Coagulation cascade common

Figure 51-1. The pathways of blood coagulation. The intrinsic and extrinsic pathways are indicated. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. New observations (dotted arrow) include the finding that complexes of tissue factor and factor Vila activate not only factor X (in the classic extrinsic pathway) but also factor IX in the intrinsic pathway, in addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). (PK, prekallikrein HK, HMW kininogen PL, phospholipids.) (Reproduced, with permission, from Roberts HR, Lozier JN New perspectives on the coagulation cascade. Hosp Pract [Off Ed] 1992Jan 27 97.)...

Some 5-25 per cent of individuals suffering from haemophilia A develop anti-factor VIII antibodies, and 3-6 per cent of haemophilia B sufferers develop anti-factor IX antibodies. This complicates treatment of these conditions and, as mentioned previously, one approach to their treatment is direct administration of factor Vila. The therapeutic rationale is that factor Vila could directly activate the final common steps of the coagulation cascade, independently of either factor VIII or IX (Figure 12.1). Factor Vila forms a complex with tissue factor that, in the presence of phospholipids and Ca2+, activates factor X. 

An overview of the coagulation cascade and sites of action for coumarins and heparin is shown in A. There are two ways to initiate the cascade (B) 1) conversion of factor XII into its active form (Xlla, intrinsic system) at intravascular sites denuded of endothelium 2) conversion of factor VII into Vila (extrinsic system) under the influence of a tissue-derived lipoprotein (tissue thromboplastin). Both mechanisms converge via factor X into a common final pathway. 

Interactions between serine proteases are common, and substrates of serine proteases are usually other serine proteases that are activated from an inactive precursor [66]. The involvement of serine proteases in cascade pathways is well documented. One important example is the blood coagulation cascade. Blood clots are formed by a series of zymogen activations. In this enzymatic cascade, the activated form of one factor catalyzes the activation of the next factor. Very small amounts of the initial factors are sufficient to trigger the cascade because of the catalytic nature of the process. These numerous steps yield a large amplification, thus ensuring a rapid and amplified response to trauma. A similar mechanism is involved in the dissolution of blood clots. A third important example of the coordinated action of serine proteases is the intestinal digestive enzymes. The apoptosis pathway is another important example of coordinated action of other types of proteases. 

The MBlectin pathway is initiated by the interaction of the MBlectin with a bacterial cell surface polysaccharide. The activation of complement component C3 is common to all three pathways. It is noted that there are similarities to the blood coagulation cascade. See Sim, R.B., Ed., Activators and Inhibitors of Complement, Kluwer Academic, Dordrecht, Netherlands, 1993 Whaley, K., Loos, M., and Weiler, J., Eds., Complement in Health and Disease, 2nd ed., Kluwer Academic, Dordrecht, Netherlands, 1993 Rother, K., Till, G.O., and Hansch, G.M., Eds., The Complement System, 2nd ed.. Springer, Berlin, 1998 Volanakis, J.E. and Erank, M.M., Eds., The Human Complement System in Health and Disease, Marcel Dekker, New York, 1998 Prodinger, W.M., Wurznen, R., Erdei, A., and Dierich, M.P., Complement, in Fundamental Immunology, Paul, W.E., Ed., Lippincott-Raven, Philadelphia, 1999, pp. 967-995 Lambis, J.D. and Holer, K.M., Eds., Therapeutic Interventions in the Complement System, Humana Press, Totowa, NJ, 2000 Szebeni, J., The Complement System Novel Roles in Health and Disease, Kluwer Academic, Boston, 2004. 

A number of more specihc ligand—metal ion interactions are hidden within Table 2.1. For example, Mg + is often associated with phosphate ligands (Chapter 10) Ca " " is most commonly coordinated by carboxylate ligands as in proteolytic enzymes of the blood coagulation cascade where Ca + is often bound to y-carboxyglutamate residues and Cu " " is often bound to histidine residues. Nonbiological metal ions which are of importance in medicine or as environmental pollutants can also use the same ligands. Thus,... 

Traditionally, the coagulation cascade has been divided into three distinct parts the intrinsic, extrinsic, and common pathways " (see Fig. 19-4). This artificial division is somewhat misleading because there are numerous interactions among the three pathways. The extrinsic pathway, sometimes referred to as the tissue factor pathway, appears to be the principal mechanism that triggers the coagulation... 

Fibrinogen concentrate may be either plasma-derived or a recombinant. It is the final protein in the common coagulation cascade, split by toombin to form insoluble fibrin. Clinical uses depend on the coxmtry, but it is often used for afibrinogenemia and dysfibrinogenemia. In Europe recently, there has been interest in using it for haemorrhage resuscitation. 

Fig. 16.2 Simplified schematic of the coagulation cascade, where clotting is initiated by either surface contact (intrinsic) or tissue factors (extrinsic) and ultimately converges at the common pathway to form thrombus...

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