Factor Villa

Activated on surface of activated platelets by tenase complex (Ca, factors Villa and IXa) and by factor Vila in presence of tissue factor and Ca. ... 

Activated by thrombin factor Villa is a cofactor in the activation of factor X by factor IXa. 

Protein C Activated to protein Ca by thrombin bound to thrombomodulin then degrades factors Villa and Va. 

Once injured or activated by a toxic substance (e.g., bacterial toxins, placenta chemicals, snake venom, etc.), endothelial cells and monocytes respond by generating tissue factor on the cell surface. This, in turn, leads to the generation of tissue factor-factor Villa complexes, followed by unregulated and excessive generation of thrombin, fibrin, systemic microthrombi and consumption of coagulation factors,... 

Factor XIa, in turn, activates factor IX. Factor IXa then promotes the activation of factor X, but only when it (i.e. IXa) is associated with factor Villa. Factor Villa is formed by the direct action of thrombin on factor VIII. The thrombin will be present at this stage because of prior activation of the intrinsic pathway. 

Administration of porcine factor VIII, which may or may not cross-react with the antibodies raised against human factor Villa. (However, the immune system will soon begin to produce antibodies against the porcine clotting factor.)... 

Protein S The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors Villa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH]... 

In the extravascular pathway (right), tissue thromboplastin (factor 111), a membrane protein in the deeper layers of the vascular wall, activates coagulation factor Vll. The activated form of this (Vila) autocatalytically promotes its own synthesis and also generates the active factors IXa and Xa from their precursors. With the aid of factor Villa, PL, and Ca factor IXa produces additional Xa, which finally— with the support of Va, PL, and Ca ""—releases active thrombin. 

Hemostasis begins with the formation of the platelet plug, followed by activation of the clotting cascade, and propagation of the clot. One of the major multicomponent complexes in the coagulation cascade consists of activated factor IX (factor IXa) as the protease, activated factor VIII (factor Villa), calcium, and phospholipids as the cofactors, and factor X as the substrate. Factor IXa can be generated by either factor Xa activation of the intrinsic pathway or by the tissue factor/factor Vila complex. 

Hakeos, W. H., Miao, H., Sirachainan, N., Kemball-Cook, G., Saenko, E. L., Kaufman, R. J. and Pipe, S. W. (2002). Hemophilia A mutations within the factor VIII A2-A3 subunit interface destabilize factor Villa and cause one-stage/two-stage activity discrepancy. J. Thromb. Haemost. 88, 781-787. 

PrekaUikrein is converted to kaUrkrem and factor XII is activated to Xlla. Factor Xlla activates Xl-XIa, which activates factor IX, which together with its co-factor Villa forms the tenase complex, resniting in activation of factor X. The minor role that the contact activation pathway has in initiating clot formation can he Ulnstrated hy the fact that patients with severe deficiencies of factor Xn, kininogen and prekaUikrein do not exhibit a bleeding disorder. 

CHAPTER 36, FIGURE 6 Cofactor proteins, factor V and factor VIII. Factor V and factor VIII coagulant (not the von Willebrand factor carrier of factor VIII) contain six distinct structural domains. The two A domains. A, and Aj at the N-terminal end of the polypeptide chain, are separated from the Aj domain by a highly glycosylated B domain. The two C domains are at the C-terminal end of the molecule. The A domain sequences are homologous to the A domains of ceruloplasmin. Both factor Va and factor Villa act as catalysts in the activation of prothrombin and factor X, respectively. Activation sites are indicated by green arrows inactivation sites by red arrows. In factor Va, complete inactivation requires cleavage of Arg ° . 

The intrinsic pathway begins with the activation of Factor XII. (The factors are identified by Roman numerals, with a subscript "a" for the active form.) Factor XII is activated by other proteins, including kininogen and kallikrein. Factor Xlla then activates Factor XI which activates Factor IX. Factor IXa, together with another factor, Factor Villa, then activates Factor X, where the pathways converge (Fig. 9.3). 

Drotrecogin is a recombinant human activated protein C that exerts an antithrombotic effect by inhibiting factor Va and factor Villa. It is indicated in the reduction of mortality in adult patients with severe sepsis who have a high risk of death. Drotrecogin alfa Drotrecogin alfa (Xigris) is a recombinant form of human activated protein C that inhibits coagulation by proteolytic inactivation of factor Va and factor Villa. It also has antiinflammatory effects. A 96-hour continuous infusion... 

The initial activation of prothrombin to thrombin is slow, because the activator cofactors. Factors Villa and Va, are only present in small amounts. However, once a small amount of thrombin is activated, it will accelerate its own production by cleaving Factors V and VIII to their active forms. 

Factor Villa forms a similar type of complex on the surface of activated platelets, but binds Factor IXa and its zymogen substrate. Factor X. Tissue factor works slightly differently because it is an integral membrane protein. However, once exposed by injury, it also binds Factor Vila and initiates complex formation. 

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