Antithrombotic effect of human recombinant tissue factor pathway inhibitor on endotoxin-induced intravascular coagulation in rats: concerted effect with antithrombin.
In our current study, we examined the antithrombotic effect of Chinese hamster ovary cell-derived human recombinant tissue factor pathway inhibitor (h-rTFPI) by intravenous injection of h-rTFPI with or without antithrombin into endotoxin-treated rats. An injection of h-rTFPI at a high dose (4 mg/kg of h-rTFPI or three doses of 1 mg/kg) significantly prevented the decrease of fibrinogen and factor VIII and the increase of fibrin/fibrinogen degradation products and glutamic-pyruvic transaminase in rats, while a single injection of 1 mg/kg of h-rTFPI or 250 U/kg of antithrombin did not significantly prevent intravascular coagulation. However, a simultaneous injection of 1 mg/kg of h-rTFPI and 250 U/kg of antithrombin did significantly prevent intravascular coagulation. From the studies on the clearance rate and immunohistochemical staining of injected h-rTFPI into normal rats, we found that most of the intravenously-injected h-rTFPI was localized on the central vein and sinusoids in the liver and catabolized via the proteoglycan-mediated pathway with a half-life of 48 min. These results suggest that h-rTFPI and antithrombin prevented endotoxin-induced intravascular coagulation in concert by binding to the vascular walls of the liver and by inhibiting fibrin formation on Kupffer cells in hepatic sinusoids.
Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan.
Y
Y
Kamikubo
T
T
Hamuro
J
J
Matsuda
N
N
Shinya
S
S
Miyamoto
A
A
Funatsu
H
H
Kato
D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use*; D001778:Blood Coagulation Disorders / Q000139:chemically induced / Q000188:drug therapy*; D016466:CHO Cells; D006224:Cricetinae; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008074:Lipoproteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008657:Metabolic Clearance Rate; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D015842:Serine Proteinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*
D004731:Endotoxins; D005343:Fibrinolytic Agents; D008074:Lipoproteins; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III