Fibrinolytic system

The plasminogen molecule contains several sites that specifically bind a number of antifibrinolytic amino acids, such as lysine [56-87-1] and S-aminocaproic acid [60-32-2] (EACA). These sites are known as lysine binding sites (LBS), and are localized mainly to the A or heavy chain of the molecule. One is located in K4 and at least one more is in K1 through K3. One LBS, which is beheved to reside in Kl, has a stronger affinity for EACA, whereas the others have a weaker affinity. The LBS are important for the interaction of plasminogen with several components of the endogenous fibrinolytic system. 

Fig. 4. Fibrinolytic system where SCUPA is single-chain urokinase plasminogen activator rTPA is recombinant tissue plasminogen activator APSAC is acylated plasminogen streptokinase activator complex SK is streptokinase and UK is urokinase.

Inhibitors of Fibrinolysis. Inhibitors of the fibrinolytic system are either endogenous naturally occurring inhibitors or modulators or... 

Several synthetic amino acids (63—65) have been identified that excite inhibition of the fibrinolytic system (Table 8). 

Machovich R (2003) Disorders of the blood coagulation-fibrinolytic system. In Keri Gy, Toth I (eds) Molecular pathomechanism and new bends in drug research. Taylor and Francis Group, London and New York, pp 458-464... 

Mor, A. Maillard, J. Favreau, C. Reboud-Ravaux, M. Reaction of thrombin and proteinases of the fibrinolytic system with a mechanism-based inhibitor, 3,4-dihydro-3-benzyl-6-chloromethyl-coumarin. Biochim. Biophys. Acta 1990, 1038, 158-163. 

The coagulation system that generates thrombin consists of intrinsic and extrinsic pathways. Both pathways are composed of a series of enzymatic reactions eventually producing thrombin, fibrin, and a stable clot. In parallel with the coagulation, the fibrinolytic system is activated locally. Plasminogen is converted to plasmin, which dissolves the fibrin mesh1 2 3 (Fig. 64—1). 

Septic shock is frequently complicated by massive activation of the coagulation system. This can occur concomitantly with biphasic change in the fibrinolytic system, involving both activation and inhibition of plasminogen activation. The net result of the altered hemostatic state in sepsis is widespread microvascular trom-bosis. The early events leading to these disturbances are incompletely understood,... 

Fio. 3. The intrinsic and extrinsic cascade fibrinolytic systems. activation H, inhibition t-PA, tissue plasminogen activator PAI, plasminogen activator inhibitor a2-M, a2-macroglobulin a2-AP, a2-antiplasmin. 

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. 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

Sundsmo, J. S., and Fair, D. S., Relationship among the complement, kinin, coagulation and fibrinolytic systems. Springer Semin, lmmmopathol. 6,127-175 (1983). 

This review will attempt to explore our current understanding of both coagulation and fibrinolytic systems, their clinical impact, and variables affecting the laboratory assessment of thrombotic and bleeding disorders. 

Bell W. R. The fibrinolytic system in neoplasia. Semin Thromb Hemost 1996 22,459-78. 

Figure 12.11 (a) The fibrinolytic system, in which tPA proteolytically converts the zymogen plasminogen into active plasmin, which in turn degrades the fibrin strands, thus dissolving the clot. tPA and plasminogen both bind to the surface of fibrin strands (b), thus ensuring rapid and efficient activation of the thrombolytic process... 

To explain the relationship between Lp(a) concentrations and risk of atherosclerosis, several hypothesis could be brought forward first, Lp(a) affects the metabolism of cholesterol and LDL secondly, Lp(a) plays a role in foam-cell and plaque formation thirdly, Lp(a) interacts with the activation of plasminogen to plasmin, the key step in the fibrinolytic system (L10, M27). Such activation can occur in two different localizations, i.e., on fibrin and its proteolytic residues, and on the surface of endothelial and monocytic cells. 

The effects of Lp(a) on the fibrinolytic system are based on the homology between plasminogen and Lp(a) (E3, E5, K4). Inactive Glu-plasminogen is converted to inactive glutamine-plasmin or inactive lysine-plasmin. Both can be converted to active lysine-plasmin, the activity of which is based on the serine protease part that splits fibrin and fibrinogen, but also factors V and Villa. In addition, Lp(a) is able to activate factor XII, factor VII, and the complement factors Cl and C3. 

The interaction of Lp(a) with the fibrinolytic system can be manifested in different places of the process (Fig. 9). 

Matsuda, H., Namba, K., Fukuda, S., Tani, T., and Kubo, M. (1986). Pharmacological study on Panax ginseng C. A. Meyer. 111. Effects of red ginseng on experimental disseminated intravascular coagulation. 2. Effects of ginsenosideson blood coagulative and fibrinolytic systems. Chem. Pharm. Bull. 34,1153-1157. 

The role of the fibrinolytic system is to dissolve any clots that are formed within the intact vascular system and so restrict clot formation to the site of injury. The digestion of the fibrin and hence its lysis is catalysed by the proteolytic enzyme, plasmin, another serine proteinase. Plasmin is formed from the inactive precursor, plasminogen, by the activity of yet other proteolytic enzymes, urokinase, streptokinase and tissue plasminogen activator (tPA) which are also serine proteinases. These enzymes only hydrolyse plasminogen that is bound to the fibrin. Any plasmin that escapes into the general circulation is inactivated by binding to a serpin (Box 17.2). 

Inactivation of the fibrinolytic system can be achieved by plasmin inhibitors, such as -aminocaproic acid, p-aminomethylbenzoic acid (PAMBA), tranexamic acid, and aprotinin, which also inhibits other proteases. 

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... 

Little intravascular coagulation of blood occurs in normal physiological conditions. Hemostasis involves the interplay of three procoagulant phases vascular, platelet, and coagulation) that promote blood clotting to prevent blood loss (Fig. 22.1). The fibrinolytic system prevents propagation of clotting beyond the site of vascular injury and is involved in clot dissolution, or lysis (Fig. 22.2). 

Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999 82 259-270. 

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