Antithrombotic effect of recombinant truncated tissue factor pathway inhibitor (TFPI1-161) in experimental venous thrombosis--a comparison with low molecular weight heparin.
The aim was to investigate whether a truncated recombinant Tissue Factor Pathway Inhibitor (TFPI1-161), which lacked the third Kunitz-type domain and the basic c-terminal region, had an antithrombotic effect comparable to LMWH in a randomised double-dummy study. The experimental thrombosis was induced in jugular veins, in a total of 40 rabbits by a combination of destruction of the endothelium and restricted blood flow. Group 1: placebo, gr 2: LMWH 60 anti-FXa IU/kg, gr 3-5: 0.1, 1.0 and 10.0 mg/kg TFPI1-161. TFPI1-161 reduced the thrombus weights in all treated groups, significantly in doses of 1.0 and 10.0 mg/kg compared to placebo. The frequency of thrombosis and occlusive thrombosis were also significantly reduced in those doses. The antithrombotic properties of TFPI1-161 (1.0-10.0 mg/kg) measured as thrombus weight, frequency of thrombosis and frequency of occlusive thrombosis was equivalent to the anti-thrombotic properties of LMWH. In the anti-FXa, APTT and PT-assays TFPI1-161 displayed a dose dependent increase of activity. Recombinant-TFPI1-161 did not influence the anti-FIIa-assay. No haemorrhagic side effects were noted.
Holst
J
J
Department of Surgery and Experimental Research, Malmö General Hospital, Lund University, Sweden.
Lindblad
B
B
Bergqvist
D
D
Nordfang
O
O
Ostergaard
P B
PB
Petersen
J G
JG
Nielsen
G
G
Hedner
U
U
D000818:Animals; D001760:Bleeding Time; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D008074:Lipoproteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013924:Thrombophlebitis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D008074:Lipoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C081249:tissue factor pathway inhibitor (1-161)