Clot dissolution—fibrinolysis

Enzyme inhibition is one of the ways in which enzyme activity is regulated experimentally or naturally. Most therapeutic drugs function by inhibition of a specific enzyme. Inhibitor studies have contributed much of the available information about enzyme kinetics and mechanisms. In the body, some of the processes controlled by enzyme inhibition are blood coagulation (hemostasis), blood clot dissolution (fibrinolysis), complement activation, connective tissue turnover, and inflammatory reactions. 

When blood is lost or clotting is initiated in some other way, a complex cascade of biochemical reactions is set in motion, which ends in the formation of a network or clot of insoluble protein threads enmeshing the blood cells. These threads are produced by the polymerisation of the molecules of fibrinogen (a soluble protein present in the plasma) into threads of insoluble fibrin. The penultimate step in the chain of reactions requires the presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in the plasma. This is initiated by factor lit (tissue thromboplastin), and subsequently involves various factors including activated factor Vn, DC, X, XI and XII, and is inhibited by antithrombin in. Platelets are also involved in the coagulation process. Fibrinolysis is the mechanism of dissolution of fibrin clots, which can be promoted with thrombolytics. For further information on platelet aggregation and clot dissolution, see Antiplatelet drugs and thrombolytics , (p.697). 

This approach is based on the fact that fibrin forms the frame- rork or structural support of a clot. Dissolution of the fibrin should result in lysis of the clot with restoration of blood flow. The significance of fibrinolysis the mtential of thrombolysis in treatment of thrombotic coronary occlusion and fibrinolytic mechanisms have been reviewed. 

Self-protection. To prevent blood loss when a vessel is injured, the blood has systems for stanching blood flow and coagulating the blood (hemostasis see p. 290). The dissolution of blood clots (fibrinolysis) is also managed by the blood itself (see p. 292). 

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). 

This chapter will review the basic mechanisms of clot formation (thrombosis) and dissolution (thrombolysis or fibrinolysis), the mechanisms of the major drug classes used in the treatment, and the results from major clinical trials. This chapter will also present evidence-based recommendations and protocols for applying thrombolytic therapy to individual patients. 

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