Analysis of fibrin formation and proteolysis during intravenous administration of ancrod.
Ancrod is a purified fraction of venom from the Malayan pit viper, Calloselasma rhodostoma, currently under investigation for treatment of acute ischemic stroke. Treatment with ancrod leads to fibrinogen depletion. The present study investigated the mechanisms leading to the reduction of plasma fibrinogen concentration. Twelve healthy volunteers received an intravenous infusion of 0.17 U/kg body weight of ancrod for 6 hours. Blood samples were drawn and analyzed before and at various time points until 72 hours after start of infusion. Ancrod releases fibrinopeptide A from fibrinogen, leading to the formation of desAA-fibrin monomer. In addition, a considerable proportion of desA-profibrin is formed. Production of desA-profibrin is highest at low concentrations of ancrod, whereas desA-profibrin is rapidly converted to desAA-fibrin at higher concentrations of ancrod. Both desA-profibrin and desAA-fibrin monomers form fibrin complexes. A certain proportion of complexes carries exposed fibrin polymerization sites E(A), indicating that the terminal component of the protofibril is a desAA-fibrin monomer unit. Soluble fibrin complexes potentiate tissue-type plasminogen activator-induced plasminogen activation. Significant amounts of plasmin are formed when soluble fibrin in plasma reaches a threshold concentration, leading to the proteolytic degradation of fibrinogen and fibrin. In the present setting, high concentrations of soluble fibrin are detected after 1 hour of ancrod infusion, whereas a rise in fibrinogen and fibrin degradation products, and plasmin-alpha(2)-plasmin inhibitor complex levels is first detected after 2 hours of ancrod infusion. Ancrod treatment also results in the appearance of cross-inked fibrin degradation product D-dimer in plasma. (Blood. 2000;96:2793-2802)
Dempfle
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University of Heidelberg, Mannheim University Hospital, First Department of Medicine, Theodor Kutzer Ufer, D-68167 Mannheim, Germany. dempfle@verw.ma.uni-heidelberg.de
Argiriou
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Kucher
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Müller-Peltzer
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Rübsamen
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Heene
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D000328:Adult; D000721:Ancrod / Q000008:administration & dosage / Q000494:pharmacology*; D001704:Biopolymers; D002122:Calcium Chloride / Q000494:pharmacology; D002850:Chromatography, Gel; D004789:Enzyme Activation / Q000187:drug effects; D005176:Factor XIII / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000096:biosynthesis / Q000378:metabolism*; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000096:biosynthesis; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005344:Fibrinopeptide A / Q000378:metabolism; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D013917:Thrombin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000378:metabolism
D001704:Biopolymers; D005338:Fibrin Fibrinogen Degradation Products; D005343:Fibrinolytic Agents; D006629:Hirudins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; C415348:desA-profibrin; D005344:Fibrinopeptide A; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D005176:Factor XIII; C065735:glycyl-prolyl-arginyl-valyl-valyl-glutamic acid; D000721:Ancrod; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D002122:Calcium Chloride