Pharmacological modulation of fibrinolysis by antithrombotic and cardiovascular drugs

Abstract

vv HEREAS THE pharmacology of thrombolytic therapy is usually discussed in terms of agents capable of directly activating fibrinolysis, many nonthrombolytic drugs produce profibrinolytic effects that are mediated by indirect endogenous mechanisms. These profibrinolytic effects may involve the following: (1) release of endogenous tissue plasminogen activator (tPA), (2) reduction of plasminogen activator inhibitor (PAI) titres, (3) modification of serine proteases involved in the fibrinolytic process, and (4) modification of the fibrinogen molecule. Several drugs exert a stimulating effect on the endothelium, facilitating the release of plasminogen activators that may produce localized and/or systemic lytic effects. Initially, the indirect profibrinolytic effects of drugs were not detectable due to the limited sensitivity of conventional tests such as the fibrinogen level and euglobulin lysis time. However, with the development of newer ultrasensitive laboratory methods for the assessment of the fibrinolytic system, subclinical activation of the fibrinolytic system can now be readily measured. Table 1 lists some of the factors that contribute to the status of the fibrinolytic state. This physiological state can be affected by drugs and mechanical or physical manipulation. The mechanism by which drugs are capable of producing a fibrinolytic state are multiple. It is now well known that several inhibitors of fibrinolysis control this process. A decrease in the levels of these inhibitors or pharmacological inhibition of their function produces a profibrinolytic state. Inhibitors, such as PAIs, a,-antiplasmin (a,-AP), and histidine-rich glycoprotein (HRG), produce marked inhibition of the fibrinolytic process.4,s6,96 A decrease in these inhibitors r&sults in the facilitation of fibrinolysis. On the other hand, an increase in the levels of fibrinolytic activators, such as tPA, urokinase plasminogen activator (uPA), and related proteases may augment fibrinolysis. Many drugs are able to modify the fibrinogen molecule making it more susceptible to the action of plasmin.lo8 Similarly, enzymes such as plasmin, plasminogen activator, and urokinase can be modified by many pharmacological agents rendering these more efficient in potentiating the fibrinolytic process.147 Physical stimuli and pharmacological agents are both capable of releasing endogenous activators of fibrinolysis. This endogenous activation results in the net augmentation of fibrinolysis. Table 2 lists the cellular sites thought to be involved in modulation of the fibrinolytic system. Many cardiovascular drugs are capable of effecting these cellular sites where both the activators and inhibitors of fibrinolysis are produced. Individual drugs produce specific effects, with commonly used cardiovascular drugs causing both potentiation and inhibition of the fibrinolytic system. Endothelial cells and fibroblasts produce various modulators that contribute significantly to the regulation of the fibrinolytic process by drugs. Release of plasminogen activators and inhibitors from vascular storage sites due to drug action is now well documented. Thus, with the introduction of new cardiovascular drugs, their modulatory effects on the fibrinolytic system need to be considered. Some drugs that modulate the fibrinolytic process and the proposed mechanism by which this occurs are listed in Table 3. Different pharmacological agents produce variable effects on the fibrinolytic system. Glycosaminoglycans, such as heparin and dermatan, produce profibrinolytic effects. These drugs release endogenous tPA into the circulation and facilitate the generation of several other profibrinolytic mediators. The effects of glycosaminoglycans signifi-