fibrin and Multiple-Sclerosis

Several studies in both multiple sclerosis (MS) and experimental autoimmune encephalitis (EAE) have shed light on the vascular mechanisms contributing to MS pathogenesis. The dysregulation of the hemostatic pathways revealed to play a pivotal role. Here, we review the numerous findings providing evidence on the involvement of hemostasis components in MS pathogenesis to highlight why they might be considered potential therapeutic targets in the disease. A literature search for articles from January 1950 to September 2021 was conducted in PubMed and Scopus. A consistent body of evidence supports the pro-inflammatory activity of activated platelets in MS pathogenesis and the beneficial effect of aspirin administration on the EAE clinical course. Further, neuropathological findings in subjects with MS and experimental studies in EAE have revealed dysregulation of coagulation/fibrinolysis system in autoimmune demyelination. Fibrin deposition in the central nervous system and its interaction with the CD11b receptor on microglia cells seems to drive neuroinflammation and autoimmune demyelination. However, at present, few and controversial clinical data are available on the implementation of drugs targeting fibrin deposition in MS therapy. In conclusion, targeting platelet activation and receptors for fibrin(ogen) deserve further research to hopefully purpose new drugs in the pharmacologic paraphernalia of MS neurologists.

Topics: Animals; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Fibrin; Hemostasis; Humans; Mice; Mice, Inbred C57BL; Multiple Sclerosis

We report the case of a 25-year-old man with multiple sclerosis (MS) who had severe headache and unconsciousness. He suffered from optic neuritis that had started at age 6. From the age of 12 years, he had suffered from multiple sclerosis (MS) cerebral lesions that relapsed three times over for 5 years. At age 25, he showed a new lesion in the cerebellar cortex, suggesting an exacerbation of the MS. However, magnetic resonance imaging findings the next day showed cerebral venous sinus thrombosis. His laboratory findings showed low antithrombin activity. Genetic analysis revealed a single-base substitution (C>T) at the codon 359 (Arg to STOP) in the 5th exon portion of the antithrombin gene, heterozygote. In the literature review, 17 cases of multiple sclerosis associated with cerebral venous sinus thrombosis, which occurred after the lumbar puncture and the treatment with high-dose methylpredonisolone in 11 of these cases. In our case, antithrombin deficiency, hyperhomocystinemia, infection, and lumbar puncture were suggested as the risk factors.

Topics: Adult; Antithrombins; Codon, Nonsense; Diffusion Magnetic Resonance Imaging; Fibrin; Heterozygote; Humans; Hyperhomocysteinemia; Male; Methylprednisolone; Multiple Sclerosis; Risk Factors; Sinus Thrombosis, Intracranial; Spinal Puncture

A condition called "chronic cerebrospinal venous insufficiency" (CCSVI) has been postulated to play a role in the pathogenesis of multiple sclerosis (MS). This hypothesis implies that a complex pattern of extracranial venous stenosis determines a venous reflux into the brain of MS patients, followed by increased intravenous pressure, blood-brain barrier breakdown and iron deposition into the brain parenchyma, thus triggering a local inflammatory response. In this review, we critically analyze the scientific basis of CCSVI, the current literature on the relationship between CCSVI and MS, as well as the ultrasound methodology that has been claimed to provide evidence of impaired cerebral venous drainage. We show that no piece of the CCSVI theory has a solid supportive scientific evidence. The CCSVI appears to be a rather alien condition and its existence should be definitely questioned. Finally, no proven (i.e., based on strict scientific methodology and on the rules of evidence-based medicine) therapeutic effect of the "liberation" procedure (unblocking the extracranial venous obstruction using angioplasty) has been shown up to date.

Topics: Animals; Brain; Disease Models, Animal; Dogs; Fibrin; Humans; Iron; Multiple Sclerosis; Venous Insufficiency

Topics: Cell Adhesion Molecules; Fibrin; Humans; Iron; Iron Overload; Macrophages; Matrix Metalloproteinases; Multiple Sclerosis; Vasculitis

In brain physiology, cerebrovascular interactions regulate both, vascular functions, such as blood vessel branching and endothelial cell homeostasis, as well as neuronal functions, such as local synaptic activity and adult neurogenesis. In brain pathology, including stroke, HIV encephalitis, Alzheimer Disease, multiple sclerosis, bacterial meningitis, and glioblastomas, rupture of the vasculature allows the entry of blood proteins into the brain with subsequent edema formation and neuronal damage. Fibrin is a blood-derived protein that is not produced by cells of the nervous system, but accumulates only after disease associated with vasculature rupture. This review presents evidence from human disease and animal models that highlight the role of fibrin in nervous system pathology. Our review presents novel experimental data that extend the role of fibrin, from that of a blood-clotting protein in cerebrovascular pathologies, to a component of the perivascular extracellular matrix that regulates inflammatory and regenerative cellular responses in neurodegenerative diseases.

