Thrombolytics: Fibrinolytic Pathway

The fibrinolytic system is the body's endogenous mechanism for dissolving blood clots after vascular repair is complete. Plasminogen, a circulating inactive zymogen, is converted to plasmin by tissue plasminogen activator (tPA), which is released from endothelial cells. Plasmin cleaves fibrin within clots into fibrin degradation products (including D-dimer, which is why D-dimer is elevated after physiological fibrinolysis and with thrombolytic therapy). The system is regulated by plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA, and alpha-2-antiplasmin, which neutralizes circulating plasmin. Therapeutic thrombolytics are exogenous activators of this system: Alteplase (tPA) is a recombinant tissue plasminogen activator with relative fibrin specificity — it preferentially activates plasminogen bound to fibrin in the clot, causing less systemic fibrinolysis than non-specific agents; however, at therapeutic doses, systemic fibrinolysis still occurs. Tenecteplase is a genetically modified tPA with longer half-life (allowing single IV bolus dosing), greater fibrin specificity, and greater resistance to PAI-1 inactivation. Reteplase is another modified tPA given as two IV boluses 30 minutes apart. Streptokinase (historical) is a bacterial protein that forms a complex with plasminogen, directly activating it; non-fibrin-specific, causes extensive systemic...