title: Streptokinase and rt-PA activate platelets by a different way: implications on the rethrombosis rate after their administration in myocardial infarction.
abstract: The natural history of acute myocardial infarction has been dramatically changed by the advent of thrombolytic treatment, with a 30% mortality reduction, a better recovery of ventricular function, and a better quality of life. This treatment notwithstanding, failure or delay in achieving reperfusion, along with reocclusion and bleeding, still worry clinicians and challenge researchers to improve thrombolytic regimens and concomitant antithrombotic treatments. Platelet activation, at least in part because of thrombolytic treatment itself, plays a pivotal role in the pathogenesis of resistance to lysis and rethrombosis. The aim of this study was to compare in vitro the effects on platelets of therapeutic concentrations of streptokinase (SK) and recombinant type plasminogen activator (rt-PA). The effects of plasmin and thrombin were also studied as a reference. Fluorescence flow cytometry was used to evaluate (1) fibrinogen binding and (2) surface expression of GMP-140, a sensitive marker of platelet release reaction. Platelet function was further studied by measuring the release of carbon 14-labeled serotonin, beta-thromboglobulin, plasminogen activator inhibitor-1 (PAI-1) and the generation of thromboxane (TxB2). We found that 10 nmol/L SK and 14 nmol/L rt-PA increased fibrinogen binding to platelets by 12 +/- 2 and 10 +/- 4 times, respectively (p = not significant). At the same concentrations, SK, but not rt-PA, also induced the platelet release reaction: surface expression of GMP-140 was increased by 6 +/- 1.5 times by SK and 1.3 +/- 0.2 times by rt-PA (p < 0.05). TxB2 production was not modified by plasmin and plasminogen activators. Our data showed that plasmin and SK stimulate fibrinogen receptor expression and platelet degranulation. Conversely, rt-PA, at concentrations up to 14 nmol/L, only promotes fibrinogen binding. These results, coupled with the less-pronounced lytic state induced by rt-PA, could explain the higher incidence of reocclusion accompanying rt-PA therapy in comparison with SK that occurs unless effective "adjunctive" antithrombotic treatment is used. Neither of the thrombolytic agents activates the arachidonate pathway. Thus aspirin is probably not an ideal agent to be used in conjuction with thrombolytic agents. We speculate that newer approaches, particularly RGD peptides and antibodies against GP llb/llla, might produce better results.
authors.affiliation: Institute of Internal and Vascular Medicine, University of Perugia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Parise
authors.forename: J
authors.initials: J
authors.lastname: Hauert
authors.forename: A
authors.initials: A
authors.lastname: Iorio
authors.forename: P
authors.initials: P
authors.lastname: Callegari
authors.forename: G
authors.initials: G
authors.lastname: Agnelli
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000097:blood; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy*; D019007:P-Selectin; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D010960:Plasminogen Activators / Q000008:administration & dosage / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D010980:Platelet Membrane Glycoproteins / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012008:Recurrence; D012701:Serotonin / Q000097:blood; D013300:Streptokinase / Q000008:administration & dosage / Q000494:pharmacology*; D013917:Thrombin / Q000494:pharmacology; D015912:Thrombolytic Therapy; D013928:Thromboxane A2 / Q000097:blood; D001620:beta-Thromboglobulin / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D019007:P-Selectin; D017395:Plasminogen Activator Inhibitor 1; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D001620:beta-Thromboglobulin; D012701:Serotonin; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D005340:Fibrinogen; D013300:Streptokinase; D010960:Plasminogen Activators; D013917:Thrombin