Topics: Amino Acid Sequence; Ancrod; Animals; Blood-Brain Barrier; Fibrin; Fibrinogen; Fibrinolytic Agents; Homeostasis; Humans; Inflammation; Macrophages; Molecular Sequence Data; Multiple Sclerosis; Myelin Sheath; Nerve Regeneration; Nervous System; Neuroglia; Neurons; Signal Transduction

Fibrin deposition is a fundamental pathophysiological event in the inflammatory component of various CNS disorders, such as multiple sclerosis (MS) and Alzheimer's disease. Beyond its traditional role in coagulation, fibrin elicits immunoinflammatory changes with oxidative stress response and activation of CNS-resident/peripheral immune cells contributing to CNS injury.. To investigate if CNS fibrin deposition can be determined using molecular MRI, and to assess its capacity as a non-invasive imaging biomarker that corresponds to inflammatory response and barrier impairment.. Specificity and efficacy of a peptide-conjugated Gd-based molecular MRI probe (EP2104-R) to visualise and quantify CNS fibrin deposition were evaluated. Probe efficacy to specifically target CNS fibrin deposition in murine adoptive-transfer experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for MS (n = 12), was assessed. Findings were validated using immunohistochemistry and laser ablation inductively coupled plasma mass spectrometry. Deposition of fibrin in neuroinflammatory conditions was investigated and its diagnostic capacity for disease staging and monitoring as well as quantification of immunoinflammatory response was determined. Results were compared using t-tests (two groups) or one-way ANOVA with multiple comparisons test. Linear regression was used to model the relationship between variables.. For the first time (to our knowledge), CNS fibrin deposition was visualised and quantified in vivo using molecular imaging. Signal enhancement was apparent in EAE lesions even 12-h after administration of EP2104-R due to targeted binding (M ± SD, 1.07 ± 0.10 (baseline) vs. 0.73 ± 0.09 (EP2104-R), p = .008), which could be inhibited with an MRI-silent analogue (M ± SD, 0.60 ± 0.14 (EP2104-R) vs. 0.96 ± 0.13 (EP2104-La), p = .006). CNS fibrin deposition corresponded to immunoinflammatory activity (R. Molecular imaging of CNS fibrin deposition provides an imaging biomarker for inflammatory CNS pathology, which corresponds to pathophysiological ECM remodelling and disease activity, and yields high signal-to-noise ratio, which can improve diagnostic neuroimaging across several neurological diseases with variable degrees of barrier impairment.

Topics: Animals; Contrast Media; Encephalomyelitis, Autoimmune, Experimental; Fibrin; Humans; Magnetic Resonance Imaging; Mice; Multiple Sclerosis

In multiple sclerosis (MS), disturbance of the plasminogen activation system (PAS) and blood brain barrier (BBB) disruption are physiopathological processes that might lead to an abnormal fibrin(ogen) extravasation into the parenchyma. Fibrin(ogen) deposits, usually degraded by the PAS, promote an autoimmune response and subsequent demyelination. However, the PAS disruption is not well understood and not fully characterized in this disorder.. Here, we characterized the expression of PAS actors during different stages of two mouse models of MS (experimental autoimmune encephalomyelitis-EAE), in the central nervous system (CNS) by quantitative RT-PCR, immunohistofluorescence and fluorescent in situ hybridization (FISH). Thanks to constitutive PAI-1 knockout mice (PAI-1 KO) and an immunotherapy using a blocking PAI-1 antibody, we evaluated the role of PAI-1 in EAE models and its impact on physiopathological processes such as fibrin(ogen) deposits, lymphocyte infiltration and demyelination.. We report a striking overexpression of PAI-1 in reactive astrocytes during symptomatic phases, in two EAE mouse models of MS. This increase is concomitant with lymphocyte infiltration and fibrin(ogen) deposits in CNS parenchyma. By genetic invalidation of PAI-1 in mice and immunotherapy using a blocking PAI-1 antibody, we demonstrate that abolition of PAI-1 reduces the severity of EAE and occurrence of relapses in two EAE models. These benefits are correlated with a decrease in fibrin(ogen) deposits, infiltration of T4 lymphocytes, reactive astrogliosis, demyelination and axonal damage.. These results demonstrate that a deleterious overexpression of PAI-1 by reactive astrocytes leads to intra-parenchymal dysfibrinolysis in MS models and anti-PAI-1 strategies could be a new therapeutic perspective for MS.

