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Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

Clinical Disorders:

Therapeutic Classes:

Mechanism Classes:

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Thrombolytic (Fibrinolytic) Drugs

Thrombolytic drugs are used to dissolve (lyse) blood clots (thrombi). Blood clots can occur in any vascular bed; however, when they occur in coronary, cerebral or pulmonary vessels, they can be immediately life-threatening - coronary thrombi are the cause of myocardial infarctions, cerebrovascular thrombi produce strokes, and pulmonary thromboemboli can lead to respiratory and cardiac failure. Therefore, it is important to rapidly diagnose and treat blood clots.

Mechanisms of Thrombolysis

Thrombolytic drugs dissolve blood clots by activating plasminogen, which forms a cleaved product called plasmin. Plasmin is a proteolytic enzyme that is capable of breaking cross-links between fibrin molecules, which provide the structural integrity of blood clots. Because of these actions, thrombolytic drugs are also called "plasminogen activators" and "fibrinolytic drugs."

There are three major classes of fibrinolytic drugs: tissue plasminogen activator (tPA), streptokinase (SK), and urokinase (UK).  While drugs in these three classes all have the ability to effectively dissolve blood clots, they differ in their detailed mechanisms in ways that alter their selectivity for fibrin clots.

fibrinolytic mechanisms for tissue plasminogen activator and streptokinase

The figure to the right illustrates the fibrinolytic mechanisms for tPA and SK. Derivatives of tPA are the most commonly used thrombolytic drugs, especially for coronary and cerebral vascular clots, because of their relative selectivity for activating fibrin-bound plasminogen. Tissue plasminogen activator produces clot lysis through the following sequence:

  1. tPA binds to fibrin on the surface of the clot
  2. Activates fibrin-bound plasminogen
  3. Plasmin is cleaved from the plasminogen associated with the fibrin
  4. Fibrin molecules are broken apart by the plasmin and the clot dissolves

Plasmin is a protease that is capable of breaking apart fibrin molecules, thereby dissolving the clot. However, it is important to note that plasmin also breaks down other circulating proteins, including fibrinogen. But because of the relative fibrin specificity of tPA, clot dissolution occurs with less breakdown of circulating fibrinogen than occurs with SK and UK. Although tPA is relatively selective for clot-bound plasminogen, it still activates circulating plasminogen thereby releasing plasmin, which can lead to the breakdown of circulating fibrinogen and cause an unwanted systemic fibrinolytic state. Normally, circulating α2-antiplasmin inactivates plasmin, but therapeutic doses of tPA (and SK) lead to sufficient plasmin formation to overwhelm the limited circulating concentrations α2-antiplasmin. In summary, although tPA is relatively selective for clot-associated fibrin, it can produce systemic lytic state and undesirable bleeding.

SK is not a protease and has no enzymatic activity; however, it forms a complex with plasminogen that releases plasmin. Unlike tPA, it does not bind preferentially to clot-associated fibrin and therefore binds equally to circulating and non-circulating plasminogen. Therefore, SK produces significant fibrinogenolysis along with clot fibrinolysis. For this reason, tPA is generally preferred as a thrombolytic agent over SK, especially when used for dissolving coronary and cerebral vascular thrombi. Because SK is derived from streptococci, patients who have had recent streptococci infections can require significantly higher doses of SK to produce thrombolysis.

It is important to note that the efficacy of thrombolytic drugs depends on the age of the clot. Older clots have more fibrin cross-linking and are more compacted; therefore, older clots are more difficult to dissolve. For treating acute myocardial infarction, the thrombolytic drugs should ideally be given within the first 2 hours. Beyond that time, the efficacy diminishes and higher doses are generally required to achieve desired lysis.

Specific Thrombolytic Drugs

Tissue Plasminogen Activators

This family of thrombolytic drugs is used in acute myocardial infarction, cerebrovascular thrombotic stroke and pulmonary embolism. For acute myocardial infarctions, tissue plasminogen activators are generally preferred over streptokinase.


Streptokinase and anistreplase are used in acute myocardial infarction, arterial and venous thrombosis, and pulmonary embolism. These compounds are antigenic because they are derived from streptococci bacteria.


Urokinase (Abbokinase®; UK) is sometimes referred to as urinary-type plasminogen activator (uPA) because it is formed by kidneys and is found in urine. It has limited clinical use because, like SK, it produces considerable fibrinogenolysis; however, it is used for pulmonary embolism. One benefit over SK is that UK is non-antigenic; however, this is offset by a much greater cost.

Adverse Effects and Contraindications

Common adverse effects of all the thrombolytic drugs is bleeding complications related to systemic fibrinogenolysis and lysis of normal hemostatic plugs. The bleeding is often noted at a catheterization site, although gastrointestinal and cerebral hemorrhages may occur. Therefore, patients who have experienced trauma injury or who have a history of cerebral hemorrhagic stroke are not usually administered thrombolytics. Re-thrombosis can occur following thrombolysis, and therefore anticoagulants such as heparin are usually co-administered, and continued after thrombolytic therapy for a period of time.

Revised 03/15/07

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.