title: Prothrombotic effects of thrombolytic therapy in a rat (Rattus norvegicus) model of venous thrombolysis.
abstract: The use of thrombolytic agents has greatly improved patient outcomes, but the prothrombotic response to these drugs in vivo is unknown. Approximately 24 h after we induced thrombosis in male Sprague-Dawley rats, we placed an infusion line in the inferior vena cava and administered either saline or a thrombolytic agent (tissue plasminogen activator [tPA] or plasmin) for 30 min. Blood was drawn immediately after infusion; rats were euthanized 24 h after infusion for collection of blood and tissue (inferior vena cava and thrombus). Thrombus size was decreased in the tPA-treated rats but not in those that received saline or plasmin; this change correlated with the significant rise in D-dimer levels noted immediately after infusion in the tPA-treated rats. Plasma soluble P-selectin, a prothrombotic marker, was elevated at 24 h in the plasmin group compared with the other treatment groups. There were no significant differences in plasma C3a, C5a, or C5b9 levels or in thrombus C3 levels between groups. According to ultrastructural analysis, thrombus structure and vein wall effects did not differ between groups. Local tPA did not induce a prothrombotic state during acute DVT or after thrombolytic therapy in a rodent model of venous thrombolysis. Conversely, levels of the prothrombotic marker plasma soluble P-selectin increased when plasmin was administered.
authors.affiliation: Merck, Rahway, New Jersey, USA. katherine.shuster@merck.com
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Shuster
authors.forename: Shirley K
authors.initials: SK
authors.lastname: Wrobleski
authors.forename: Angela E
authors.initials: AE
authors.lastname: Hawley
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
authors.forename: Dorothy R
authors.initials: DR
authors.lastname: Sorenson
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Bergin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sigler
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Guire
authors.forename: Megan H
authors.initials: MH
authors.lastname: Nowland
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Wakefield
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Myers
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D003165:Complement System Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D051381:Rats; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014680:Veins / Q000473:pathology*; D020246:Venous Thrombosis / Q000209:etiology*
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D; D003165:Complement System Proteins; D010959:Tissue Plasminogen Activator