increased inflammatory and decreased thrombotic states, yet suicide in MDD correlates with both proinflammatory and prothrombotic states, via the activation of an extrinsic coagulation pathway, namely tissue factor and FVII.[97] [98] Another study shows higher levels of FVII and FX among MDD patients.[99] Duca et al examined the potential correlation between inflammation and thrombosis among systemic lupus erythematosus patients suffering from anxiety/depression and found antiphospholipid antibodies (APLAs), intracellular adhesion molecule-1, and anti-ribosomal P antibodies to be highly prevalent among these patients.[100] APLA has been documented in patients suffering from severe mental illnesses.[101] APLAs bind endothelial cells in the brain, causing microthrombosis, immunoglobulin G (IgG) leakage, and BBB disruption; eventually APLAs enter the brain circulation and directly bind neurons and glial cells. These changes provoke behavioral changes and neuropsychiatric illnesses.[102] [103] IgG builds up in hippocampal and cortical neurons, inducing hyperactive behavior in mice immunized with β2-glycoprotein I.[104] Recent studies have examined the possible link between low levels of tissue plasminogen activator and the development of schizophrenia. This hypothesis is supported by high prevalence of conditions that lead to lower levels of tissue plasminogen activator, including APLA, high levels of cytokines and insulin, and hyperhomocysteinemia, among schizophrenia patients.[105] Hoirisch-Clapauch and Nardi found a correlation between protein S deficiency and schizophrenia. Besides, protein S deficiency is associated with a 145-fold increase in the risk of developing schizophrenia among first-degree relatives.[106] Psychotic patients who received warfarin chronically had longer psychosis-free intervals.[107]

 

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Conclusion

The crosstalk between coagulation factors and the inflammatory system in the brain is crucial for the development of many CNS diseases, including psychiatric disorders. For example, studies show that antiphospholipid syndrome is associated with depression and schizophrenia through microthromboses, vascular damage, and BBB disruption. This is further supported by the effect of warfarin on psychosis. However, we suggest examining the possible impact of anticoagulants and the intrinsic coagulation pathway both on cellular and clinical levels.

 

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Conflict of Interest

None declared.

