thromboplastin and Multiple-Sclerosis

Tissue factor is the primary initiator of the coagulation cascade. Formation of the TF:FVIIa complex activates both FX and FIX, with subsequent thrombin generation, fibrin deposition and activation of platelets. In addition to playing important role in hemostasis and thrombosis, TF and downstream coagulation proteases can mediate intracellular signaling via activation of protease-activated receptors (PARs). Maintaining hemostasis in the brain is of utmost importance: bleeding or thrombosis within this organ can lead to significant morbidity and mortality. Both TF and PARs are widely expressed within the CNS, with TF expressed predominantly by astrocytes and PARs expressed in multiple cell types including astrocytes, neurons, microglia and oligodendrocytes [1-4]. PARs activation can result in either neuronal survival or death and link the coagulation system with the inflammatory response. In this brief review we summarize the contribution of the coagulation system to brain hemostasis as well as to the pathophysiology of stroke and multiple sclerosis.

Topics: Animals; Astrocytes; Autoimmunity; Blood Coagulation; Brain; Hemorrhage; Hemostasis; Humans; Inflammation; Multiple Sclerosis; Stroke; Thromboplastin

The interaction of coagulation factors with the perivascular environment affects the development of disease in ways that extend beyond their traditional roles in the acute hemostatic cascade. Key molecular players of the coagulation cascade like tissue factor, thrombin, and fibrinogen are epidemiologically and mechanistically linked with diseases with an inflammatory component. Moreover, the identification of novel molecular mechanisms linking coagulation and inflammation has highlighted factors of the coagulation cascade as new targets for therapeutic intervention in a wide range of inflammatory human diseases. In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer. Genetic and pharmacologic studies have unraveled pivotal roles for fibrinogen in determining the extent of local or systemic inflammation. As cellular and molecular mechanisms for fibrinogen functions in tissues are identified, the role of fibrinogen is evolving from a marker of vascular rapture to a multi-faceted signaling molecule with a wide spectrum of functions that can tip the balance between hemostasis and thrombosis, coagulation and fibrosis, protection from infection and extensive inflammation, and eventually life and death. This review will discuss some of the main molecular links between coagulation and inflammation and will focus on the role of fibrinogen in inflammatory disease highlighting its unique structural properties, cellular targets, and signal transduction pathways that make it a potent proinflammatory mediator and a potential therapeutic target.

Topics: Alzheimer Disease; Animals; Arthritis, Rheumatoid; Bacterial Infections; Blood Coagulation; Brain Injuries; Colitis; Fibrinogen; Humans; Inflammation; Kidney Diseases; Multiple Sclerosis; Muscular Dystrophy, Duchenne; Neoplasms; Pulmonary Fibrosis; Spinal Cord Injuries; Stroke; Thrombin; Thromboplastin; Vascular Diseases

Microparticles are submicron vesicles shed from plasma membranes in response to cell activation, injury, and/or apoptosis. The measurement of the phospholipid content (mainly phosphatidylserine; PSer) of microparticles and the detection of proteins specific for the cells from which they are derived has allowed their quantification and characterization. Microparticles of various cellular origin (platelets, leukocytes, endothelial cells) are found in the plasma of healthy subjects, and their amount increases under pathological conditions. Endothelial microparticles (EMP) not only constitute an emerging marker of endothelial dysfunction, but are also considered to play a major biological role in inflammation, vascular injury, angiogenesis, and thrombosis. Although the mechanisms leading to their in vivo formation remain obscure, the release of EMP from cultured cells can be caused in vitro by a number of cytokines and apoptotic stimuli. Recent studies indicate that EMP are able to decrease nitric-oxide-dependent vasodilation, increase arterial stiffness, promote inflammation, and initiate thrombosis at their PSer-rich membrane, which highly co-expresses tissue factor. EMP are known to be elevated in acute coronary syndromes, in severe hypertension with end organ damage, and in thrombotic thrombocytopenic purpura, all conditions associated with endothelial injury and pro-thrombotic state. The release of EMP has also been associated with endothelial dysfunction of patients with multiple sclerosis and lupus anticoagulant. More recent studies have focused on the role of low shear stress leading to endothelial cell apoptosis and subsequent EMP release in end-stage renal disease. Improved knowledge of EMP composition, their biological effects, and the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.

Topics: Animals; Apoptosis; Biomarkers; Blood Vessels; Cardiovascular Diseases; Cell-Derived Microparticles; Cytokines; Endothelial Cells; Humans; Inflammation; Kidney Failure, Chronic; Lupus Coagulation Inhibitor; Multiple Sclerosis; Neovascularization, Pathologic; Nitric Oxide; Phosphatidylserines; Shear Strength; Thromboplastin

Topics: Apoptosis; Cytokines; Helicobacter Infections; Helicobacter pylori; Humans; Lipid Peroxidation; Multiple Sclerosis; Platelet Aggregation; Reactive Oxygen Species; Scleroderma, Systemic; Thromboplastin

Although multiple sclerosis (MS) and antiphospholipid syndrome (AS) are usually defined by specific criteria that make them distinguishable, in some cases, transition between the two diseases based on clinical and brain imaging findings is not clear.. Our study included 62 patients (sex ratio F/M = 1.48; mean age 43.4 +/- 23.6 years) with diagnosis of MS according to Poser criteria and 31 control subjects (sex ratio F/M = 9.3, mean age 37 +/- 17 years). We examined the level of antibodies against phospholipids (anticardiolipid, anti beta 2-glycoprotein 1 and antiphosphatidylethanolamine antibodies), antinuclear, anti native DNA, antiprothrombinase antibodies and rheumatoid factor.. Antiphospholipid antibodies were found with a significant level (anticardiolipid > 30 UI, anti beta 2-glycoprotein 1 positive) in only five patients (8%) with MS; two others showed an increase in antinuclear antibodies (1/320 degrees and 1/1280 degrees).. In contrast with data recently reported, this study failed to find a significant level of antiphospholipid antibodies in MS. This result argues for the existence of different pathogenic mechanisms in MS and AS.

Topics: Adult; Antibodies, Antinuclear; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Autoantibodies; Cardiolipins; Diagnosis, Differential; Female; Humans; Male; Multiple Sclerosis; Phosphatidylethanolamines; Rheumatoid Factor; Thromboplastin

To investigate the function of peripheral blood monocytes in multiple sclerosis (MS), we measured the production of the cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), and interleukin-6 (IL-6), and the procoagulant, tissue factor (TF) in 17 patients with chronic progressive MS and 15 normal controls. Monocyte activity was tested under unstimulated, minimal endotoxin conditions and after culture with various stimuli, including Escherichia coli lipopolysaccharide (LPS), crude supernatant from anti-CD3-activated T cells, recombinant interleukin-2 (rIL-2), and recombinant interferon-gamma (rIFN-gamma). A higher number of MS patients than controls had circulating monocytes which spontaneously secreted IL-6 or contained detectable cell-associated IL-1 beta. Monocyte responses to LPS were comparable between the two groups; LPS caused production and secretion of all cytokines and TF in every MS patient and control. In contrast, crude T cell supernatants, rIL-2, and rIFN-gamma induced IL-1 beta release in a higher number of MS monocytes than that in controls, whereas the production and secretion of the other cytokines and TF activity were similar between the groups. We conclude that some MS patients have "primed" circulating monocytes, as shown by excessive spontaneous IL-6 release and intracellular IL-1 beta synthesis. Unstimulated MS monocytes, however, are not different from controls with respect to spontaneous secretion of small amounts of IL-1 beta and TNF alpha and expression of cell surface TF. Excessive IL-1 beta secretion by MS monocytes after stimulation with T-cell-derived lymphokines suggests dysregulation of T cell-monocyte interactions which may be most relevant in the central nervous system plaques where activated T cells are found.

Topics: Humans; Interferon-gamma; Interleukin-1; Interleukin-2; Interleukin-6; Lipopolysaccharides; Monocytes; Multiple Sclerosis; Recombinant Proteins; T-Lymphocytes; Thromboplastin; Tumor Necrosis Factor-alpha

Topics: Humans; Multiple Sclerosis; Thromboplastin