Topics: Animals; Astrocytes; Central Nervous System; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Fibrin; In Situ Hybridization, Fluorescence; Mice; Mice, Knockout; Multiple Sclerosis; Plasminogen Activator Inhibitor 1; Serpin E2

Topics: Abciximab; Allergy and Immunology; Animals; Blood-Brain Barrier; Bloodless Medical and Surgical Procedures; Encephalitis; Fibrin; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Immunity, Innate; Immunotherapy; Mice; Multiple Sclerosis; Tumor Necrosis Factor-alpha

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelination and axonal damage of the central nervous system. The pathogenesis of MS has also been linked to vascular inflammation and local activation of the coagulation system, resulting in perivascular fibrin deposition. Treatment of experimental autoimmune encephalomyelitis (EAE), a model of human MS, with antithrombotic and antiinflammatory activated protein C (APC) reduces disease severity. Since recombinant APC (Drotecogin alfa), originally approved for the treatment of severe sepsis, is not available for human MS studies, we tested the hypothesis that pharmacologic activation of endogenous protein C could likewise improve the outcome of EAE. Mice were immunized with murine myelin oligodendrocyte glycoprotein (MOG) peptides and at the onset of EAE symptoms, were treated every other day with either WE thrombin (25 μg/kg; i.v.), a selective recombinant protein C activator thrombin analog, or saline control. Mice were monitored for changes in disease score until euthanized for ex vivo analysis of inflammation. Administration of WE thrombin significantly ameliorated clinical severity of EAE, reduced inflammatory cell infiltration and demyelination, suppressed the activation of macrophages comprising the CD11b + population and reduced accumulation of fibrin (ogen) in the spinal cord. These data suggest that symptomatic MS may respond to a treatment strategy that involves temporal pharmacological enhancement of endogenous APC generation.

Topics: Animals; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Enzyme Activation; Fibrin; Fibrinogen; Humans; Intercellular Adhesion Molecule-1; Macrophage Activation; Male; Mice; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Point Mutation; Protein C; Spinal Cord; Spleen; Thrombin; Treatment Outcome; Tumor Necrosis Factor-alpha; White Matter

Increased permeability of blood vessels is an indicator for various injuries and diseases, including multiple sclerosis (MS), of the central nervous system. Nanoparticles have the potential to deliver drugs locally to sites of tissue damage, reducing the drug administered and limiting associated side effects, but efficient accumulation still remains a challenge. We developed peptide-functionalized polymeric nanoparticles to target blood clots and the extracellular matrix molecule nidogen, which are associated with areas of tissue damage. Using the induction of experimental autoimmune encephalomyelitis in rats to provide a model of MS associated with tissue damage and blood vessel lesions, all targeted nanoparticles were delivered systemically. In vivo data demonstrates enhanced accumulation of peptide functionalized nanoparticles at the injury site compared to scrambled and naive controls, particularly for nanoparticles functionalized to target fibrin clots. This suggests that further investigations with drug laden, peptide functionalized nanoparticles might be of particular interest in the development of treatment strategies for MS.

Topics: Animals; Carbocyanines; Drug Carriers; Encephalomyelitis, Autoimmune, Experimental; Female; Fibrin; Fluorescent Dyes; Hydrophobic and Hydrophilic Interactions; Lactones; Laminin; Membrane Glycoproteins; Multiple Sclerosis; Nanoparticles; Oligopeptides; Polyethylene Glycols; Rats; Rats, Inbred F344; Spinal Cord; Up-Regulation

Dysferlin is a muscle protein involved in cell membrane repair and its deficiency is associated with muscular dystrophy. We describe that dysferlin is also expressed in leaky endothelial cells. In the normal central nervous system (CNS), dysferlin is only present in endothelial cells of circumventricular organs. In the inflamed CNS of patients with multiple sclerosis (MS) or in animals with experimental autoimmune encephalomyelitis, dysferlin reactivity is induced in endothelial cells and the expression is associated with vascular leakage of serum proteins. In MS, dysferlin expression in endothelial cells is not restricted to vessels with inflammatory cuffs but is also present in noninflamed vessels. In addition, many blood vessels with perivascular inflammatory infiltrates lack dysferlin expression in inactive lesions or in the normal-appearing white matter. In vitro, dysferlin can be induced in endothelial cells by stimulation with tumor necrosis factor-alpha. Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis.

Topics: Animals; Biomarkers; Cerebral Cortex; Dysferlin; Encephalomyelitis, Autoimmune, Experimental; Female; Fibrin; Humans; Immunohistochemistry; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Muscle Proteins; Nerve Tissue Proteins; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Diseases

Early signs of inflammatory demyelination include entry of fibrin(ogen) into the central nervous system (CNS), which is normally excluded by the blood-brain barrier, and up-regulation of components of the plasminogen activator system. Using mice deficient in tissue-type plasminogen activator (tPA-/-) and urokinase plasminogen activator receptor (uPAR-/-), we investigated the involvement of the PA system on the clinical and pathological features of experimental allergic encephalomyelitis, an animal model of multiple sclerosis. tPA-/- mice suffered an early and a more severe acute disease characterized by incomplete recovery when compared to wild-type controls, with significantly higher CNS levels of plasminogen activator inhibitor-1. This correlated with fibrin accumulation, which co-localized with nonphosphorylated neurofilament on thickened axons in experimental allergic encephalomyelitis tissue. In contrast, uPAR-/- mice had a delayed, less acute disease reflected in delayed infiltration of inflammatory cells. These animals developed chronic disease as a result of steadily increased inflammation, increased levels of urokinase-type plasminogen activator (uPA), and greater degree of demyelination. Thus, the plasminogen activator system can modulate both inflammatory and degenerative events in the CNS through the respective effects of tPA and uPAR on fibrinolysis and cell adhesion/migration, manipulation of which may have therapeutic implications for multiple sclerosis.

Topics: Animals; Axons; Central Nervous System; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Female; Fibrin; Fibrinolysis; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Nerve Degeneration; Plasminogen Activator Inhibitor 1; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator

In multiple sclerosis, in which brain tissue becomes permeable to blood proteins, extravascular fibrin deposition correlates with sites of inflammatory demyelination and axonal damage. To examine the role of fibrin in neuroinflammatory demyelination, we depleted fibrin in two tumor necrosis factor transgenic mouse models of multiple sclerosis, transgenic lines TgK21 and Tg6074. In a genetic analysis, we crossed TgK21 mice into a fibrin-deficient background. TgK21fib(-/-) mice had decreased inflammation and expression of major histocompatibility complex class I antigens, reduced demyelination, and a lengthened lifespan compared with TgK21 mice. In a pharmacologic analysis, fibrin depletion, by using the snake venom ancrod, in Tg6074 mice also delayed the onset of inflammatory demyelination. Overall, these results indicate that fibrin regulates the inflammatory response in neuroinflammatory diseases. Design of therapeutic strategies based on fibrin depletion could potentially benefit the clinical course of demyelinating diseases such as multiple sclerosis.

Topics: Animals; Cell Line; Demyelinating Diseases; Fibrin; Inflammation; Macrophage Activation; Mice; Mice, Transgenic; Multiple Sclerosis; Plasminogen Activators; Tumor Necrosis Factor-alpha; Up-Regulation

To examine the vascular changes occurring in three archival cases of acute multiple sclerosis, and to provide immunohistochemical evidence of early endothelial cell activation and vascular occlusion in this condition.. Central nervous system tissues from three cases of acute active multiple sclerosis and six non-inflammatory controls were stained using the following methods: haematoxylin and eosin, Luxol fast blue, cresyl violet, Bielschowsky's silver, and reticulin. Tissues were also immunostained with specific antibodies against collagen type IV, factor XIIIa, class II antigens, glial fibrillary acidic protein, and fibrinogen.. Early vascular endothelial cell activation which may progress to vasculitis and vascular occlusion including class II antigen expression and fibrin deposition were identified. The vascular changes were seen prior to cerebral parenchymal reaction and demyelination, and were not seen in control cerebral tissues.. It is proposed that vascular endothelial cell activation may be an early and pivotal event in the evolution of multiple sclerosis, and that demyelination may have an ischaemic basis in this condition. The vascular endothelium may contain an early element in the evolution of multiple sclerosis.

