Tissue factor pathway.
Blood coagulation is initiated in response to vessel damage in order to preserve the integrity of the mammalian vascular system. The coagulation cascade can also be initiated by mediators of the inflammatory response, and fibrin deposition has been noted in a variety of pathological states. The cascade of coagulation zymogen activations which leads to clot formation is initiated by exposure of flowing blood to tissue factor (TF), the cellular receptor and cofactor for factor VII (FVII). FVII binds to the receptor in a 1:1 stoichiometric complex and is rapidly activated. FVIIa undergoes an active site transition upon binding TF in the presence of calcium which enhances the fundamental properties of the enzyme. This results in rapid autocatalytic activation of FVII to VIIa thereby amplifying the response by generating more TF-VIIa complexes. The TF-VIIa activates both FIX and FX. Further FXa generation by the IXa-VIIIa-Ca(2+)-phospholipid complex is required to sustain the coagulation mechanism, since the TF-VIIa complex is rapidly inactivated. Structure and function studies have identified a number of regions on both TF and FVII involved in this interaction. It is clear, however, that the molecular structures of TF, FVII and the TF-VII complex will have to be solved before we fully understand this complex interaction. The activity of the TF-VIIa complex is controlled by two inhibitors:tissue factor pathway inhibitor (TFPI) and antithrombin III (AT-III). TFPI circulates in plasma, is associated with vascular cell surface and is released from platelets following stimulation by thrombin. TFPI requires the formation of an active TF-VIIa complex and FXa generation before inhibition can occur. Similarly, AT-III which is unable to inhibit circulating FVIIa requires the formation of the TF-VIIa complex. TFPI prevents further participation of TF in the coagulation process by forming a stable quaternary complex, TF-VIIa-Xa-TFPI. In contrast, the AT-III-VIIa complex is thought to dissociate from TF allowing it to interact with additional FVII-VIIa. TFPI has been considered the primary regulator of TF-VIIa activity during haemostasis. Whether AT-III in the presence of glycosaminoglycans on cell surfaces expressing TF can function as an auxiliary second physiological regulator is not known.
Haemostasis Research Group, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
J H
JH
McVey
D000990:Antithrombin III / Q000494:pharmacology; D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000502:physiology; D004730:Endothelium, Vascular / Q000293:injuries / Q000378:metabolism; D005167:Factor VII / Q000737:chemistry; D005337:Fibrin / Q000502:physiology; D006801:Humans; D007249:Inflammation; D008074:Lipoproteins / Q000737:chemistry / Q000502:physiology; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*
D001779:Blood Coagulation Factors; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III; D005167:Factor VII; D005337:Fibrin; D013925:Thromboplastin