title: Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo.
abstract: BACKGROUND
  In many case-control as well as epidemiological studies, increased lipoprotein(a) [Lp(a)] levels are considered to constitute an independent risk factor for premature coronary artery and cerebrovascular disease. Lp(a) resembles an LDL particle with an additional linked protein [apolipoprotein(a), apo(a)], whose molecular structure has been demonstrated to be homologous to the fibrinolytic proenzyme plasminogen. Because of the high similarity between plasminogen and apo(a), apo(a) may potentially interfere in the fibrinolytic system by competing with plasminogen for fibrin binding sites. In vitro studies have demonstrated that Lp(a) indeed competes with plasminogen binding to fibrin and inhibits tissue plasminogen activator (TPA)-mediated activation of plasminogen. No direct in vivo studies to test this hypothesis have been performed.
  
  
  RESULTS
  To test this hypothesis, we studied the effect of a recombinant form of apo(a) on endogenous and TPA-mediated thrombolysis in an in vivo model of experimental venous thrombosis. Thrombi containing either 16 microg r-apo(a), 8 microg r-apo(a), or vehicle (HEPES-buffered saline, control) were formed in the jugular veins of a rabbit and showed significantly reduced endogenous thrombolysis after 60 minutes in a dose-dependent fashion, ID 2.7+/-0.9% and 4.6+/-1.8%, respectively, versus 7.4+/-1.6% of that of the control. High concentrations of incorporated apo(a) significantly reduced TPA-induced thrombolysis (12.2+/-2.5% versus 22.2+/-2.6% in the control thrombi), but no effect of lower concentrations of incorporated r-apo(a) was demonstrated on the exogenous TPA-induced thrombolysis.
  
  
  CONCLUSIONS
  The present study demonstrates the attenuation of endogenous fibrinolysis by apo(a) in an in vivo model of experimental venous thrombosis, lending support to the proposed mechanism of impaired fibrinolysis by which Lp(a) may contribute to atherothrombotic disorders.
authors.affiliation: Center for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Center, University of Amsterdam, Netherlands.
authors.forename: B J
authors.initials: BJ
authors.lastname: Biemond
authors.forename: P W
authors.initials: PW
authors.lastname: Friederich
authors.forename: M L
authors.initials: ML
authors.lastname: Koschinsky
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: W
authors.initials: W
authors.lastname: Sangrar
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: H R
authors.initials: HR
authors.lastname: Büller
authors.forename: J W
authors.initials: JW
authors.lastname: ten Cate
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000187:drug effects*; D007601:Jugular Veins; D009994:Osmolar Concentration; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013924:Thrombophlebitis / Q000097:blood* / Q000139:chemically induced; D010959:Tissue Plasminogen Activator
chemical_list: D001054:Apolipoproteins A; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator