title: Role of plasminogen activator inhibitor-1 in promoting fibrin deposition in rabbits infused with ancrod or thrombin.
abstract: The role of defective fibrinolysis caused by elevated activity of plasminogen activator inhibitor-1 (PAI-1) in promoting fibrin deposition in vivo has not been well established. The present study compared the efficacy of thrombin or ancrod, a venom-derived enzyme that clots fibrinogen, to induce fibrin formation in rabbits with elevated PAI-1 levels. One set of male New Zealand rabbits received intravenous endotoxin to increase endogenous PAI-1 activity followed by a 1-hour infusion of ancrod or thrombin; another set of normal rabbits received intravenous human recombinant PAI-1 (rPAI-1) during an infusion of ancrod or thrombin. Thirty minutes after the end of the infusion, renal fibrin deposition was assessed by histopathology. Animals receiving endotoxin, rPAI-1, ancrod, or thrombin alone did not develop renal thrombi. All endotoxin-treated rabbits developed fibrin deposition when infused with ancrod (n = 4) or thrombin (n = 6). Fibrin deposition occurred in 7 of 7 rabbits receiving both rPAI-1 and ancrod and in only 1 of 6 receiving rPAI-1 and thrombin (P < .01). In vitro, thrombin but not ancrod was inactivated by normal rabbit plasma and by purified antithrombin III or thrombomodulin. The data indicate that elevated levels of PAI-1 promote fibrin deposition in rabbits infused with ancrod but not with thrombin. In endotoxin-treated rabbits, fibrin deposition that occurs with thrombin infusion may be caused by decreased inhibition of procoagulant activity and not increased PAI-1 activity.
authors.affiliation: Department of Hematology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
authors.forename: C
authors.initials: C
authors.lastname: Krishnamurti
authors.forename: C
authors.initials: C
authors.lastname: Bolan
authors.forename: C A
authors.initials: CA
authors.lastname: Colleton
authors.forename: T M
authors.initials: TM
authors.lastname: Reilly
authors.forename: B M
authors.initials: BM
authors.lastname: Alving
mesh_terms: D000721:Ancrod / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004731:Endotoxins / Q000633:toxicity; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000494:pharmacology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D004731:Endotoxins; D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins; D005337:Fibrin; D000721:Ancrod; D013917:Thrombin; D010959:Tissue Plasminogen Activator