• References

• 1 Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med 2005; 15 (07) 254-259
• 2 Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 2012; 34 (01) 43-62
• 3 Jennewein C, Tran N, Paulus P, Ellinghaus P, Eble JA, Zacharowski K. Novel aspects of fibrin(ogen) fragments during inflammation. Mol Med 2011; 17 (5–6): 568-573
• 4 Chapman J. Coagulation in inflammatory diseases of the central nervous system. Semin Thromb Hemost 2013; 39 (08) 876-880
• 5 Esmon CT. The interactions between inflammation and coagulation. Br J Haematol 2005; 131 (04) 417-430
• 6 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (2, Suppl): S26-S34
• 7 Schouten M, Wiersinga WJ, Levi M, van der Poll T. Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol 2008; 83 (03) 536-545
• 8 Cho A, McKelvey KJ, Lee A, Hudson AL. The intertwined fates of inflammation and coagulation in glioma. Mamm Genome 2018; 29 (11–12): 806-816
• 9 Mi Y, Qi G, Vitali F. et al. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration. Nat Metab 2023; 5 (03) 445-465
• 10 Kim H, Leng K, Park J. et al. Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin. Nat Commun 2022; 13 (01) 6581
• 11 Rothhammer V, Quintana FJ. Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol 2015; 37 (06) 625-638
• 12 Muhlethaler-Mottet A, Di Berardino W, Otten LA, Mach B. Activation of the MHC class II transactivator CIITA by interferon-gamma requires cooperative interaction between Stat1 and USF-1. Immunity 1998; 8 (02) 157-166
• 13 Nikcevich KM, Gordon KB, Tan L. et al. IFN-gamma-activated primary murine astrocytes express B7 costimulatory molecules and prime naive antigen-specific T cells. J Immunol 1997; 158 (02) 614-621
• 14 Sun D, Coleclough C, Whitaker JN. Nonactivated astrocytes downregulate T cell receptor expression and reduce antigen-specific proliferation and cytokine production of myelin basic protein (MBP)-reactive T cells. J Neuroimmunol 1997; 78 (1–2): 69-78
• 15 Yang JF, Tao HQ, Liu YM. et al. Characterization of the interaction between astrocytes and encephalitogenic lymphocytes during the development of experimental autoimmune encephalitomyelitis (EAE) in mice. Clin Exp Immunol 2012; 170 (03) 254-265
• 16 Lin CC, Lee IT, Wu WB. et al. Thrombin mediates migration of rat brain astrocytes via PLC, Ca²⁺, CaMKII, PKCα, and AP-1-dependent matrix metalloproteinase-9 expression. Mol Neurobiol 2013; 48 (03) 616-630
• 17 Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 2017; 35: 441-468
• 18 Han C, Xia X, Jiao S, Li G, Ran Q, Yao S. Tripartite motif containing protein 37 involves in thrombin stimulated BV-2 microglial cell apoptosis and interleukin 1β release. Biochem Biophys Res Commun 2019; 516 (04) 1252-1257
• 19 Ye X, Zuo D, Yu L. et al. ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia. Biochem Biophys Res Commun 2017; 485 (02) 499-505
• 20 Yang Y, Zhang M, Kang X. et al. Thrombin-induced microglial activation impairs hippocampal neurogenesis and spatial memory ability in mice. Behav Brain Funct 2015; 11 (01) 30
• 21 Huang C, Ma R, Sun S. et al. JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. J Neuroimmunol 2008; 204 (1–2): 118-125
• 22 Lee DY, Park KW, Jin BK. Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: proteolytic and non-proteolytic actions. Biochem Biophys Res Commun 2006; 346 (03) 727-738
• 23 Iannucci J, Renehan W, Grammas P. Thrombin, a mediator of coagulation, inflammation, and neurotoxicity at the neurovascular interface: implications for Alzheimer's disease. Front Neurosci 2020; 14: 762
• 24 Gofrit SG, Shavit-Stein E. The neuro-glial coagulonome: the thrombin receptor and coagulation pathways as major players in neurological diseases. Neural Regen Res 2019; 14 (12) 2043-2053
• 25 Kant R, Halder SK, Fernández JA, Griffin JH, Milner R. Activated protein C attenuates experimental autoimmune encephalomyelitis progression by enhancing vascular integrity and suppressing microglial activation. Front Neurosci 2020; 14: 333
• 26 Huuskonen MT, Wang Y, Nikolakopoulou AM. et al. Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C. J Exp Med 2022; 219 (01) e20211372