Topics: Acute Disease; Adolescent; Adult; Brain; Endothelium, Vascular; Female; Fibrin; HLA-D Antigens; Humans; Immunoenzyme Techniques; Male; Microcirculation; Multiple Sclerosis; Thrombosis; Vascular Diseases; Vasculitis

Cryostat sections of central nervous system (CNS) tissues of patients with multiple sclerosis (MS) and other CNS diseases were stained with antibodies to fibronectin, a macrophage fibronectin receptor component, fibrin/fibrinogen, and albumin using immunoperoxidase. In active, but not inactive, MS plaques vessel fibronectin was increased (to approximately 57% of Factor VIII+ vessels) over uninvolved MS and normal control white matter (P less than 0.001 for both). Fibronectin was primarily localized to vessel walls and amount of staining correlated with degree of inflammation. Active plaques and necrotic lesions also had extracellular fibronectin and fibrin/ogen. These molecules and the fibronectin receptor were found on macrophages. Albumin was more widely and diffusely distributed in lesions than fibronectin. Thus, in addition to extravasation from damaged vessels, fibronectin may be deposited on or synthesized by endothelial cells and macrophages in the CNS. Fibronectin could facilitate monocyte adhesion to endothelial cell luminal surfaces, promote migration of mononuclear cells, and enhance myelin phagocytosis in MS lesions.

Topics: Antibodies; Brain; Fibrin; Fibrinogen; Fibronectins; Humans; Immunohistochemistry; Microcirculation; Multiple Sclerosis; Receptors, Fibronectin; Receptors, Immunologic; Serum Albumin

Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis.

Topics: Cerebral Hemorrhage; Cerebral Infarction; Cerebral Veins; Cerebrovascular Disorders; Fibrin; Hemosiderin; Humans; Intracranial Embolism and Thrombosis; Iron; Multiple Sclerosis; Vasculitis

Experimental allergic encephalomyelitis (EAE) and other analogous neuroimmunologic diseases of animals and humans, including multiple sclerosis (MS), are discussed within the context of 1) host lymphoid cells autoreactive with myelin basic protein (MBP) or other neural antigens that elude normal immunoregulatory mechanisms, 2) development of subsets of cytotoxic effector cell clones directed against MBP and other central nervous system (CNS) antigenic components, and 3) neurophysiological and CNS inflammatory structural changes, respectively, which reflect the binding of these effector cell subsets to host CNS target tissue. One set of cytotoxic cells reactive with MBP appears to cause increased permeability of the cerebrovasculature with deposition of fibrin, development of edema, and appearance of clinical paralytic signs of EAE, unaccompanied by infiltrating host inflammatory cells. A second subset of cytotoxic effector cells reactive with non-MBP neural antigen(s) appears to cause the focal, perivascular host inflammatory cell response, which in turn leads to various degrees of demyelination, an important feature of EAE, and the identifying hallmark of the MS process. Indirect evidence, secured by a sensitive radioimmunoassay (RIA), implicates endogenous circulating MBP serum factors (MBP-SFs), characterized by high-affinity binding to anti-MBP antibodies represented in the RIA reagent antiserum, as being of paramount importance in preventing proliferation of neuroreactive cytotoxic lymphoid cells. In this sense MBP-SFs act as neuroautotolerogens. Based on the foregoing concepts and observations, major pathways of CNS injury and inflammation are postulated and discussed.

Topics: Animals; Brain; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental; Fibrin; Humans; Lymphocytes; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteins; Rats; Rats, Inbred Lew

Topics: Arthritis; Cell Membrane; Cell Physiological Phenomena; Endocytosis; Exudates and Transudates; Fibrin; Humans; Inclusion Bodies; Microscopy, Electron; Multiple Sclerosis; Pseudopodia; Psoriasis; Synovial Fluid; Synovial Membrane

Topics: Animals; Antigens; Bacterial Infections; Brain; Cross Reactions; Demyelinating Diseases; Disease Models, Animal; Edema; Encephalomyelitis, Autoimmune, Experimental; Exudates and Transudates; Fibrin; Guinea Pigs; Haplorhini; Hemorrhage; Heparin; Humans; Immunization, Passive; Inflammation; Leukocytes; Lymphocytes; Multiple Sclerosis; Myelin Sheath; Pertussis Vaccine; Proteins; Rats; Virus Diseases

Topics: Blood Coagulation; Blood Viscosity; Fibrin; Hemophilia A; Hemophilia B; Humans; Kinetics; Multiple Sclerosis; Parkinson Disease; Polymers; Thrombelastography

Topics: Adult; Animals; Antifibrinolytic Agents; Arthritis, Rheumatoid; Blood Sedimentation; Coronary Disease; Erythrocytes; Fibrin; Fibrinogen; Humans; Middle Aged; Multiple Sclerosis; Neurotic Disorders; Protamines; Rabbits; Rats; Staphylococcal Infections

Topics: Coagulants; Extracellular Space; Fibrin; Fibrinogen; Hemostatics; Humans; Multiple Sclerosis; Plasma