Therapeutics targeting the fibrinolytic system

Abstract

The function of the fibrinolytic system was first identified to dissolve fibrin to maintain vascular patency. Connections between the fibrinolytic system and many other physiological and pathological processes have been well established. Dysregulation of the fibrinolytic system is closely associated with multiple pathological conditions, including thrombosis, inflammation, cancer progression, and neuropathies. Thus, molecules in the fibrinolytic system are potent therapeutic and diagnostic targets. This review summarizes the currently used agents targeting this system and the development of novel therapeutic strategies in experimental studies. Future directions for the development of modulators of the fibrinolytic system are also discussed.

Preparation of Peptide and Recombinant Tissue Plasminogen Activator Conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) Magnetic Nanoparticles for Dual Targeted Thrombolytic Therapy

“…The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of circulating rtPA and inactivation of rtPA by PAI-1 is the main cause for the short half-life of rtPA [39]. Therefore, it will be highly desirable that the PMNP-rtPA and pPMNP-rtPA developed in this study will not only retain its fibrinolytic activity (Figure 3c), but also prolong the circulation time of rtPA.…”

Serpins in Hemostasis as Therapeutic Targets for Bleeding or Thrombotic Disorders

“…PAI-1's antifibrinolytic properties (due to the inhibition of tPA) have prompted a search for PAI-1 inhibitors of value in the treatment of thrombotic disorders. In the vasculature, tPA is considered to be the main promoter of fibrinolysis; it binds to fibrin and converts plasminogen into plasmin, which in turn catalyzes fibrin proteolysis ( 45 ). Along with the use of anticoagulant drugs to downregulate the procoagulant pathway, treatment of thrombosis may require the use of thrombolytic therapy to restore blood flow in occluded vessels.…”

“…However, it is also associated with life-threatening adverse bleeding events ( 46 ). Given that PAI-1 deficiency is characterized only by mild-to-moderate bleeding without spontaneous bleeding episodes (whereas high plasma levels of PAI-1 have been linked to the development of thrombosis), PAI-1 inhibition might safely promote thrombolysis in the treatment of vascular thrombosis ( 45 ). Several research groups have attempted to develop small-molecule PAI-1 inhibitors ( 47 , 48 ).…”

Platelets in aging and cancer—“double-edged sword”

“…Taking the above into account, it is perhaps surprising to realize that fibrinolysis, the process of dissolving a blood clot, can also play a tumor-promoting role [162]. The main enzyme promoting fibrinolysis is plasmin, while the platelet-derived plasminogen activator inhibitor (PAI) is the main suppressor of this system.…”

“…On the other hand, plasminogen itself contributes to metastasis by degradation of the extracellular matrix surrounding tumor cells. In addition, the fibrinolytic system contributes to inflammation, angiogenesis, the release of tumor growth factors, and other tumor-promoting functions [162]. Thus, coagulation and fibrinolysis play double roles in cancer, highlighting platelet performance as double-edged sword [166].…”