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.

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Artikel online veröffentlicht:
23. Januar 2025