Inhibition of endotoxin-induced coagulation in rats by xk, a potent and selective tissue factor-factor vila inhibitor

Kevin M. Conricode, Rhonda M. Lachance, Thomas J. Girard

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Sepsis is frequently complicated by disseminated intravascular coagulation (DIG) with associated consumption of blood coagulation factors. Animal model studies of endotoxin- and bacteria-induced DIG have implicated tissue factor (TF) as the trigger for activation of coagulation. We have tested the effectiveness of a highly potent and selective inhibitor of TF-factor Vila in reducing endotoxin-induced DIG in rats. This unique inhibitor, referred to here as XK, is a chimeric protein which consists of the gla domain-containing light chain of factor X linked to the first Kunitz domain of TFPI (Science 148:1421-4). Endotoxin-induced coagulation was evaluated by determining plasma thrombinantithrombin complex (TAT) levels following iv. injection of 0.3 mg/kg LPS into anesthetized rats. In control (vehicle-infused) rats, TAT increased from 0.4 + 0.1 u,g/l (mean + S.E.) at baseline to 8.9 + 0.9 ng/1 at 120 min after LPS injection and 19.2 + 1.8 Jlg/1 at 180 min (n=17). Infusion of XK, at 15 ng/kg/min (started 30 min prior to and continued until 180 min after LPS injection) reduced plasma TAT to 2.3 + 0.4 ng/1 at 120 min and 13.5 + 2.7 Hg/1 at 180 min (n=7) , while infusion at 60 |ig/kg/min further decreased TAT to 1.0 + 0.3 (ig/1 and 7.8 + 3.0 fig/1 at 120 and 180 min, respectively (n=5). Plasma XK, levels reached approximately 4 fig/ml with the low dose and 25 Jig/ml, a concentration which prolongs the prothrombin time of human plasma by more than 10-fold, with the high dose. The consumption of plasma fibrinogen at 240 nun after LPS injection was attenuated by the high dose of XK, (112 + 14 mg/dl versus 134 + 9 mg/dl for control and high dose XK, groups, respectively; n=4 in each group). Blood loss following tail transection was also increased from 0.132 + 0.022 g with the vehicle (n=13) to 0.319 + 0.042 g with low dose XK, (n=3) and 0.538 + 0.084 g with high dose XK, (n=4). We conclude that XK, at least partially reduces endotoxin-induced coagulation in rats. The possible complete blockade of coagulation by very high doses of XK, in this model remains to be demonstrated.

Original languageEnglish
Pages (from-to)54a
Issue number11 PART I
StatePublished - Dec 1 2000
Externally publishedYes

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