Thrombin activates which factors

Overall, it becomes increasingly clear that the deposition of different coagulation factors in the CNS tissue may trigger exacerbation of inflammation, thereby limiting regenerative mechanisms. A prominent role was especially described for fibrinogen, thrombin, and factor XII.

As novel molecular and cellular binding partners are identified, the role of coagulation factors is evolving from hemostasis regulators to multi-faceted signal molecules, which control the balance between immune defense mechanisms and extensive inflammation. Interestingly, the binding of coagulation factors to their cellular targets requires distinct non-overlapping epitopes and is usually independent of their protease function.

Taking advantage of this knowledge, targeted inhibition of coagulation factors that facilitate disease pathogenesis without affecting their protease activity represents an ideal strategy for pharmacological intervention in different neuroinflammatory disorders without unwarranted side-effects like bleeding. Therefore, future studies are needed to elucidate the exact contribution of blood proteins to autoimmune neurodegeneration.

KG drafted the manuscript. KG and TC funded the study. All authors provided substantial input throughout the process. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature —9. Blood coagulation factors as inflammatory mediators. Blood Cells Mol Dis 34 1 —7.

McMichael M. New models of hemostasis. Top Companion Anim Med 27 2 —5. Factor XI activation in a revised model of blood coagulation. Science — Milestones and perspectives in coagulation and hemostasis.

Semin Thromb Hemost 35 1 :9— Strukova SM. Thrombin as a regulator of inflammation and reparative processes in tissues. Biochemistry Mosc 66 1 :8— Mackman N. The many faces of tissue factor. J Thromb Haemost 7 Suppl 1 —9. Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34 1 — Inhibition of platelet adhesion and aggregation by a defined region GlyLys of high molecular weight kininogen.

J Biol Chem 26 — A novel antithrombotic role for high molecular weight kininogen as inhibitor of plasminogen activator inhibitor-1 function. J Biol Chem 36 — Regulation of leukocyte recruitment by polypeptides derived from high molecular weight kininogen. International union of pharmacology. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences.

Pharmacol Rev 57 1 — Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature — Early detection of thrombin activity in neuroinflammatory disease. Ann Neurol 75 2 —8. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CDmediated modulation of dendritic cells.

Nat Commun Prothrombin and factor X are elevated in multiple sclerosis patients. Ann Neurol 80 6 — Bradykinin B1 receptor expression and function on T lymphocytes in active multiple sclerosis. Neurology 53 9 — Kinin B1 receptor expression and function on human brain endothelial cells.

J Neuropathol Exp Neurol 59 10 — Stavrou E, Schmaier AH. Thromb Res 3 —5. Schmaier AH. The elusive physiologic role of Factor XII. J Clin Invest 9 —9. In vivo roles of factor XII. Blood 22 — Monitoring thrombin generation: is addition of corn trypsin inhibitor needed? Thromb Haemost 6 — Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.

J Exp Med 3 —8. Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 13 —7. Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking. J Autoimmun 36 2 — Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system.

Nat Med 15 7 — The role of kinin receptors in preventing neuroinflammation and its clinical severity during experimental autoimmune encephalomyelitis in mice. PLoS One 6 11 :e The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis EAE in mice: evidence for the involvement of astrocytes. Neurobiol Dis — J Neuroinflammation Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors.

Attenuation of experimental autoimmune demyelination in complement-deficient mice. J Immunol 10 — Cutting edge: C3, a key component of complement activation, is not required for the development of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis in mice.

J Immunol 2 —6. Complement in experimental autoimmune encephalomyelitis revisited: C3 is required for development of maximal disease. Mol Immunol 44 12 —6. Deletion of both ICAM-1 and C3 enhances severity of experimental autoimmune encephalomyelitis compared to C3-deficient mice. Neurosci Lett 2 — Complement C5 in experimental autoimmune encephalomyelitis EAE facilitates remyelination and prevents gliosis.

Am J Pathol 3 — Effects of complement C5 on apoptosis in experimental autoimmune encephalomyelitis. J Immunol 9 —6. Expression of C5a in the brain does not exacerbate experimental autoimmune encephalomyelitis. Neurosci Lett 3 —8. The plasminogen activator system: involvement in central nervous system inflammation and a potential site for therapeutic intervention. A role for the plasminogen activator system in inflammation and neurodegeneration in the central nervous system during experimental allergic encephalomyelitis.

