title: In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator.
abstract: The effects of heparin and the synthetic competitive thrombin inhibitor (2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfon yl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (Argatroban) on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) was studied in groups of six or seven rabbits with arterial thrombosis. The model consisted of a whole-blood clot produced in a 1-cm isolated femoral arterial segment with superimposed endothelial damage and distal high-grade stenosis. rt-PA was injected as an intravenous bolus of 0.45 mg/kg body wt at 15-minute intervals until recanalization, or up to a maximum of four boluses. In seven rabbits given an intravenous injection of 17 mg/kg aspirin, rt-PA induced transient reflow in only one animal. In seven rabbits that received intravenous heparin (200 units/kg over 60 minutes), rt-PA administration produced reflow in five animals, which was persistent in two rabbits. Combined administration of aspirin and heparin in seven rabbits was associated with similar rt-PA-induced recanalization. rt-PA administration in six rabbits given intravenous Argatroban (100 micrograms/kg/min for 60 minutes) caused recanalization in five, with persistent patency in three. In six rabbits given aspirin and Argatroban, rt-PA caused recanalization in all, with persistent patency in five animals. Reflow occurred significantly more rapidly with Argatroban (14 +/- 7 minutes) than with heparin (35 +/- 11 minutes), reflow was obtained with fewer boluses of rt-PA in combination with Argatroban (median value of one bolus) than with heparin (median value, three boluses), and reocclusion after reflow was less frequent with Argatroban (0 of 11 versus 5 of 10 rabbits). Furthermore, the degree of thrombolysis determined by pathological analysis was significantly more extensive with Argatroban than with heparin, and patency persisted during a 3-hour observation period, despite elimination of Argatroban from the circulation. Thus, Argatroban, relative to heparin, enhances and sustains thrombolysis with rt-PA. It may offer promise as an adjunctive agent for thrombolytic therapy of arterial thrombosis.
authors.affiliation: Cardiac Unit, Massachusetts General Hospital, Boston 02114.
authors.forename: I K
authors.initials: IK
authors.lastname: Jang
authors.forename: H K
authors.initials: HK
authors.lastname: Gold
authors.forename: R C
authors.initials: RC
authors.lastname: Leinbach
authors.forename: J T
authors.initials: JT
authors.lastname: Fallon
authors.forename: D
authors.initials: D
authors.lastname: Collen
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000627:therapeutic use*; D001120:Arginine / Q000031:analogs & derivatives; D001780:Blood Coagulation Tests; D005260:Female; D005263:Femoral Artery; D008297:Male; D010875:Pipecolic Acids / Q000627:therapeutic use*; D011817:Rabbits; D013449:Sulfonamides; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D000991:Antithrombins; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban