Improving Therapeutic Fibrinolysis
- Gurewich V.
- Therapeutic Fibrinolysis: How Efficacy and Safety Can Be Improved. J Am Coll Cardiol 2016;68:2099-2106.
The following are key points to remember from this review about the efficacy and safety of therapeutic fibrinolysis:
- An occlusive intravascular thrombus triggers the cardiovascular diseases that are the leading causes of death and disability worldwide. The only pharmacological means to remove the thrombus is fibrinolysis.
- There are two plasminogen activators in the blood responsible for fibrinolysis: tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (uPA).
- There is a noteworthy contrast between the limited therapeutic efficacy of t-PA and its efficacy in the endogenous fibrinolytic system, especially because most of the t-PA in blood is in an inactive complex with its inhibitor, plasminogen activator inhibitor-1 (PAI-1).
- The efficacy of endogenous fibrinolysis is of interest due to its relevance as a model for therapeutic fibrinolysis. The only difference between the two systems is that the endogenous system utilizes t-PA in combination with uPA.
- Two different gene knockout studies showed that eliminating t-PA had no apparent effect on lysis of an intravascular clot and did not induce fibrin deposition, whereas knocking out uPA caused significant inhibition of clot lysis and some fibrin deposition.
- t-PA and pro-uPA have complementary modes of action, as each activates a different fibrin-bound plasminogen, and it is fibrin-bound plasmin that is responsible for fibrinolysis.
- The complementary functions of the activators also make their combined effects synergistic in fibrinolysis and provide an explanation for the efficiency of endogenous fibrinolysis.
- In vitro, a synergistic effect of t-PA and pro-uPA combinations has long been recognized and shown in vivo in animals.
- Fibrinolytic therapy with high-dose t-PA has been inadequate and risky, which has limited its use and resulted in its partial replacement by endovascular procedures for certain indications.
- Fibrinolysis, however, remains an essential therapeutic option, being the only means by which rapid, pharmacological removal of a thrombus is possible and reperfusion can be restored at a time when the greatest benefit is achievable.
- A different fibrinolytic regimen from t-PA monotherapy is required for this objective, and the efficient biological paradigm of endogenous fibrinolysis provides an example that may be difficult to improve upon.
Keywords: Acute Coronary Syndrome, Anticoagulants, Endovascular Procedures, Fibrin, Fibrinolysis, Gene Knockout Techniques, Plasminogen Activator Inhibitor 1, Thrombolytic Therapy, Thrombosis, Tissue Plasminogen Activator, Urokinase-Type Plasminogen Activator, Pharmacology
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