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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2793-2802
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Analysis of fibrin formation and proteolysis during
intravenous administration of ancrod
Carl-Erik Dempfle,
Sotiria Argiriou,
Klaus Kucher,
H. Müller-Peltzer,
Klaus Rübsamen, and
Dieter L. Heene
From the University of Heidelberg, Mannheim University
Hospital, First Department of Medicine, Theodor Kutzer Ufer, D-68167
Mannheim, Germany; Knoll AG, D-67008 Ludwigshafen, Germany.
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 EA, 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- 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.
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