TISSUE FACTOR PATHWAY INHIBITOR PREVENTS THROMBUS FORMATION ON PROCOAGULANT SUBENDOTHELIAL MATRIX

The effect of recombinant tissue factor pathway inhibitor (rTFPI) on e xtracellular matrix procoagulant activity was studied in a human ex vi vo model of thrombogenesis. Extracellular matrix of endotoxin stimulat ed 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 t he matrix with the combination of rTFPI, factor VIIa (FVIIa) and facto r Xa (FXa) reduced fibrin deposition to levels observed with matrix fr om non-stimulated endothelial cells (7 +/- 6% fibrin coverage, P < 0.0 01). 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 a s well as FXa. The results from this study suggest a future role for r TFPI as an agent for prevention of TF-induced vascular thrombosis.