Molecular basis of fibrinolysis, as relevant for thrombolytic therapy.
The fibrinolytic system comprises an inactive proenzyme, plasminogen, that is converted by plasminogen activators to the active enzyme, plasmin, that degrades fibrin. Two physiological plasminogen activators have been identified: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Plasminogen activation for clot lysis is regulated by specific molecular interactions between tissue-type plasminogen activator (t-PA), plasminogen and fibrin, whereby the lysine-binding sites of the plasminogen molecule play a crucial role by mediating its binding to fibrin, and by controlling the inhibition rate of plasmin by alpha 2-antiplasmin. The recognition that thrombosis within the infarct related coronary artery plays a major role in the pathogenesis of acute myocardial infarction and the observation that early administration of thrombolytic agents results in recanalization of occluded coronary arteries, have provided the basis for the development of thrombolytic therapy in acute myocardial infarction. The elucidation of the biochemical mechanism of fibrin-specific plasminogen activation has fueled the hope that specific and efficacious thrombolytic agents might become available. Comparative studies between the non-fibrin-selective streptokinase and fibrin-selective recombinant t-PA (rt-PA) have shown a difference in efficacy for early coronary artery recanalization, whereas the GUSTO trial has established that clinical benefit in patients with acute myocardial infarction is indeed correlated with the rapidity and frequency of sustained recanalization and that effective thrombolysis requires adequate anticoagulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Collen
D
D
Center for Molecular and Vascular Biology, University of Leuven, Belgium.
Lijnen
H R
HR
D002986:Clinical Trials as Topic; D004789:Enzyme Activation / Q000187:drug effects; D005341:Fibrinolysin / Q000737:chemistry / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy; D010958:Plasminogen / Q000737:chemistry / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D015849:Plasminogen Inactivators / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000627:therapeutic use; D015912:Thrombolytic Therapy; D000979:alpha-2-Antiplasmin / Q000378:metabolism
D005343:Fibrinolytic Agents; D015849:Plasminogen Inactivators; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin