Fibrinolytic function

Investigators have shown that a decrease in the release of tissue plasminogen activator (tPA) and an elevation of plasminogen activator inhibitor 1 (PAI-1) will reduce fibrinolytic function. It has emerged that triacylglycerol-rich lipoproteins stimulate PAI-1 secretion from endothelial cells, and furthermore it has been shown that OxLDL induces secretion, whereas native LDL has no detectable... 

Plasma Inhibitors, In Vivo Anticoagulants. Fourteen naturally occurring compounds that normally exert an inhibiting effect on the activity of coagulation, platelet function, and fibrinolytic activity and complement systems have been identified within the circulating blood. 

CYP2J2 is abundant in cardiovascular tissue and active in the metabolism of arachidonic acid to eicosanoids that possess potent anti-inflammatory, vaso-dilatory, and fibrinolytic properties. Polymorphic alleles with reduced function are known. Some other CYP2 subfamilies and isozymes listed in Table 1 are still not well characterized, in part because most of them were discovered in the course of the human genome project. 

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. 

B30. De Boer, J. R, Creasey, A. A., Chang, A., Abbink, J. J., Roem, D., Eerenberg, A. J., Hack, C. E., and Taylor, F. B., Alpha-2 macroglobulin functions as an inhibitor of fibrinolytic, clotting and neutrophilic proteinases in sepsis Studies using a baboon model. Infect. Immun. 61,5035-5043 (1993). 

Fondaparinux does not inactivate thrombin (activated Factor II) and has no known effect on platelet function, fibrinolytic activity, or bleeding time. 

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. 

As well as their core intracellular activities, many annexins have evolved other, specialised extracellular functions, such as the immunomodulatory action of annexin 1 or the pro-fibrinolytic activity of annexin 2. In this guise they contribute to homeostasis and repair regulating and resolving infection and trauma, and will doubtless prove to be involved in many pathological processes. In the case of autoimmunity, when these mechanisms become disturbed, annexins are again implicated (for example in APL, SLE and diabetes) which underscores their importance as key regulatory factors. 

The endothelium plays a relatively important role in the modulation of overall coagulation and fibrinolytic and platelet dependent processes. Endothelial cells are reactive to various physiologic and pathologic states and release various mediators, which modulate plasmatic processes. The role of endothelial function in mediating the overall coagulation process can be summarized by the following ... 

Savonitto S, Armstrong PW, Lincoff AM, et al. Risk of intracranial haemorrhage with combined fibrinolytic and glycoprotein llb/llla inhibitor therapy in acute myocardial infarction. Dichotomous response as a function of age in the GUSTO V trial. Eur Heart J 2003 24 1807. 

Embolism associated with long flights is generally due to thrombus formation in deep leg veins (deep-vein thrombosis, or DVT). The thrombus may move to the pulmonary circulation, where effects on lung function depend on the extent of the blockage produced. A massive embolus may occlude the main pulmonary artery, resulting in hypotension, shock and possibly death multiple small emboli cause little problem and are lysed by the fibrinolytic system. Sometimes surgical removal of the embolus is necessary, but in Pats/s case clot lysis was successful and she made an uneventful recovery. 

The development of thrombin inhibitors that lack the functionalized TSA highlights a major new approach to type I peptidomimetics. In 1995, a Lilly group found that D-Phe-Pro-Agmatine analogs showed increased selectivity for thrombin over other fibrinolytic enzymes despite a 100-fold loss in potency caused by the removal of the aldehyde group (160). These studies paved the way for Merck s development of picomolar thrombin inhibitors (161,162), which use a similar motif Removal of an a-ketoamide transition state mimic from L-370,518 (89) (Fig. 15.39,... 

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