Fibrinolysis

In fibrinolysis, plasmin, an endopeptidase that is converted from plasminogen by an activator, hydrolyzes fibrin, fibrinogen, factor V, and factor VIII to their inactive products. Hageman factor (factor XII) converts a proactivator to the active activator. Agents such as thrombin, streptokinase, and urokinase therefore enhance the formation of plasmin and hence have fibrinolytic properties. Epsilon-aminocaproic acid inhibits the activator-mediated formation of plasmin and hence may be used as an antidote to streptokinase-urokinase, or in a defibrination syndrome when bleeding from a mucous membrane occurs. 

The pathogenesis of thrombocytopenia will become clearer when the mechanism of production of autoimmune disease is discussed. Only a few salient points are mentioned here. A number of drugs, among them allylisopropylacetyl carbamide (Sedormid), quinine, quinidine, are known to autosensitize platelets. In affected patients, the combination of platelet, drugs, and serum leads to thrombocytopenia a large number of patients with idiopathic thrombocytopenia have antiplatelet antibodies in their blood. If the blood of such patients is injected to normal individuals, thrombocytopenia occurs. 

The immune reaction to platelets is associated with three major alterations of platelet. There is an increased tendency to agglutination, the rate of platelets lysis is accelerated, and the susceptibility of platelets to phagocytosis is increased. Platelet precursors are also altered in thrombocytopenia. The megakaryocytes of the marrow are rare and immature. 

thrombocytopenia results from the alteration of the circulating platelets and their precursors. The platelet number drops from 250,000/mm to 60,000/ mm. The drop in the platelet count is usually accompanied by hemorrhagic diathesis, taking the form of purpura. Small hemorrhages occur underneath the skin and the mucosa-serosa, especially under those portions of skin or mucosa (stomach) or serosa (visceral pericardium) that cover muscle contracting actively. Occasionally, the hemorrhage may be more extensive and spontaneous or traumatic ecchymosis may develop. 

The spleen is moderately enlarged in patients with thrombocytopenia, possibly because thrombocytolysis is activated in the spleen. In any event, splenectomy often procures temporary relief or even permanent cure for thrombocytopenia. The various types of thrombocytopenia and other forms of defects in blood coagulation are summarized in Table 7-4. 

Hemostasis in small capillaries is particularly intriguing. It can no longer be explained by capillary constriction or platelet formation. No capillary plugs are observed. 

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Table 3. Sequence Homologies for Serine Proteases Involved in Coagulation and Fibrinolysis ...

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

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

Figure 2.19 Organization of polypeptide chains into domains. Small protein molecules like the epidermal growth factor, EGF, comprise only one domain. Others, like the serine proteinase chymotrypsin, are arranged in two domains that are required to form a functional unit (see Chapter 11). Many of the proteins that are involved in blood coagulation and fibrinolysis, such as urokinase, factor IX, and plasminogen, have long polypeptide chains that comprise different combinations of domains homologous to EGF and serine proteinases and, in addition, calcium-binding domains and Kringle domains.

There are several additional plasmin inhibitors in the blood, e.g., a2-macroglobulin, ai-proteinase inhibitor, antithrombin, but their role in the control of fibrinolysis is questionable, because their action on plasmin is eliminated by fibrin. 

Similarly to blood coagulation, reactions of fibrinolysis occur on the interface of fluid-and solid-phase structures, generally in transiently formed compartments. 

Enzymology of proteases in a water-phase is well known, but its alteration in a compartment is poorly understood. There are dramatical changes in reaction rates, in enzyme contractions and in enzyme sensitivity to inhibitors, which are not exactly described. In addition, besides fibrin and platelets there are several cellular and molecular components present in a thrombus compartment, where their influence on the basic fibrinolytic reactions is not known. To study this aspect of fibrinolysis is a task of the near future [4]. 

Summarizing the fibrinolytic therapy, it should be emphasized that efficient treatment needs urgent application of plasminogen activator (within a few hours) to prevent the formation of crosslinks in the fibrin structure (Fig. 2) and to find the localization of thrombus to emerge plasmin on the surface of fibrin to prevent rapid inactivation of the enzyme by the inhibitor system of fibrinolysis (Fig. 3). 

Kolev K, Machovich R (2003) Molecular and cellular modulation of fibrinolysis. Thromb Haemost 89 610-621 (Review article)... 

Urokinase-type plasminogen activator (uPA, urokinase) is synthesized by endothelial and tumor cells as a single-chain glycoprotein (scuPA) without catalytic activity. When it is converted to a two-chain protein (tcuPA) by plasmin, an active serine protease center develops, which activates plasminogen. Thus, uPA (55 kDa) results in the amplification of fibrinolysis. 

Mandle RJ, Kaplan A Hageman factor substrates. Human plasma prekallikrein mechanism of activation by Hageman factor and participation in Hageman factor-dependent fibrinolysis. J Biol Chem 1977 252 6097-6104. 

Schreiber A, Kaplan A, Austen K Inhibition by 62 ClINH of Hageman factor fragment activation of coagulation, fibrinolysis, and kinin generation. J Clin Invest 1973 52 1402-1409. 

Familial lipoprotein(a) excess Lp(a) consists of 1 mol of LDL attached to 1 mol of apo(a). Apo(a) shows structural homologies to plasminogen. Premature coronary heart disease due to atherosclerosis, plus thrombosis due to inhibition of fibrinolysis. 

Basic aspects of the proteins of the blood coagulation system and of fibrinolysis are described in this chapter. Some fundamental aspects of platelet biology are also presented. Hemorrhagic and thrombotic states can cause serious medical emergencies, and thromboses in the coronary and cerebral arteries are major causes of death in many parts of the world. Rational management of these conditions requires a clear understanding of the bases of blood clotting and fibrinolysis. 

Figure 51-7. Scheme of sites of action of streptokinase, tissue plasminogen activator (t-PA), urokinase, plasminogen activator inhibitor, and Kj-antiplasmin (the last two proteins exert inhibitory actions). Streptokinase forms a complex with plasminogen, which exhibits proteolytic activity this cleaves some plasminogen to plasmin, initiating fibrinolysis. 

TableS1-4. Molecules synthesized by endothelial cells that play a role in the regulation of thrombosis and fibrinolysis. ...

Collen D, Lijnen HR Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 199T,78 3114. 

Plasminogen activator inhibitors have been shown to be present in a large variety of different cells and tissues. These inhibitors are thought to play an important role in regulating tissue fibrinolysis. One of these inhibitors has been purified from cultured bovine aortic epithelial cells. This inhibitor has been shown to be a serine protease inhibitor and inhibits the function of two proteolytic enzymes urokinase and tissue plasminogen activator, both of which cleave and activate plasminogen. The mechanism by which this inhibitor functions is very similar to that described above with a-l-PI. Thus, the inhibitor forms a binary complex with the proteolytic enzyme and thereby inhibits its activity. Again in a situation comparable to that with a-l-PI, it was found that when the purified bovine aortic epithelial inhibitor was exposed to Al-chlorosuccinimide,... 

Administer heparin without a loading dose when aPTT <2 x control after fibrinolysis... 

Initiate reperfusion therapy in appropriate candidates (fibrinolysis or primary PCI)... 

Is reperfusion therapy with fibrinolysis indicated at this time ... 

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