• 27 Arai T, Miklossy J, Klegeris A, Guo JP, McGeer PL. Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain. J Neuropathol Exp Neurol 2006; 65 (01) 19-25
• 28 Deschepper CF, Bigornia V, Berens ME, Lapointe MC. Production of thrombin and antithrombin III by brain and astroglial cell cultures. Brain Res Mol Brain Res 1991; 11 (3–4): 355-358
• 29 Dihanich M, Kaser M, Reinhard E, Cunningham D, Monard D. Prothrombin mRNA is expressed by cells of the nervous system. Neuron 1991; 6 (04) 575-581
• 30 Shlobin NA, Har-Even M, Itsekson-Hayosh Z, Harnof S, Pick CG. Role of thrombin in central nervous system injury and disease. Biomolecules 2021; 11 (04) 562
• 31 Park GH, Ryu JR, Shin CY. et al. Evidence that protease-activated receptor-2 mediates trypsin-induced reversal of stellation in cultured rat astrocytes. Neurosci Res 2006; 54 (01) 15-23
• 32 De Luca C, Virtuoso A, Maggio N, Papa M. Neuro-coagulopathy: blood coagulation factors in central nervous system diseases. Int J Mol Sci 2017; 18 (10) 2128
• 33 Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64 (06) 1057-1068
• 34 Nystedt S, Emilsson K, Wahlestedt C, Sundelin J. Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A 1994; 91 (20) 9208-9212
• 35 Ishihara H, Connolly AJ, Zeng D. et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 1997; 386 (6624): 502-506
• 36 Xu WF, Andersen H, Whitmore TE. et al. Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci U S A 1998; 95 (12) 6642-6646
• 37 Suo Z, Wu M, Ameenuddin S. et al. Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J Neurochem 2002; 80 (04) 655-666
• 38 Ubl JJ, Vöhringer C, Reiser G. Co-existence of two types of [Ca2+]i-inducing protease-activated receptors (PAR-1 and PAR-2) in rat astrocytes and C6 glioma cells. Neuroscience 1998; 86 (02) 597-609
• 39 Wang KC, Koprivica V, Kim JA. et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 2002; 417 (6892): 941-944
• 40 Wang Y, Richter-Landsberg C, Reiser G. Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling. Neuroscience 2004; 126 (01) 69-82
• 41 Déry O, Corvera CU, Steinhoff M, Bunnett NW. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 1998; 274 (06) C1429-C1452
• 42 Peach CJ, Edgington-Mitchell LE, Bunnett NW, Schmidt BL. Protease-activated receptors in health and disease. Physiol Rev 2023; 103 (01) 717-785
• 43 Sokolova E, Reiser G. Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases. Thromb Haemost 2008; 100 (04) 576-581
• 44 Rohatgi T, Sedehizade F, Reymann KG, Reiser G. Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection: thrombin as signaling molecule in the brain. Neuroscientist 2004; 10 (06) 501-512
• 45 Noorbakhsh F, Vergnolle N, Hollenberg MD, Power C. Proteinase-activated receptors in the nervous system. Nat Rev Neurosci 2003; 4 (12) 981-990
• 46 Smith-Swintosky VL, Zimmer S, Fenton II JW, Mattson MP. Opposing actions of thrombin and protease nexin-1 on amyloid beta-peptide toxicity and on accumulation of peroxides and calcium in hippocampal neurons. J Neurochem 1995; 65 (03) 1415-1418
• 47 Perraud F, Besnard F, Sensenbrenner M, Labourdette G. Thrombin is a potent mitogen for rat astroblasts but not for oligodendroblasts and neuroblasts in primary culture. Int J Dev Neurosci 1987; 5 (03) 181-188
• 48 Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 3 (08) 1800-1814
• 49 Shavit E, Beilin O, Korczyn AD. et al. Thrombin receptor PAR-1 on myelin at the node of Ranvier: a new anatomy and physiology of conduction block. Brain 2008; 131 (Pt 4): 1113-1122
• 50 Zhang Y, Guo H, Kwan H, Wang JW, Kosek J, Lu B. PAR-1 kinase phosphorylates Dlg and regulates its postsynaptic targeting at the Drosophila neuromuscular junction. Neuron 2007; 53 (02) 201-215
• 51 Woods DF, Hough C, Peel D, Callaini G, Bryant PJ. Dlg protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia. J Cell Biol 1996; 134 (06) 1469-1482
• 52 Gurwitz D, Cunningham DD. Thrombin modulates and reverses neuroblastoma neurite outgrowth. Proc Natl Acad Sci U S A 1988; 85 (10) 3440-3444
• 53 Suidan HS, Bouvier J, Schaerer E, Stone SR, Monard D, Tschopp J. Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. Proc Natl Acad Sci U S A 1994; 91 (17) 8112-8116
