Reactome: A Curated Pathway Database

Extrinsic Pathway of Fibrin Clot Formation (R-HSA-140834)

Species Homo sapiens


Factor VII, the protease that initiates the normal blood clotting cascade, circulates in the blood in both its proenzyme (factor VII) and its activated (factor VIIa) forms. No clotting occurs, however, because neither form of the protein has any catalytic activity when free in solution. Blood clotting is normally initiated when tissue factor (TF), an intrinsic plasma membrane protein, is exposed to the blood by injury to the wall of a blood vessel. TF is then able to bind factor VIIa from plasma, and possibly also factor VII, to form complexes capable of catalyzing the conversion of factor X, from plasma, into its activated form, factor Xa. Factor Xa catalyzes the conversion of additional factor VII molecules to their activated form, increasing the amount of tissue factor:factor VIIa complex available at the site of injury, accelerating the generation of factor Xa, and allowing the activation of factor IXa as well. This process is self-limiting because as levels of factor Xa increase, tissue factor:factor VIIa complexes become trapped in the form of catalytically inactive heterotetramers with factor Xa and the protein TFPI (tissue pathway factor inhibitor). At this point the intinsic pathway, as an independent source of activated factor X, is thought to become critical for the continuation of clot formation (Broze 1995; Mann et al. 2003).
The nature of the initial tissue factor:factor VII complexes formed is controversial. One model, building on the observation that the complex of factor VII and TF has low but measurable proteolytic activity on factor X, suggests that this complex begins the activation of factor X, and that as factor VIIa accumulates, tissue factor:factor VIIa complexes also form, accelerating the process (Nemerson 1988). A second model, building on the observation that normal plasma contains low levels of activated factor VII constitutively, suggests that complexes with factor VIIa form immediately at the onset of clotting (Rapaport and Rao 1995). The two models are not mutually exclusive, and in any event, the central roles of tissue factor and factor VIIa in generating an initial supply of factors IXa and Xa, and the self-limiting nature of the process due to the action of TFPI, are all well-established.
These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions, and blue lines connect output activated enzymes to the other reactions that they catalyze.

Locations in the PathwayBrowser
Additional Information
Compartment extracellular region
GO Biological Process blood coagulation, extrinsic pathway (0007598)
Cross References
Database Identifier
BioModels Database BIOMD0000000340, BIOMD0000000335, BIOMD0000000338, BIOMD0000000339, BIOMD0000000336
Literature References
pubMedId Title Journal Year
7598447 Tissue factor pathway inhibitor and the revised theory of coagulation Annu Rev Med 1995