Factor Xlla

Factor XI. Factor XI is a Hver-synthesized glycoprotein that circulates in a zymogen form as a dimer. It is converted to its active serine protease form by Factor Xlla in the presence of high molecular weight kininogen. Calcium is not required for this activation step. 

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. 

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... 

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. 

Pixley R, Schapira M, Colman R The regulation of 63 human factor Xlla by plasma proteinase inhibitors. 

N9. Nuijens, J. H., Huijbregts, C. C., Eerenberg-Belmer, A. J., Abbink, J. J Strack Van Schijndel, R. J., Felt-Bersma, R. J., Thijs, L. G., and Hack, C. E Quantification of plasma factor Xlla-Cl-inhibitor and kallikrein-C-inhibitor complexes in sepsis. Blood 72, 1841-1848 (1988). 

Factor Xlla can proteolytically cleave and, hence, activate two substrates ... 

Figure 12.2 The steps unique to the intrinsic coagulation pathway. Factor Xlla can also convert prekal-likrein to kallikrein by proteolysis, but this is omitted for the sake of clarity. Full details are given in the main text. The final steps of the coagulation cascade, which are shared by both extrinsic and intrinsic pathways, are outlined in Figure 12.3...

Figure 17.1 Summary of the four cascades that result from trauma or bleeding and the reactions they catalyse. These are all activated by the blood clotting factor, Xlla (also known as the Hageman factor). Details of each cascade are presented in Figures 17.2, 17.4 and 17.6. Factor XII is activated by collagen and negatively charged surfaces to form the active form, Xlla.

Bradykinin is a small peptide that is released from a precursor, kininogen, by the action of the proteolytic enzyme kallikrein, which itself is formed from a precursor, prekallikrein, by the action of the blood clotting factor, Xlla (Figure 17.4). Bradykinin is responsible for the pain, vasodilation and increased permeability of the blood vessels by stimulating formation and release of prostaglandins and prostacyclins from the endothelial cells (see Chapter 11). 

Tincture of the dried seed, on agar plate at a concentration of 30 p,L/disc, was inactive on Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Extract of 10 g plant material in 100 mL ethanol was used b Anticoagulation activity. Serpin BSZx (an inhibitor of trypsin and chemotrypsin) inhibited thrombin, plasma kallikrein, factor Vlla/tissue factor, and factor Xa at heparin-independent association rates. Only factor Xa turned a significant fraction of BSZx over as substrate. Activated protein C and leukocyte elastase were slowly inhibited by BSZx, whereas factor Xlla, urokinase and tissue type plasminogen activator, plasmin and pancreas kallikrein, and elastase were not or only weakly affected. Trypsin from Fusarium was not inhibited, while interaction with subtilisin Carlsberg and Novo was rapid, but most BSZx was cleaved as a substrate L... 

This pentasaccharide sequence induces a conformational change in AT III which probably causes the complex to be more accessible to the active site of the proteases. The most relevant protease affected by the pentasaccharide 3 is factor Xa, but factor Xlla and plasma kallikrein activities can also be potentiated. Sequence 3 occurs in heparin as well as in various heparan sulfate proteoglycans of different origin including the vascular endothelium. 

Rajapakse, N., Jung, W. K., Mendis, E., Moon, S. H., and Kim, S. K. (2005). A novel anticoagulant purified from fish protein hydrolysate inhibits factor Xlla and platelet aggregation. Life Sci. 76, 2607-2619. 

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