THE EFFECT OF 2-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 fa ctor on the surface of monocytes and endothelial cells. Tissue factor pathway inhibitor (TFPI) is a factor Xa-dependent feedback inhibitor o f the tissue factor-factor VIIa complex. In the present study the effe ct on DIC of a two-domain TFPI analogue (2D-TFPI), consisting of the f irst two Kunitz domains of TFPI but lacking the third domain, was test ed. DIC was induced in rabbits by two intravenous bolus injections of endotoxin from Escherichia coli (10 and 50 mug/kg) 24 h apart. Simulta neously 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 we re submitted to histological examination. The degree of fibrin deposit ion 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 s ignificant decrease in platelet count (65%), plasma fibrinogen (41%), antithrombin III (25%), and factor VIII (63%), and a significant prolo ngation of the aPTT (14%). Furthermore, massive fibrin deposition was detected in the renal glomeruli at 31 h. Infusions of 2D-TFPI inhibite d all the endotoxin-induced changes in a dose-dependent manner. In con clusion, the data demonstrate that inhibition of the TF/FVIIa complex by infusion of 2D-TFPI significantly counteracts endotoxin-induced coa gulopathy in rabbits, and might thus be an attractive drug for treatme nt of endotoxin-induced DIC in humans.