The effect of two-domain tissue factor pathway inhibitor on endotoxin-induced disseminated intravascular coagulation in rabbits.
Disseminated intravascular coagulation (DIC) is a common complication in sepsis, and may result from endotoxin-induced exposure of tissue factor on the surface of monocytes and endothelial cells. Tissue factor pathway inhibitor (TFPI) is a factor Xa-dependent feedback inhibitor of the tissue factor-factor VIIa complex. In the present study the effect on DIC of a two-domain TFPI analogue (2D-TFPI), consisting of the first two Kunitz domains of TFPI but lacking the third domain, was tested. DIC was induced in rabbits by two intravenous bolus injections of endotoxin from Escherichia coli (10 and 50 micrograms/kg) 24 h apart. Simultaneously with the last endotoxin injection an infusion of 2D-TFPI (0, 0.3, 1.0 or 3.0 mg/kg/h) was given. Blood samples were obtained at 0 h, 24 h and 31 h. At 31 h the animals were sacrificed and the kidneys were submitted to histological examination. The degree of fibrin deposition in glomeruli was scored blindly using an arbitrary scale from 0 to 3. Between 24 and 31 h the group receiving endotoxin alone showed a significant decrease in platelet count (65%), plasma fibrinogen (41%), antithrombin III (25%), and factor VIII (63%), and a significant prolongation of the aPTT (14%). Furthermore, massive fibrin deposition was detected in the renal glomeruli at 31 h. Infusions of 2D-TFPI inhibited all the endotoxin-induced changes in a dose-dependent manner. In conclusion, the data demonstrate that inhibition of the TF/FVIIa complex by infusion of 2D-TFPI significantly counteracts endotoxin-induced coagulopathy in rabbits, and might thus be an attractive drug for treatment of endotoxin-induced DIC in humans.
Bregengård
C
C
Novo Nordisk A/S, Gentofte, Denmark.
Nordfang
O
O
Wildgoose
P
P
Svendsen
O
O
Hedner
U
U
Diness
V
V
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D004731:Endotoxins; D004926:Escherichia coli; D005167:Factor VII / Q000037:antagonists & inhibitors*; D005169:Factor VIII / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008074:Lipoproteins / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D011517:Prothrombin Time; D011817:Rabbits; D013918:Thrombin Time
D004731:Endotoxins; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D000990:Antithrombin III; D005167:Factor VII; D005169:Factor VIII; D005337:Fibrin; D005340:Fibrinogen