title: Novel thrombolytic agents.
abstract: The fibrinolytic system comprises an inactive pro-enzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two immunologically distinct plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation is regulated by specific molecular interactions between its main components, as well as by controlled synthesis and release of plasminogen activator inhibitors, primarily from endothelial cells. The observed association between abnormal fibrinolysis and a tendency toward bleeding or thrombosis demonstrates the (patho)physiological importance of the fibrinolytic system. Transgenic animals are a suitable experimental model to examine the in vivo impact of fibrinolytic components in thrombosis and thrombolysis. Inactivation, by homologous recombination, of the tissue-type plasminogen activator genes in mice impairs thrombolysis in a significant manner whereas inactivation of the plasminogen activator-1 gene enhances the rate of spontaneous lysis. Despite their widespread use all currently available thrombolytic agents suffer from a number of significant limitations, including resistance to reperfusion, the occurrence of acute coronary reocclusion and bleeding complications. Therefore, the quest for thrombolytic agents with a higher thrombolytic potency, specific thrombolytic activity and/or a better fibrin-selectivity continues. Several lines of research toward improvement of thrombolytic agents are being explored, including the construction of mutants and variants of plasminogen activators, chimeric plasminogen activators, conjugates of plasminogen activators with monoclonal antibodies, or plasminogen activators from animal or bacterial origin.
authors.affiliation: Center for Molecular and Vascular Biology, University of Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Verstraete
authors.forename: H R
authors.initials: HR
authors.lastname: Lijnen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins