FIBRINOLYTIC AGENTS help in the dissolution of thrombi or blood clots. Some agents used clinically are versions of endogenous agents, and others are agents foreign to the body, with a number of modes of action. Blood coagulation involves the conversion of fluid blood to a solid gel or a clot. The formation of a clot helps in the process of haemostasis (see HAEMOSTATICS). The formation of fibrin filament, together with the adhesion and activation of platelets, helps form the haemostatic plug, which serves to block the damaged blood vessel wall. The actual elements of the clot, insoluble strands of fibrin, are the end-product of a cascade largely involving serine protease enzymes, notably thrombin, and blood-borne proteins. A thrombus is the unwanted formation of a haemostatic plug in blood vessels, often within the veins or arteries of the heart, commonly in pathological conditions associated with arterial disease or where there is stasis. Pieces of the thrombus may break off and form an embolism, which may lodge in vessels in the lungs or brain causing damage to the tissues supplied.

Thrombolytic drugs are able actually to dissolve thrombi. In contrast, neither antiplatelet drugs nor anticoagulants are necessarily thrombolytic. However, antiplatelet drugs -normally given prophylactically – do diminish the adhesion of platelets, which reduces their potential contribution to thrombus formation (see PLATELET AGGREGATION INHIBITING AGENTS). Similarly, anticoagulants – particularly when used prophylactically – can protect individuals at risk of thrombus formation. It is often beneficial to give agents from two or three of these classes in concert (vide infra).

Regarding intrinsic fibrinolytic factors in the body, when the intrinsic’ coagulation system is activated, the fibrinolytic system is also set in motion, and the latter involves endogenous plasminogen activators. The endogenous activators are of two types – tissue-type plasminogen activators (t-PA) and urokinase-type plasminogen activators (u-PA). The main role of the t-PA is fibrinolysis, and that of u-PA is mainly in cell migration and tissue remodelling processes. In the blood, some plasminogen activator derives from the vascular endothelium and from phagocytic cells, or by the action of factor XII on pro-activators in plasma and or tissues. Plasminogen is a serum β-globulin (MW 143,000) that is deposited on fibrin strands within the thrombus. The plasmogen activators, which have a short half-life in the bloodstream, are serine protease enzymes that split an Arg-Val bond in plasminogen, to release the enzyme plasmin (also known as fibrinolysin). Plasmin is a trypsin-like serine protease that acts on Arg-Lys bonds to digest many blood components, including fibrin, fibrinogen and factors II, V, VIII and a number of other proteins. Plasmin is normally formed only locally within the clot since plasminogen is adsorbed onto fibrin, and is rapidly broken down in the bloodstream. There is a second mechanism for stimulating fibrinolysis which involves activation of protein C, a coagulation inhibitor.

Turning to extrinsic fibrinolytic agents used medically to enhance or mimic the normal fibrinolytic processes, and dissolve thrombi, there are only a few agents available. The most commonly used is streptokinase, a non-enzymic protein obtained from cultures of Streptococcus haemolyticus, which acts indirectly by forming a stable complex with plasminogen, and imparts greater activity to that enzyme through a conformational change. Though effective, there may be a dangerous sensitivity reaction to this foreign protein. Anistreplase (APSAC) is a complex of human Lys-plasminogen and streptokinase, and is used in acute myocardial infarction. Of plasminogen activators similar to those found normally in vivo, alteplase is a single-chain recombinant tissue-type plasmin activator, whereas duteplase is a double-chain recombinant tissue-type plasmin activator. Urokinase (tca-PA or r-scu-PA) is an endogenous serine protease with many actions, which binds to a urokinase receptor found on the membrane of monocytes and other cells. It is normally secreted from cells as a single-chain proenzyme (scu-PA) from which the double-chain active form (tcu-PA) is derived by proteolysis. Clinically, tcu-PA urokinase is the form used (which is derived from human embryonic kidney cells), and acts directly as a plasminogen activator. Also under development is saruplase (recombinant human single-chain urokinase-type plasminogen activator, r-scuPa urokinase), which is converted to urokinase on binding to fibrin. Urokinase has the advantage of being non-immunogenic, and is used mainly for thrombolysis in the eye, and in arteriovenous shunts.

The dangers of most of these treatments are significant, and include, in addition to sensitivity reactions, the risk of excessive bleeding, particularly gastrointestinal bleeding, and haemorrhagic stroke. It is therefore necessary to know the best treatment under given circumstances, and to this end a number of multicentre controlled trials have been undertaken – particularly addressing the question of treatment of myocardial infarction, which is a major cause of death in the developed countries. They all consider the effects of particular fibrinolytic drugs given in concert with antiplatelet and anticoagulant therapy. The trials – entitled ISIS-3, GISSI-2, ISG and GUSTO – have studied very large numbers of patients, and suggest that streptokinase therapy is the best emergency treatment (in conjunction with oral aspirin), to which heparin did not add any advantage. However, the GUSTO trial suggests that rapid intravenous t-PA saved more lives than streptokinase (both with intravenous heparin in conjunction with oral aspirin). With the current development of newer fibrinolytic treatments, clearly the question is still not fully resolved.