Coagulation cascade system

Factor C is the LPS-sensitive intracellular serine protease zymogen that initiates the coagulation cascade system. It exists as a single- and a double-chain form (Ding et al., 1993). While the catalytic site of the molecule is found in the light chain, the... 

The Role of Plasma Cascade Systems in Sepsis 4.1.1. The Coagulation System... 

There are various inhibitors within the coagulation system that counterregulate activation of the coagulation cascade. Among them, antithrombin III (AT-III) and protein C (PC) are the most important (SI). AT-III binds in the presence of heparin the activated factors F-IXa, F-Xa, and F-IIa (thrombin). PC is activated by a complex formed between thrombin and thrombomodulin, a surface protein of endothelial cells. Once activated, PC in the presence of protein S (PS) specifically degrades activated factors F-Va and F-VIIIa. PC decreases in the course of sepsis in relation to the severity of the condition (L15). Experimental studies have... 

With respect to both the coagulation and fibrinolytic cascade systems, in 28 patients who developed septic shock a relation was found between lowered plasma levels of F-XII and antithrombin III and elevated levels of PAI-1 and thrombin-antithrombin III complexes at the diagnosis of sepsis and the severity of disease, expressed according to the APACHE II scoring system (L7). Nevertheless, administration of inhibitors of coagulation or enhancement of fibrinolysis did not improve the outcome in patients with sepsis (B35). 

Interaction with Other Cascade Systems. Interactions between the complement system, the kinin, and the coagulation and fibrinolytic systems have repeatedly been reported (S37, PI9). Activation of one system induces activation of the other systems. The reciprocal activation of the various cascade systems may have an important role in the pathogenesis of ARDS and MODS as complications of sepsis. Nevertheless, until now no convincing prophylactic or therapeutic effects of intervention in the complement cascade system on the severity of septic complications have been reported. 

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. 

Physiologically, the maintenance of blood circulating freely in the vascular system reflects a meticulous balance between coagulation and fibrinolysis. After microvascular injury subendothelial structures are exposed to which platelets adhere. This is followed by their aggregation and activation of the coagulation cascade with the ultimate conversion of fibrinogen to fibrin. 

Pathophysiologically, thrombosis is the same sequence of events but now occurring in abnormal anatomical sites with intravascular obstruction that results in distal tissue ischaemia. These are often systemic disorders affecting the whole circulation and are described as hypercoagulable syndromes. Defects may lie at the level of the endothelium, inappropriate activation of the coagulation cascade or impaired activity of the fibrinolytic system. Segments of thrombus can become detached and travel peripherally in arterial tree, giving rise to acute insufficiency. Conversely, on the venous side, these are... 

In several animal studies severe adverse effects of hypothermia were clotting abnormalities and coagulopathy (22,42). In baboons, systemic hypothermia led to increased bleeding times (43). In men the enzymatic reactions of the coagulation cascade were shown to be strongly inhibited by hypothermia (44,45). However, severe clotting abnormalities have... 

A series of proteins collectively called the complement participate in the immune response to the entry of foreign cellular or viral material into the organism. This group of proteins consists of about 20 entities, some of which are enzymes. Complement was first associated with the lysis of foreign red blood cells in the nineteenth century it also participates in the lysis of bacterial cells. The complement activation cascade, very similar to the blood coagulation cascade, involves the stepwise activation, via proteolysis, of various components of the complement system until a final protein complex, the membrane attack unit (also called the C5b-9 complex), is generated. It then punches holes in the membrane to which it is bound. 

Physical trauma to the vascular system, such as a puncture or cut, initiates a complex series of interactions between platelets, endothelial cells, and the coagulation cascade. This results in the formation of a platelet-fibrin plug. The creation of an unwanted thrombus involves many of the same steps, except that the triggering stimulus is a pathologic condition in the vascular system rather than physical trauma. 

Many pharmaceutical companies are actively working on the development of orally active inhibitors of the serine protease thrombin as one important enzyme in the blood coagulation cascade. In many cases, however, the systemic exposure to thrombin inhibitors... 

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. 

An increased consumption of coagulation factors is found in extensive disseminated intravascular coagulopathy. Secondary hyperfibrinolysis evolves. Simultaneous activation of the coagulation cascade or fibrinolysis system leads to the consumption of coagulation factors as well as inhibitors. 

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