Fibrinogen can bind to users of three major families of integrins, beta-1 (alpha5-beta1), beta-2 (CD11b/CD18 and CD11c/CD18), and beta-3 (alpha-v-beta3), that are expressed by leukocytes on their surface (92). The conversion of fibrinogen to insoluble fibrin exposes the cryptic epitope 377C395. Altogether, these studies spotlight the role of the coagulation pathway in the pathophysiology of MS and suggest possible therapeutic targets that may match existing treatments. (TF) pathway, after vessel damage blood-based coagulation factor VII links with TF, which is present in the subendothelial tissue and fibroblasts as well as in a smaller quantity in circulating form on monocytes, to form an activated complex TF-FVIIa. FVII is also activated by FXa, FIXa, FXIIa and thrombin. Under some pathologic circumstances, TF is usually expressed also by Rabbit polyclonal to ZNF317 monocytes, neutrophils, endothelial cells, and platelets with increased levels of circulating TF-positive microparticles that amplify the process of coagulation cascade. The activated complex TF-FVIIa activates coagulation factors FIX and FX. Intrinsic pathway, which mainly activates thrombin, begins with formation of the primary complex on uncovered collagen by factor XII, high-molecular-weight kininogen, prekallekerin, and factor XI. Endothelial collagen is usually exposed only in course of endothelial damage. Factor XII convers in active FXIIa that converts FXI into activated FXIa. FXIa further activates factor IX, which acts with its cofactor FVIII to form tenase complex on a phospholipid surface and to activate factor X to FXa. In common pathway FXa along with its cofactor FVa, tissue phospholipids, platelet phospholipids and calcium forms the prothrombinase complex, which activates prothrombin to thrombin. Thrombin activates FV and FVIII, releasing the latter from its link with vWF. Thrombin further cleaves Procyanidin B1 circulating fibrinogen to insoluble fibrin and activates factor XIII, which covalently crosslinks fibrin polymers incorporated in the platelet plug. This creates a fibrin network the building block of a hemostatic plug. Thrombin has also pro-inflammatory effects fascinating the PAR present on monocytes, lymphocytes, endothelium and dendritic cells. In addition, it is the most important platelet activator activating FVIII and FV and their inhibitor protein C in the presence of thrombomodulin (TM). Platelets Procyanidin B1 Numerous studies have highlighted the contribution of blood platelets to the inflammatory process that characterizes MS. These cells may be involved also in the pathophysiology of other neurological diseases, such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (47). The role of blood platelets during the acute and chronic phase of inflammation is not marginal. These cells release proinflammatory mediators, display molecules on their surface with inflammatory functions and interact with endothelial cells and leukocytes (48). Platelets release several proinflammatory mediators. Three types Procyanidin B1 of secretory granules have been explained in platelets: dense granules, lysosomes, and alpha-granules (48). The latter type is the most abundant. They are produced during megakaryocyte maturation and are considered crucial for platelet functions. Hundreds of soluble factors are stored in these alpha-granules, including prothrombin, tissue factor, high molecular excess weight kininogen, chemokines (RANTES, CXCL1, CXCL4, CXCL5, CXCL7, CXCL8, CXCL12, CCL2, macrophage inflammatory protein 1-alpha), proangiogenic and antiangiogenic proteins, growth factors, and inhibitory proteases [e.g., plasminogen activator inhibitor, alpha2-antiplasmin, antithrombin III (AT III), protein S, protease nexin-2, plasminogen, and tissue factor pathway inhibitor](48). Procyanidin B1 Dense granules store ATP, GDP, ADP, 5-HT, Ca, Mg and histamine, whereas lysosomal granules contain glycohydrolases, and acid proteases (48). Interestingly, platelets synthesize and secrete matrix metalloproteinases (MMPs) as well as tissue inhibitors of MMPs (TIMPs). The main MMP in platelets is usually MMP-1, which is usually important because it activates protease activated receptor 1 (PAR-1), which, in turn, is important for platelet aggregation (48). Through the cyclooxygenase (COX) and platelet activating Procyanidin B1 factor (PAF) pathways, platelets are also able to synthesize lipid mediators, including eicosanoids. PAF can also induce the production.