Factor Xa, produced by either the extrinsic or the intrinsic path way, activates prothrombin (factor II) to thrombin (factor IIa) (see Figure 1; Table 1).
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.)
Table1. Numerical System for the Nomenclature of Blood Clotting Factors
The activation of prothrombin, like that of factor X, occurs on a procoagulant membrane surface and requires the assembly of a prothrombinase complex, consisting of Ca2+, and factors Va and Xa. The assembly of the prothrombinase complex, like that of the tenase complex, takes place on the phosphatidylserine exposing membrane surface, often activated platelets.
Factor V (330 kDa) is synthesized in the liver, spleen, and kidney and is found in platelets as well as in plasma. Factor Va functions as a cofactor in the prothrombinase complex in a manner similar to that of factor VIIIa in the tenase complex. Factor V is activated to factor Va by traces of thrombin, and binds specifically to a procoagulant membrane (often that of platelets) (Figure 2) and forms a complex with factor Xa and prothrombin. It is subsequently inactivated by activated protein C, thereby providing a means of limiting the activation of prothrombin to thrombin. Prothrombin (72 kDa; see Figure 2) is a single-chain glycoprotein synthesized in the liver. The amino-terminal region of prothrombin (see Figure 3) contains 10 Gla residues, and the serine-dependent active protease site is in the catalytic domain close to the carboxyl-terminal region of the molecule. On binding to the complex of factors Va and Xa on the procoagulant mem brane (see Figure 2), prothrombin is cleaved by factor Xa at two sites to generate the active, two-chain thrombin molecule, which is then released from the membrane surface.
Fig2. Schematic representation of the prothrombinase complex bound to the procoagulant plasma membrane. The prothrombinase complex contains factors Va, Xa, and prothrombin. A central theme in blood coagulation is the assembly of protein complexes, that is, the tenase complexes and the prothrombinase com plex, in a Ca2+-dependent fashion, on membrane surfaces on which phosphatidylserine is exposed. The catalytic efficiency of zymogen activation is increased by many orders of magnitude by the mem brane-bound complexes. γ-Carboxyglutamate residues (indicated by Y) on vitamin K–dependent proteins bind calcium and contribute to the exposure of membrane-binding sites on these proteins (black ovals, Xa, and prothrombinase).
Fig3. The structural domains of selected proteins involved in coagulation and fibrinolysis. Shared domains are a result of gene duplication and exon shuffling that contributed to the molecular evolution of the coagulation system. The domains are as identified at the bottom of the figure and include signal peptide, propeptide, Gla (γ-carboxyglutamate) domain, epidermal growth factor (EGF) domain, apple domain, kringle domain, fibronectin (types I and II) domain, the zymogen activation region, aromatic amino acid stack, and the catalytic domain. Interdomain disulfide bonds are indicated, but numerous intradomain disulfide bonds are not. Sites of proteolytic cleavage in synthesis or activation are indicated by arrows (dashed and solid, respectively). (FVII, factor VII; FIX, factor IX; FX, factor X, FXI; factor XI; FXII, factor XII; t-PA, tissue plasminogen activator.)
