Fibrinolitic drugs

When a small blood vessel is cut, a repair mechanism (hemostasis) is activated that eventually seals the cut and prevents further blood loss. What is in fact a lifesaving mechanism that protects the wounded body from hemorrhage becomes life threatening when clots (thrombi) form within functional blood vessels (thrombosis). Thrombosis tends to occur in blood vessels damaged by artherosclerosis or in vessels with a sluggish blood flow. In veins, portions of the thrombi (emboli) may break off and pass along the bloodstream to become lodged in the arteries of the heart. The drugs described in this section either inhibit hemostasis or they act to enhance the mechanisms that lyse, or dissolve, trombi.

The clotting process essentially involves the conversion of a soluble plasma protein, fibrinogen, into strands of the insoluble protein fibrin, which forms a mesh that traps platelets. The trigger for hemostasis is an injury to the endothelium, the cells lining the blood vessels, so that the underlying layer of collagen is exposed. The series of events leading to clot formation in a cut blood vessel are (1) constriction of the blood vessel by serotonin, epinephrine, and the thromboxane A, which diminishes blood loss; (2) formation of a plug of platelets (the platelet phase) by ADP and thromboxane A, also released by platelets, which act in a positive feedback process that makes more platelets adhere to the collagen and to each other, and (3) the conversion of the plug into a clot of fibrin (the coagulation phase). The formation of fibrin entails the sequential interaction of more than a dozen clotting factors, which are protease enzymes (i.e., they accelerate the breakdown of proteins). Each of these clotting factors activates the next in a coagulation cascade of proteolytic reactions that break down protein molecules. The penultimate reaction is the conversion of the soluble fibrinogen to soluble fibrin under the influence of the enzyme thrombin (factor IIa). Soluble fibrin is converted to insoluble fibrin strands by activated factor XIII (fibrin-stabilizing factor), and covalent cross-linkages form between the fibrin strands to give a strong and rigid network. Several of the clotting factors (II. VII, IX, X) require the presence of vitamin K for their activation. Consequently, inhibition of vitamin K blocks the propagation of coagulation pathways.

Under normal conditions the adhesion of platelets to vessel walls is prevented by the vascular endothelial cells, at least in part by their ability to release prostaglandins called prostacyclin or prostaglandin I, which reduce platelet stickiness and cause dilation of the blood vessels.

A fibrinolytic system exists in the body that restricts thrombus propagation beyond the site of injury and is also involved in the lysis of clots as wounds heal.

Fibrinolytic drugs activate the fibrinolytic pathway and lyse clots. The fibrinolytic drugs are distinct from the coumarin derivatives and heparin, which inhibit the formation of clots.

Tissue plasminogen activator (TPA) stimulates fibrinolysis, and it has several important advantages over streptokinase and urokinase in treating coronary thrombosis. It binds readily to fibrin and after intravenous administration activates only the plasminogen that is bound to the thrombus; thus, fibrinolysis occurs in the absence of an extensive breakdown of the coagulation factors. It may be used to initiate treatment of heart attack victims en route to the hospital, eliminating the time spent in the hospital preparing the patient for intracoronory injections of sfreptokinase. This is extremely useful because the rapid reestablishment of coronary blood flow is critically important to minimize the amount of damage to myocardial cells after an infarction.

An elevation in the level of circulating plasmin because of excessive activation of the fibrinolytic system may result in fibrinogenolysis and hemorrhage. The antifibrinolytic drug aminocaproic acid is a specific antagonist of plasmin and inhibits the effects of fibrinolytic drugs.

Streptokinase is produced from streptococcal bacteria. When administered systemically, streptokinase lyses acute deep-vein, pulmonary, and arterial thrombi; however, the drug is less effective in treating chronic occlusions. Streptokinase administered by intracoronary artery infusion soon after a coronary occlusion has formed is effective in reestablishing the flow of blood through the heart and vessels after a myocardial infarction and in limiting the size of the area of infarct (or tissue death). Intracoronary infusion permits the delivery of a high concentration of the drug to a localized area and speeds the activation of the fibrinolytic pathway. Intracoronary infusion minimizes the amount of streptokinase inactivated by antibodies that are normally present in blood. Heparin and aspirin can be added to therapy to help prevent the recurrence of occlusive thrombi. An overdose of streptokinase may lead to bleeding from systemic fibrinogenolysis, which is the breakdown of the coagulation factors by plasmin.

Urokinase is a protease enzyme that activates plasminogen directly. Because it is obtained from tissue culture of human kidney cells, it is not antigenic. Urokinase lyses recently formed pulmonary emboli, and, compared to streptokinase, it produces fibrinolysis without extensive breakdown of the coagulation factors. The usefulness of intravenous or intracoronary urokinase after myocardial infarction is not known.