The extrinsic pathway involves tissue factor, factors VII and X, and Ca2+ and results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). The extrinsic pathway is initiated at the site of tissue injury with the exposure of tissue factor(TF; see Figure 1), located in the subendothelium and on activated monocytes. TF interacts with and activates factor VII (53 kDa, a zymogen containing vitamin K–dependent γ-carboxyglutamate [Gla] residues), synthesized in the liver. It should be noted that in the Gla-containing zymogens (factors II, VII, IX, and X), the Gla residues in the amino-terminal regions of the molecules serve as high-affinity binding sites for Ca2+. TF acts as a cofactor for factor VIIa, enhancing its enzymatic activity to activate factor X (56 kDa). The reaction by which factor X is activated requires the assembly of the extrinsic tenase complex (Ca2+-TF-factor VIIa) formed on a cell membrane surface exposing the procoagulant anionic aminophospholipid phosphatidylserine. Factor VIIa cleaves an Arg-Ile bond in factor X to produce the two-chain serine protease, factor Xa. TF and factor VIIa also activate factor IX in the intrinsic pathway. Indeed, the formation of complexes between membrane-bound TF and factor VIIa is now considered to be the key process involved in initiation of blood coagulation in vivo.

Fig1. The pathways of blood coagulation, with the extrinsic pathway indicated at the top left and the intrinsic path way at the top right. The pathways converge in the formation of active factor X (ie, factor Xa) and culminate in the formation of cross linked fibrin (lower right). Complexes of tissue factor and factor VIIa activate not only factor X (extrinsic Xase [tenase]) but also factor IX in the intrinsic pathway (dotted arrow). In addition, thrombin feedback activates at the sites indicated (dashed arrows) and also activates fac tor XIII to factor XIIIa (dashed-dotted arrow) and activates factor VII to factor VIIa (not shown). The three predominant complexes, extrinsic Xase, intrinsic Xase, and prothrombinase, are indicated within the large arrows; these reactions require anionic procoagulant phospholipid membrane and calcium. Activated proteases are in solid-out lined boxes; active cofactors are in dash-outlined boxes; and inactive factors are not in boxes. (HK, high-molecular-weight kininogen; PK, prekallikrein.)

Tissue factor pathway inhibitor (TFPI) is a major physiologic inhibitor of coagulation. TFPI is a protein that circulates in the blood where it directly inhibits factor Xa by binding to the enzyme near its active site. This factor Xa-TFPI complex then inhibits the factor VIIa-TF complex.

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