Tissue factor pathway inhibitor prevents thrombus formation on procoagulant subendothelial matrix.
The effect of recombinant tissue factor pathway inhibitor (rTFPI) on extracellular matrix procoagulant activity was studied in a human ex vivo model of thrombogenesis. Extracellular matrix of endotoxin stimulated endothelial cells perfused with human non-anticoagulated blood at a wall shear rate of 100/s induced pronounced fibrin deposition, which covered 82 +/- 11% of the matrix surface within 5 min. Preincubating the matrix with the combination of rTFPI, factor VIIa (FVIIa) and factor Xa (FXa) reduced fibrin deposition to levels observed with matrix from non-stimulated endothelial cells (7 +/- 6% fibrin coverage, P < 0.001). Preincubation with rTFPI plus FXa also reduced fibrin deposition significantly, but to a lesser extent (41 +/- 6% fibrin coverage, P < 0.001). Preincubation with rTFPI alone, or with rTFPI plus FVIIa, did not affect fibrin deposition. The inhibition of thrombus formation on procoagulant extracellular matrix by rTFPI seemed to be FXa-dependent, and a result of TFPI's ability to bind and inhibit both TF activity as well as FXa. The results from this study suggest a future role for rTFPI as an agent for prevention of TF-induced vascular thrombosis.
Lindahl
A K
AK
Hematological Research Laboratory, Aker University Hospital, Oslo, Norway.
Sandset
P M
PM
Thune-Wiiger
M
M
Nordfang
O
O
Sakariassen
K S
KS
D001777:Blood Coagulation / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D015942:Factor VIIa / Q000494:pharmacology; D015951:Factor Xa / Q000494:pharmacology; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D004731:Endotoxins; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D013925:Thromboplastin; D015942:Factor VIIa; D015951:Factor Xa