Am J Pathol 2 — Kinin B1 receptor expression on multiple sclerosis mononuclear cells: correlation with magnetic resonance imaging T2-weighted lesion volume and clinical disability. Arch Neurol 62 5 — Weisel JW. Fibrinogen and fibrin. Adv Protein Chem — Fibrinogen: structure, function, and surface interactions. J Vasc Interv Radiol 12 6 — Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost 25 3 —9.

Fibrin clot formation and lysis: basic mechanisms. Semin Thromb Hemost 26 6 — Lijnen HR. Elements of the fibrinolytic system.

Ann N Y Acad Sci — Chronic relapsing experimental allergic encephalomyelitis CREAE in plasminogen activator inhibitor-1 knockout mice: the effect of fibrinolysis during neuroinflammation.

Neuropathol Appl Neurobiol 34 2 — Fibrin mechanisms and functions in nervous system pathology. Mol Interv 4 3 — Human plasma fibrinogen is synthesized in the liver. Blood 5 —4. Lowe GD. Fibrinogen measurement to assess the risk of arterial thrombosis in individual patients: not yet.

J Thromb Haemost 3 4 —7. Distinct roles for the alpha and beta subunits in the functions of integrin alphaMbeta2. J Biol Chem 2 — Perez RL, Roman J. Fibrin enhances the expression of IL-1 beta by human peripheral blood mononuclear cells.

Implications in pulmonary inflammation. J Immunol 4 — PubMed Abstract Google Scholar. Transcriptional regulation of the interleukin-1beta promoter via fibrinogen engagement of the CD18 integrin receptor. Fibrin ogen exacerbates inflammatory joint disease through a mechanism linked to the integrin alphaMbeta2 binding motif. J Clin Invest 11 — Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha M beta 2 engagement of fibrinogen.

Cancer Res 70 7 — Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 9 — Immunohistochemical study of vascular injury in acute multiple sclerosis. J Clin Pathol 47 2 — The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion.

Brain Pt 8 — The fibrin-derived gamma peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med 3 — Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis.

Paterson PY. Experimental allergic encephalomyelitis: role of fibrin deposition in immunopathogenesis of inflammation in rats. Fed Proc 35 13 — Google Scholar. Fibrinogen depleting agent batroxobin has a beneficial effect on experimental autoimmune encephalomyelitis. Cell Mol Neurobiol 31 3 — Suppression of cell-transferred experimental autoimmune encephalomyelitis in defibrinated Lewis rats.

J Neuroimmunol 71 1—2 —7. The modification of experimental allergic encephalomyelitis with epsilon aminocaproic acid. Neurology 28 9 Pt 2 —5. Involvement of tissue plasminogen activator in onset and effector phases of experimental allergic encephalomyelitis. J Neurosci 22 24 —9. Suppression of experimental autoimmune encephalomyelitis by extracellular adherence protein of Staphylococcus aureus.

J Exp Med 4 — Experimental allergic encephalomyelitis-inducing activity of synthetic polyadenylic and polyuridylic homopolymers and complexes in guinea pigs. Cell Immunol 21 1 — Plasminogen activators in multiple sclerosis lesions: implications for the inflammatory response and axonal damage. Brain Pt 10 — Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors. Brain Pt 7 —8. Cerebrospinal fluid activity of tissue plasminogen activator in patients with neurological diseases.

J Clin Pathol 49 7 — Lupus anticoagulant-hypoprothrombinemia syndrome: report of 8 cases and review of the literature. Medicine Baltimore 91 5 — Congenital prothrombin deficiency: an update. Semin Thromb Hemost 39 6 — Hirano K, Hirano M. Current perspective on the role of the thrombin receptor in cerebral vasospasm after subarachnoid hemorrhage.

J Pharmacol Sci 2 — Increased thrombin inhibition in experimental autoimmune encephalomyelitis. J Neurosci Res 79 3 —9. Rheumatoid arthritis. Lancet — Arthritis is linked to local and systemic activation of coagulation and fibrinolysis pathways. It has a mitogenic effect stimulating growth of mammalian cells, fibroblasts and macrophage-like tumor cell lines. It has also been implicated in brain development. A molecule with multifunctional roles such as thrombin has its activity in vivo modulated by only a few endogenous inhibitors.

Abstract Thrombin is an unique molecule that functions both as a procoagulant and anticoagulant. Publication types Review. Substances Prothrombin Thrombin.