Plasminogen activation without changes in tPA and PAI-1 in response to subcutaneous administration of ancrod.
Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of ischemic stroke. The therapeutic effect is ascribed to a lowering of plasma fibrinogen. Thirty-two healthy volunteers received subcutaneous ancrod at doses of 1.0, 1.5 and 2.0 IU/kg body weight or placebo. Blood samples were drawn before the injection and at various time points until 96 h after the injection. Ancrod leads to the formation of desAA-fibrin, which serves as cofactor in tissue plasminogen activator activity (tPA)-induced plasminogen activation. Unchanged concentrations of prothrombin fragment F1.2 and thrombin-antithrombin complex (TAT) indicate that fibrin formation occurs independent of thrombin. Plasmin generation is independent of an increase in tPA activity or changes in plasminogen activator inhibitor-1 (PAI-1) concentration in plasma. Subcutaneous injection of ancrod leads to a generalized fibrino(geno)lytic response caused solely by providing tPA with soluble fibrin as its cofactor in plasminogen activation. Maximal plasmin activity is present 12 h after subcutaneous injection.
Dempfle
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First Department of Medicine, Mannheim University Hospital, University of Heidelberg, Theodor Kutzer Ufer, D-68167 Mannheim, Germany. dempfle@verw.ma.uni-heidelberg.de
Alesci
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Kucher
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Müller-Peltzer
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Rübsamen
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Borggrefe
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D000328:Adult; D000721:Ancrod / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D010958:Plasminogen / Q000187:drug effects* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011516:Prothrombin / Q000187:drug effects / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000097:blood
D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D011516:Prothrombin; D005337:Fibrin; D010958:Plasminogen; C065735:glycyl-prolyl-arginyl-valyl-valyl-glutamic acid; D000721:Ancrod; D010959:Tissue Plasminogen Activator