Fibrinolysis physiology

Y. P. Konttiaen, Fibrinolysis—Chemisty, Physiology, Pathology, Oystar Ah Pubhshers, Tampere, Einland, 1968, pp. 1—643. 

Administration of activated protein C (drotrecogin) to promote fibrinolysis and associated antiinflammatory mechanisms may be beneficial in patients with an APACHE II (Acute Physiology and Chronic Health Evaluation II) score greater than 25. This agent reduced mortality in severe sepsis but poses an increased risk of serious bleeding. 

With alteplase, another endogenous plasminogen activator (tissue plasminogen activator, tPA) is available. With physiological concentrations this activator preferentially acts on plasminogen bound to fibrin. In concentrations needed for therapeutic fibrinolysis this preference is lost and the risk of bleeding does not differ with alteplase and streptokinase. Alteplase is rather short-Liillmann, Color Atlas of Pharmacology... 

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. 

Modulates physiological processes such as cell adhesion and migration, fibrinolysis, and coagulation... 

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. 

Wiman, B., and Collen, D. (1978). Molecular mechanism of physiological fibrinolysis. Nature 272, 549-550. 

Serine proteases (SP) are a family of enzymes that use a uniquely activated serine residue in the substrate-binding pocket to catalytically hydrolyze peptide bonds [66], SP carry out a diverse array of physiological functions, of which the best known are digestion, blood clotting, fibrinolysis, fertilization, and complement activation during immune responses [67], They have also been shown to be abnormally expressed in many diseases including cancer, arthritis, and emphysema [42, 43, 67-70],... 

Some adverse effects are associated with all antifibrinolytic agents, reflecting their effect on clot stability. Dissolution of extravascular blood clots may be resistant to physiological fibrinolysis. These drugs should not to be used to treat hematuria due to blood loss from the upper urinary tract, as this can provoke painful clot retention and even renal insufficiency associated with bilateral ureteric obstruction (25-31). 

Fibrinolysis has previously been reviewed.70 80 The physiologic process in which a fibrin clot is dissolved and the regulation of that process is not completely understood. The main proenzyme in the blood is plasminogen, a Ps globulin, which when activated is converted to the fibrin lysis enzyme plasmin, a globulin. Plasmin is usually bound by many other proteins and inactivated in the plasma. If this did not occur, pro-... 

Summary - Many diverse novel compounds that inhibit different platelet functions show great promise, not only for potential anti-thrombotic agents, but also for more specific effects on prostaglandin and/or thromboxane A2 synthesis, and serotonin or calcium uptake and release. Many active compounds can be used as tools in the search toward a more complete understanding of the physiologic interactions of the hemostatic mechanisms. This better understanding would lead to the development and use of more potent and selective synthetic compounds in the inhibition of platelet aggregation and fibrin formation, and in the enhancement of fibrinolysis for the control of both arterial and venous thrombosis. It is hoped that some of these new compounds will be evaluated clinically in the near fu ture. 

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... 

H. R. Lijnen and D. Collen Mechanisms of physiological fibrinolysis. Bail-lieres Clinical Haematology 8,277-290 (1995). 

Magnusson, S. Primary structure of antithrombin III (Heparin Cofactor). Partial homology between oci antitrypsin and antithrombin-III, in Collen DW, Wiman B, Verstraete M (eds) The Physiological Inhibitions of Blood Coagulation and Fibrinolysis. Amsterdam, The Netherlands, Elsevier/North-Holland Biomedical Press, 1979, p 43. 

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