In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator

I. K. Jang, H. K. Gold, R. C. Leinbach, J. T. Fallon, D. Collen

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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- quinolinesulfonyl)-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 μg/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, enchances and sustains thrombolysis with rt-PA. It may offer promise as an adjunctive agent for thrombolytic therapy of arterial thrombosis.

Original languageEnglish
Pages (from-to)1552-1561
Number of pages10
JournalCirculation Research
Volume67
Issue number6
DOIs
StatePublished - 1990
Externally publishedYes

Keywords

  • Acute myocardial infarction
  • Argatroban
  • Recanalization

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