title: Effect of thrombin inhibition on the dynamics of thrombolysis and on platelet function during thrombolytic therapy.
abstract: To evaluate the effect of thrombin on the dynamics of thrombolysis, we infused rabbits with heparin or hirudin alone or in conjunction with tissue-type plasminogen activator (t-PA) and monitored the kinetics of fibrinolysis and changes in ex vivo platelet aggregation responses over time. Both heparin and hirudin enhanced total fibrinolysis in an ex vivo arteriovenous shunt preparation: 82 +/- 2% and 79 +/- 2%, respectively, compared with 51 +/- 8% for t-PA alone (P less than 0.05) and 50 +/- 4% for t-PA plus aspirin (p less than 0.05). Heparin coadministered with t-PA significantly reduced the half-time for clot lysis compared with t-PA alone (p less than 0.05), whereas hirudin coadministered with t-PA significantly reduced the half-time for clot lysis compared with that for t-PA alone, t-PA plus aspirin, and t-PA plus heparin (5.5 +/- 0.6 versus 12.1 +/- 2.0 versus 12.6 +/- 2.2 versus 10.0 +/- 0.8 minutes, respectively; p less than 0.05). Both heparin and hirudin prevented the increase in ADP-induced platelet aggregation normally seen with t-PA alone (p less than 0.01 by t test; p less than 0.05 by two-way analysis of variance). These data demonstrate that selective, antithrombin III-independent thrombin inhibitors can enhance the efficacy of thrombolysis by modulating the dynamics of the process and preventing platelet activation associated with plasminogen activator therapy.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: M A
authors.initials: MA
authors.lastname: Rudd
authors.forename: D
authors.initials: D
authors.lastname: George
authors.forename: M T
authors.initials: MT
authors.lastname: Johnstone
authors.forename: R T
authors.initials: RT
authors.lastname: Moore
authors.forename: L
authors.initials: L
authors.lastname: Collins
authors.forename: L E
authors.initials: LE
authors.lastname: Rabbani
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000502:physiology*; D005260:Female; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D015539:Platelet Activation; D010974:Platelet Aggregation; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors*; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
chemical_list: D006629:Hirudins; D006493:Heparin; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D001241:Aspirin