he active serine proteases and their factors, conferring the 'cascade' description of the system. Fibrinolysis follows coagulation, to lyse fibrin and protect against blood clotting. Several anticoagulant systems are in place to tightly regulate coagulation. An intimate relationship exists between blood coagulation and the complement system of innate immunity, cross-talking occurring at various points. The two systems are believed to have originated from a common ancestor, and the dual requirement to stop bleeding and prevent against infection subsequent to injury underscores the need to for the exquisite balance they've established.
The extrinsic route is initiated when coagulation factor 3 (F3), known as tissue factor (TF), binds factor VII (F7). F7 can be in its inactive (and predominant) form or as active (F7a) enzyme; however, without bound F3, it has very weak activity. F3 is unique among coagulation factors, being an integral membrane protein and not being subject to proteolysis. F7 is one of several vitamin K-dependent (VKD) proteins. Vitamin K serves as a cofactor in the reaction that modifies specific glutamine (Glu) residues to gamma-carboxyglutamate (Gla) residues. Glas (10 to 12) in the amino terminal Gla domain (click to access the PFAM entry) mediate the reversible, calcium-dependent, binding to negatively charged phospholipids (phosphatidylserine or phosphatidic acid) of membranes. The TF/F7a complex binds factor X (F10), to form an 'extrinsic tenase complex' that activates F10 to F10a; it can also catalyze the formation of active factor IX (F9a) from F9. F10a is the core component of the common pathway which activates thrombin (F2), in turn converting fibrinogen to fibrin - the main component of a clot. The extrinsic pathway generates small amounts of F10a and sustained F10a production, and thus coagulation, is mediated by the intrinsic pathway. The small amount of thrombin that the extrinsic pathway generates can serve as a signal for the coagulation-amplifying intrinsic pathway, through the many interactions thrombin establishes.

The intrinsic (contact) pathway is initiated by factor XII (F12) whose binding to a negatively charged surface promotes autoactivation to F12a. F12a catalyzes the conversion of factor XI (F11) to active FXIa (F11a) and of plasma prekallikrein zymogen (pKlkb1) to kallikrein (Klkb1). The latter is the first step of the kallikrein-kinin cascade, and also provides a positive feedback to coagulation. Klkb1 activates the high molecular weight kininogen precursor to the active bradykinin peptide and converts F12 to the active F12a protease. F12a, in sufficient amount, converts F11 to F11a, which then converts F9 to F9a. F11 displays features different from other proteases in the system: it is not a vitamin K-dependent protein and the active F11a is a dimer. Each subunit contains four apple domains (A1 to A4) and a trypsin-like serine catalytic domain (click to see a crystal structure). In addition to F12a, various forms of thrombin can activate F11 and possibly, F11 activates itself. F9a activation occurs via two sequential cleavage reactions. F9a, along with its activated cofactor - factor VIII (F8a), calcium and phospholipid, forms the 'tenase complex' which promotes the activation of F10 to F10a. Prior to activation, F8 is in a complex with von Willebrand factor (Vwf). Activated F10a, along with activated factor V (F5a) - its non-enzymatic cofactor, calcium and phospholipid, forms the 'prothrombinase complex' which activates prothrombin/F2 to thrombin/F2a. Thrombin, the final enzyme in the cascade, cleaves fibrinogen into fibrin peptides which then aggregate to form insoluble fibrin polymers. Cross-linking by factor XIII (F13) contributes to clot stability and overall fibrin gel architecture. F13 exists as a plasma or cytoplasmic protein. The tetrameric plasma F13 (pF13), consisting of two catalytic A-subunits and two B-subunits, is the form involved in the coagulation cascade. There are several ways to activate pF13, thrombin providing the main one. Thrombin/F2 also activates F8 and F5, the two cofactors of F9 and F10, respectively. F2, F9 and F10, like F7, are vitamin K-dependent proteins. In addition to components of the coagulation cascade, F2 substrates include protein C anticoagulant (Proc) and members of the protease activated receptors (PARs). PARs are G protein-coupled receptors (GPCR) involved in many responses and can elicit distinct downstream events depending on the identity of the protease and cellular environment; the alternative outcomes are referred to as 'biased signaling'. Of the four members, Par1/F2R, 3/F2RL2 and 4/F2RL3 are activated by F2, Par2/F2RL1 is activated by F10a. Cleavage of PARs gives rise to a new N-terminus acting as a tethered agonist. Thrombin is allosterically modulated by sodium, which converts a slow form to a fast form; the two forms appear to have different substrate specificities. Fibrinogen consists of two sets of Aalpha, Bbeta and gamma chains with multiple disulfide bonds; the three chains are encoded by separate genes. There are multiple interaction sites, of which some become available upon cleavage while others are present in the native protein. Cleavage of fibrinopeptide A (FPA) initiates fibrin assembly. Cleavage of fibrinopeptide B (FPB) is slower and exposes an independent polymerization site. Binding sites for plasminogen precursor in fibrinogen and for tissue-type plasminogen activator (tPA/PLAT) and other sites in fibrin(ogen) modulate fibrinolysis.

The coagulation cascade is tightly regulated by several anticoagulation/inhibitory systems. Tissue factor pathway inhibitor (Tfpi) primarily targets the extrinsic tenase complex (F7a, F10a), and is aided by protein S, a component of the protein C anticoagulant pathway. Serpinc1, known as antithrombin (AT-III), targets activated thrombin as well as factors 9 and 10. Activated factors 8 and 5, the cofactors for F9a and 10a, respectively, are the targets of activated protein C (Proc_act). Activation of Proc is dependent upon thrombin/F2, which in combination with thrombomodulin receptor (Thbd), acquires anticoagulant properties. Serping1, known as C1-inhibiting factor, targets upstream elements of the intrinsic pathway, activated factors 12 and 11 as well as well as Klkb1 of the kinin-kallikrein system. Serpina10 (protein Z-dependent protease inhibitor, ZPI) also targets activated factor 10; its activity is dependent upon interaction with protein Z (Proz) cofactor. Alterations in the coagulation cascade can lead to excessive bleeding or pathological clotting, thrombosis. Anticoagulation drugs, such as warfarin and related coumarins, target the vitamin K cycle, and thus indirectly the vitamin K-dependent proteases - F2, F7 F9, and F10 (note that protein S and protein C of the anticoagulant pathway, and protein Z, are also vitamin K-dependent). Newer drugs directly target the components of the coagulation cascade. Active coagulation proteases are highlighted in green, main anticoagulant proteins are highlighted in red. To see the ontology report for GViewer, annotations and download, click here...(less)