Coagulation proteins factor Vila

Tissue factor pathway inhibitor (TFPI), a 42-kDa protein with three Kunitz domains, is a potent inhibitor of coagulation. It inhibits tissue factor-factor Vila complex upon binding to the active site of Kunitz domain one. Factor Xa is inhibited upon binding to the active site of the second Kunitz domain of TFPI (27). 

Coagulation protein concentrates became available in the 1970s, a significant step in the prevention and management of bleeding. The factors that are currently available are factor VII, factor Vila, factor VIII, factor IX, factor XI, and factor XIII. There is also a factor VIII inhibitor bypassing factor, activated prothrombin... 

Tissue factor is a membrane protein found in organs and surrounding the vasculature. Tissue factor is exposed to blood as a consequence of vessel wall damage or inflammatory cytokine release from vascular cells or monocytes. Coagulation is initiated when factor Vila binds to exposed or expressed tissue factor (see Fig. 100-2). The factor Vlla-tissue factor complex activates factors IX and X. Activated platelets form complexes with factor IXa-factor Vnia (tenase) and factor... 

Antithrombin III (AT3), a protein (432 aa, Mr 58 kDa) acting as inhibitor of thrombin and all active proteases of the blood clotting system ( serpins) except Factor Vila by binding to them in 1 1 complex in similar manner as BPTI binds to trypsin. The presence of heparin enhances the inhibitory activity of antithrombin by several hundredfold. In antithrombin, Arg is the reactive center residue that provides a specific cleavage site for thrombin [T. Halkier, Mechanisms in Blood Coagulation, Fibrinolysis and the Complement System, Cambridge University Press, 1991). 

Anti-coagulants Factor VIII, factor Vila, r-factor IX factor XIII, r-thrombomodulin protein C, ai-antitrypsin, SLPI... 

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. 

When TF is exposed to blood, it spontaneously binds factor VII, a serine protease of the coagulation system that possesses a gla domain (Table 11.1). The TF VII complex therefore adheres to the negatively charged surface of activated platelets. About 0.4% of factor VII is activated in blood by fatty acid- or triglyceride-mediated activation of factor IX and binds similarly to TF. The TF Vila complex (Fig. 11.6a) has proteolytic activity and cleaves (converts) another gla protein that also binds to the activated platelets, factor X. Factor Xa is a serine protease that converts the remainder of the TF VII complex, generating additional Xa proteolytic activity that ultimately converts prothrombin to thrombin for... 

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