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:

  1. 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.
  2. There are two plasminogen activators in the blood responsible for fibrinolysis: tissue-type plasminogen activator (t-PA) and urokinase plasminogen activator (uPA).
  3. 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).
  4. 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.
  5. 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.
  6. 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.
  7. The complementary functions of the activators also make their combined effects synergistic in fibrinolysis and provide an explanation for the efficiency of endogenous fibrinolysis.
  8. In vitro, a synergistic effect of t-PA and pro-uPA combinations has long been recognized and shown in vivo in animals.
  9. 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.
  10. 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.
  11. 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.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Dyslipidemia, Anticoagulation Management and ACS, Lipid Metabolism, Novel Agents

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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