Factor XII

Factor XII activators pLOOD, COAGULANTS AND ANTICOAGULANTS] (Vol 4) -inhibitors in foods pOOD TOXICANTS, NATURALLY OCCURRING] (Volll)... 

Sequences have been determined for plasminogen and bovine Factor XII, and they are not homologous with the other serine proteases. The amino-terminal sequence of Factor XII is homologous, however, with the active site of several naturally occurring protease inhibitors (11). 

Congenital deficiency of Factor XII is inherited as an autosomal recessive trait. Deficiency of this factor is rarely associated with any coagulopathy. It has been observed that people deficient in this factor may have an increased frequency of thromboembolic compHcations. 

Factor Xlla is a serine protease that activates FXI to FXIa (Fig. 5). This system is not of physiologic relevance since patients with hereditary deficiencies of factor XII, prekallikrein, and high-molecular weight kininogen do not present with bleeding symptoms. 

Kleinschnitz C, Stoll G, Bendszus M et al (2006) Targeting coagulation Factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 203 513-518... 

The various interactions of the constituents required for the formation of bradykinin are shown in figure 2. The initiating step is a slow autoactivation of factor XII [10]. However, once this has occurred and prekallikrein is converted to kallikrein, there is... 

Fig. 2. A diagrammatic representation of the piasma kinin-forming cascade indicating the steps inhibitabie by Cl iNH. Aii functions of factor Xiia and kaiiikrein are affected. The iower figure indicates that further digestion of factor Xiia by kaiiikrein and piasmin generates factor Xii fragment (Xiif), which is an initiator of the compiement cascade. Both factor Xiif and Cl are inhibited by Cl iNH.

One function of HK is to present the substrates of factor Xlla in a conformation that facilitates their activation [25, 26]. More difficult to explain is the effect of HK on the rate of factor XII activation in plasma since HK does not interact with factor XII, nor does it augment the activity of kaiiikrein. This effect seems to be largely indirect. First, HK is required for efficient formation of kaiiikrein in surface-activated plasma [26, 27]. Second, since kaiiikrein can disassociate from surface-bound... 

HK it can interact with surface-bound factor XII on an adjacent particle thereby disseminating the reaction [25, 28]. As a result the effective kallikrein/factor XII ratio is increased in the presence of HK [25], Finally, in plasma, HK can displace other adhesive glycoproteins such as fibrinogen from binding to the surface [29]. In this sense, HK, like factor XII and prekallikrein, is also a coagulation cofactor because it is required for the generation of kalUkrein (a factor XII activator) as well as the activation of factor XI. 

Affinity chromatography using factor XII as ligand leads to purification of u-PAR rather selectively, with only trace quantities of cytokeratin 1 or gClqR present [K. Joseph and A. Kaplan, unpubl. observations]. It is of interest that none of these three proteins possesses a transmembrane domain but u-PAR has a phos-phatidylinositol linkage within the cell membrane. Nevertheless, each of them has been isolated from purified cell membranes and they have been demonstrated to exist within the cell membrane by immunoelectron microscopy [41] presumably... 

Fig. 3. Diagrammatic representation of the binding of factor Xii and the primariiy HK-PK compiex to endotheiiai ceiis indicating that factor Xii binds to the u-PAR-cytokeratin 1 complex, HK binds to the gCIqR-cytokeratin 1 complex, and that activation to produce bradykinin can occur along the cell surface. 

An alternative pathway for activating the cascade has recently been demonstrated in which factor XII is absent from the reaction mixture [42-45]. Two different groups have isolated two different proteins, each of which seems to activate the HK-prekallikrein complex. One is heat-shock protein 90 [46] and the other is a prolylcarboxypeptidase [47]. Neither protein is a direct prekallikrein activator as is factor Xlla or factor Xllf because each activator requires HK to be complexed to the prekallikrein. In addition, the reaction is stoichiometric, thus the amount of prekallikrein converted to kallikrein equals the molar input of heat-shock protein 90 (or prolylcarboxypeptidase). These proteins can be shown to contribute to factor Xll-independent prekallikrein activation and antisera to each protein have been shown to inhibit the process. When whole endothelial cells are incubated with normal plasma or factor Xll-deficient plasma, the rate of activation of the deficient plasma is very much slower than that of the normal plasma, the latter being factor Xll-dependent [45]. Under normal circumstances (with factor XII present), formation of any kallikrein will lead to factor Xlla formation even if the process were initiated by one of these cell-derived factors. 

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

Tankersley DL, Finlayson JS Kinetics of activation and autoactivation of human factor XII. Biochemistry 1984 23 273-279. 

Griffin JH Role of surface in surface-dependent SO activation of Hageman factor (blood coagulation factor XII). Proc Natl Acad Sci USA 1978 75 1998-2002. 

Schmaier AH Factor XII does not initiate prekal- 58 likrein activation on endothelial cells. Thromb Haemost 1998 80 74-81. 

Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired Cl-inhibitor deficiencies. Immunopharmacology 1996 33 361-364. 

Dewald G, Bork K Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal Cl inhibitor. Biochem Biophys Res Commun 2006 343 1286-1289. 

The intrinsic pathway (Figure 51-1) involves factors XII, XI, IX, VIII, and X as well as prekallikrein, high-molecular-weight (HMW) kininogen, Ca, and platelet phospholipids. It results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). 

XII No bleeding Prolonged aPTT Normal PT Normal thrombin time Specific factor XII assay... 

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