• 54 Emilsson K, Wahlestedt C, Sun MK, Nystedt S, Owman C, Sundelin J. Vascular effects of proteinase-activated receptor 2 agonist peptide. J Vasc Res 1997; 34 (04) 267-272
• 55 Steinhoff M, Vergnolle N, Young SH. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 2000; 6 (02) 151-158
• 56 Lee PR, Johnson TP, Gnanapavan S. et al. Protease-activated receptor-1 activation by granzyme B causes neurotoxicity that is augmented by interleukin-1β. J Neuroinflammation 2017; 14 (01) 131
• 57 Noorbakhsh F, Tsutsui S, Vergnolle N. et al. Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J Exp Med 2006; 203 (02) 425-435
• 58 Rezaie AR. Protease-activated receptor signalling by coagulation proteases in endothelial cells. Thromb Haemost 2014; 112 (05) 876-882
• 59 Rajput PS, Lamb J, Kothari S. et al. Neuron-generated thrombin induces a protective astrocyte response via protease activated receptors. Glia 2020; 68 (02) 246-262
• 60 Itsekson-Hayosh Z, Shavit-Stein E, Katzav A. et al. Minimal traumatic brain injury in mice: protease-activated receptor 1 and thrombin-related changes. J Neurotrauma 2016; 33 (20) 1848-1854
• 61 Bushi D, Stein ES, Golderman V. et al. A linear temporal increase in thrombin activity and loss of its receptor in mouse brain following ischemic stroke. Front Neurol 2017; 8: 138
• 62 Esmon CT. The protein C pathway. Chest 2003; 124 (3, Suppl): 26S-32S
• 63 Thiyagarajan M, Fernández JA, Lane SM, Griffin JH, Zlokovic BV. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J Neurosci 2008; 28 (48) 12788-12797
• 64 Wang J, Rao G, Ma Y, Zhang J, Shen J, Shi C. Neuroprotective effect of activated protein C on blood-brain barrier injury during focal cerebral ischemia/reperfusion. Dose Response 2020; 18 (02) 1559325820917288
• 65 Golderman V, Ben-Shimon M, Maggio N. et al. Factor VII, EPCR, aPC modulators: novel treatment for neuroinflammation. J Neuroinflammation 2022; 19 (01) 138
• 66 Davalos D, Ryu JK, Merlini M. et al. Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 2012; 3: 1227
• 67 Adams RA, Bauer J, Flick MJ. et al. The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 2007; 204 (03) 571-582
• 68 Petersen MA, Ryu JK, Chang KJ. et al. Fibrinogen activates BMP signaling in oligodendrocyte progenitor cells and inhibits remyelination after vascular damage. Neuron 2017; 96 (05) 1003-1012.e7
• 69 Verbout NG, Yu X, Healy LD. et al. Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in experimental autoimmune encephalomyelitis. Metab Brain Dis 2015; 30 (01) 57-65
• 70 Han MH, Hwang SI, Roy DB. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008; 451 (7182): 1076-1081
• 71 Beilin O, Karussis DM, Korczyn AD. et al. Increased thrombin inhibition in experimental autoimmune encephalomyelitis. J Neurosci Res 2005; 79 (03) 351-359
• 72 De Meyer SF, Denorme F, Langhauser F, Geuss E, Fluri F, Kleinschnitz C. Thromboinflammation in stroke brain damage. Stroke 2016; 47 (04) 1165-1172
• 73 Petrovic-Djergovic D, Goonewardena SN, Pinsky DJ. Inflammatory disequilibrium in stroke. Circ Res 2016; 119 (01) 142-158
• 74 Delvaeye M, Conway EM. Coagulation and innate immune responses: can we view them separately?. Blood 2009; 114 (12) 2367-2374
• 75 Amara U, Rittirsch D, Flierl M. et al. Interaction between the coagulation and complement system. Adv Exp Med Biol 2008; 632: 71-79
• 76 Anrather J, Iadecola C. Inflammation and stroke: an overview. Neurotherapeutics 2016; 13 (04) 661-670
• 77 Bushi D, Chapman J, Katzav A. et al. Quantitative detection of thrombin activity in an ischemic stroke model. J Mol Neurosci 2013; 51 (03) 844-850
• 78 Bushi D, Ben Shimon M, Shavit Stein E, Chapman J, Maggio N, Tanne D. Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus. J Neurochem 2015; 135 (06) 1140-1148
• 79 Bushi D, Chapman J, Wohl A, Stein ES, Feingold E, Tanne D. Apixaban decreases brain thrombin activity in a male mouse model of acute ischemic stroke. J Neurosci Res 2018; 96 (08) 1406-1411
• 80 Stein ES, Itsekson-Hayosh Z, Aronovich A. et al. Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke. Sci Rep 2015; 5: 7912
• 81 Krenzlin H, Lorenz V, Danckwardt S, Kempski O, Alessandri B. The importance of thrombin in cerebral injury and disease. Int J Mol Sci 2016; 17 (01) 84
