Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo

• Published in: Circulation (New York, N.Y.) Vol. 96; no. 5; pp. 1612 - 1615
• Main Authors: BIEMOND, B. J, FRIEDERICH, P. W, KOSCHINSKY, M. L, LEVI, M, SANGRAR, W, XIA, J, BÜLLER, H. R, TEN CATE, J. W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 02.09.1997; American Heart Association, Inc
• Subjects: Animals; Apolipoproteins A - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dose-Response Relationship, Drug; Fibrinolysis - drug effects; Jugular Veins; Medical sciences; Osmolar Concentration; Rabbits; Recombinant Proteins - pharmacology; Thrombophlebitis - blood; Thrombophlebitis - chemically induced; Tissue Plasminogen Activator; Pharmacologic test; Animal model; Rabbit; Cardiovascular disease; Lagomorpha; Thrombosis; Lipoprotein a; Venous disease; Vascular disease; Vertebrata; Mammalia; Alteplase; Animal; Risk factor; Vein; Fibrinolytic
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.96.5.1612

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. 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. 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.