Factor Xllla

Figure 51-5. Formation of a fibrin clot. A Thrombin-induced cleavage of Arg-Gly bonds of the Aaand B(3 chains of fibrinogen to produce fi-brinopeptides (left-hand side) and the a and p chains of fibrin monomer (right-hand side). B Cross-linking of fibrin molecules by activated factor XIII (factor Xllla).

AbdAlla, S., Lother, H., Danger, A., el Earamawy, Y., and Quitterer, U. (2004) Factor XlllA transglutaminase crosslinks AT(1) receptor dimers of monocytes at the onset of atherosclerosis. Cell. 119, 343-354. 

Reid, M. B., Gray, C., Fear, J. D., and Bird, C. C. (1986) Immunohistological demonstration of factors Xllla and XIIIs in reactive and neoplastic fibroblastic and fibro-histiocytic lesions. Histopathol. 10,1171-1178. 

Both intrinsic and extrinsic pathways generate activated factor X. This protease, in turn, catalyses the proteolytic conversion of prothrombin (factor II) into thrombin (Ha). Thrombin, in turn, catalyses the proteolytic conversion of fibrinogen (I) into fibrin (la). Individual fibrin molecules aggregate forming a soft clot. Factor Xllla catalyses the formation of covalent crosslinks between individual fibrin molecules, forming a hard clot (Figures 9.4 and 9.5). 

Figure 9.8. Formation of a hard clot via the action of factor Xllla. This activated factor displays a transglutaminase activity, which catalyses direct formation of a covalent linkage between a glutamine side-chain of one fibrin molecule and a lysine side-chain of a second fibrin molecule. The resultant highly crosslinked hard clot is both tough and insoluble...

In much the same way the number of interventions are possible at the level of fibrinolysis including thrombin-activateable fibrinolysis inhibitor, agents that block factor Xllla or inhibit plasminogen activator inhibitor therapy. 

Antifibrinolytic compounds can block the conversion of plasminogen to plasmin, or directly bind to the active site of plasmin to inhibit fibrinolysis. The plasma protein, a 2-macroglobulin, is a primary physiological inhibitor of plasmin. Plasmin released from fibrin is also very rapidly inactivated by a2-antiplasmin, which plays a role in the regulation of the fibrinolytic process (Aoki and Harpel, 1984). 2-anti plasmin inactivates plasmin in a very rapid reaction, interferes with plasminogen binding to fibrin, and is ligated to fibrin by Factor Xllla (Sakata and Aoki, 1980). After a2-antiplasmin is covalendy linked to fibrin s G-terminal a chain, it retains it ability to inhibit plasmin, a function that helps to prevent premature clot lysis. 

The mechanical properties of many types of clots have been measured, but the origin of clot viscoelasticity is a mystery. Factor Xllla-induced crosslinking sites have been identified in the primary sequence, but the structure of the crosslinked C-terminal 7 chains is a matter of debate and that of the a chains is unknown. The biochemistry of fibrinolysis has been determined, but less is known of the physical mechanisms involved or of the interactions of regulatory systems. 

Specific Factor Xllla inhibitors, such as tridegin and others mentioned earlier, may provide an interesting and novel approach to preventing fibrin stabilization. It is important to identify this polymorphism since the Leu34 variant associated with increased Factor Xllla activity reduces the activity of thrombolytic therapy (21,22). 

Rinas, U., Risse, B., Jaenicke, R., Broker, M., Karges, H.E., Kupper, H.A., and Zettlmeissl, G. (1990). Characterization of recombinant factor Xllla produced in Saccharomyces cerevisiae. Bio/Technology 8, 543 546. 

Thrombin cleaves at Arg(16)-Gly(17) of the a-chain, and at Arg(14)-Gly(15) of the P-chain. This results in the release of activation peptides (byproducts) from fibrinogen. The resulting fibrin spontaneously forms a soft clot. Thrombin also catalyzes the activation of factor XIII, and factor Xllla catalyzes the covalent cross-linking of different fibrins with each other. The result is a firm clot. 

Noncovalently associated fibrin is physiologically unsatisfactory because the dissociation of the fibrin results in recurrent bleeding. Fibrin monomer dissociation is prevented by formation of covalent cross-links between different Fnllm molecules. The result of this covalent cross-linking is an insoluble fibrin and a stable hemostatic plug. These cross-links are formed by the action of factor Xllla, plasma, and/or platelet transglutaminase (see below). Multiple cross-links are formed among a chains of several different fibrin monomers. This creates a molecular species designated a polymer (see Fibrinolysis below). Two... 

Neurotized melanocytic nevi may be distinguished from neurofibroma factor Xllla is found in neurofibroma, not in melanocytic nevi. 

Nemes Z, Thomazy V. Factor Xllla and the classic histiocytic markers in malignant fibrous histiocytoma A comparative immunohistochemical study. Hum Pathol. 1988 19 822-829. 

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