• 82 Grammas P, Samany PG, Thirumangalakudi L. Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: implications for disease pathogenesis. J Alzheimers Dis 2006; 9 (01) 51-58
• 83 Alabanza LM, Bynoe MS. Thrombin induces an inflammatory phenotype in a human brain endothelial cell line. J Neuroimmunol 2012; 245 (1–2): 48-55
• 84 Brailoiu E, Shipsky MM, Yan G, Abood ME, Brailoiu GC. Mechanisms of modulation of brain microvascular endothelial cells function by thrombin. Brain Res 2017; 1657: 167-175
• 85 Birukova AA, Birukov KG, Smurova K. et al. Novel role of microtubules in thrombin-induced endothelial barrier dysfunction. FASEB J 2004; 18 (15) 1879-1890
• 86 Liu DZ, Ander BP, Xu H. et al. Blood-brain barrier breakdown and repair by Src after thrombin-induced injury. Ann Neurol 2010; 67 (04) 526-533
• 87 Rao HV, Thirumangalakudi L, Desmond P, Grammas P. Cyclin D1, cdk4, and Bim are involved in thrombin-induced apoptosis in cultured cortical neurons. J Neurochem 2007; 101 (02) 498-505
• 88 Smirnova IV, Vamos S, Wiegmann T, Citron BA, Arnold PM, Festoff BW. Calcium mobilization and protease-activated receptor cleavage after thrombin stimulation in motor neurons. J Mol Neurosci 1998; 10 (01) 31-44
• 89 Kaplan AP, Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010; 47 (13) 2161-2169
• 90 Dzik S. Complement and coagulation: cross talk through time. Transfus Med Rev 2019; 33 (04) 199-206
• 91 Amara U, Flierl MA, Rittirsch D. et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185 (09) 5628-5636
• 92 Huber-Lang M, Sarma JV, Zetoune FS. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006; 12 (06) 682-687
• 93 Hertle E, van Greevenbroek MM, Arts IC. et al. Distinct associations of complement C3a and its precursor C3 with atherosclerosis and cardiovascular disease. The CODAM study. Thromb Haemost 2014; 111 (06) 1102-1111
• 94 Barrett CD, Hsu AT, Ellson CD. et al. Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy. Clin Exp Immunol 2018; 194 (01) 103-117
• 95 Dumais A, Lesage AD, Alda M. et al. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am J Psychiatry 2005; 162 (11) 2116-2124
• 96 Blair-West GW, Cantor CH, Mellsop GW, Eyeson-Annan ML. Lifetime suicide risk in major depression: sex and age determinants. J Affect Disord 1999; 55 (2–3): 171-178
• 97 Yang Y, Chen J, Liu C. et al. The extrinsic coagulation pathway: a biomarker for suicidal behavior in major depressive disorder. Sci Rep 2016; 6: 32882
• 98 Hedner U. Recombinant activated factor VII as a universal haemostatic agent. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S147-S152
• 99 Doulalas AD, Rallidis LS, Gialernios T. et al. Association of depressive symptoms with coagulation factors in young healthy individuals. Atherosclerosis 2006; 186 (01) 121-125
• 100 Duca L, Roman N, Teodorescu A, Ifteni P. Association between inflammation and thrombotic pathway link with pathogenesis of depression and anxiety in SLE patients. Biomolecules 2023; 13 (03) 567
• 101 Gris JC, Brenner B. Antiphospholipid antibodies: neuropsychiatric presentations. Semin Thromb Hemost 2013; 39 (08) 935-942
• 102 Katzav A, Shoenfeld Y, Chapman J. The pathogenesis of neural injury in animal models of the antiphospholipid syndrome. Clin Rev Allergy Immunol 2010; 38 (2–3): 196-200
• 103 Gris JC, Nobile B, Bouvier S. Neuropsychiatric presentations of antiphospholipid antibodies. Thromb Res 2015; 135 (Suppl. 01) S56-S59
• 104 Katzav A, Menachem A, Maggio N, Pollak L, Pick CG, Chapman J. IgG accumulates in inhibitory hippocampal neurons of experimental antiphospholipid syndrome. J Autoimmun 2014; 55: 86-93
• 105 Hoirisch-Clapauch S, Amaral OB, Mezzasalma MAU, Panizzutti R, Nardi AE. Dysfunction in the coagulation system and schizophrenia. Transl Psychiatry 2016; 6 (01) e704
• 106 Hoirisch-Clapauch S, Nardi AE. Markers of low activity of tissue plasminogen activator/plasmin are prevalent in schizophrenia patients. Schizophr Res 2014; 159 (01) 118-123
• 107 Hoirisch-Clapauch S, Nardi AE. Psychiatric remission with warfarin: should psychosis be addressed as plasminogen activator imbalance?. Med Hypotheses 2013; 80 (02) 137-141

Publication History

Article published online:
23 January 2025