Role of heparan sulfate proteoglycans in the uptake and degradation of tissue factor pathway inhibitor-coagulation factor Xa complexes

Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of blood coagulation factor Xa. (fXa) and factor VIIa. We have recently shown that fXa binding stimulates the uptake and degradation of cell surface-bound I-125-TFPI (He, G., Toomey, J. pg., Broze, G. J., Jr., and Schmartz, A. L. (1996) J. Biol. Chem. 271, 9497-9502). in the present study ave examined the role of cell surface glycosaminoglycans (GAGs) in this process, Removal of cell surface GAG chains by treatment of Cells with heparinase or heparitinase but not chondroitinase markedly reduced fXa-stimulated I-125-TFPI uptake and degradation, Inhibition of GAG sulfation by growth of cells in chlorate-containing medium similarly decreased fXa-stimulated I-125-TFPI degradation. These results suggest that heparan sulfate proteoglycans (HSPGs) are required fur the uptake and degradation of I-125-TFPI.fXa complexes. Chemical cross-linking/immunoprecipitation analyses revealed that I-125-TFPI was directly associated with HSPGs on the cell surface and that fXa binding increased the amount of I-125-TFPI bound, Of the several cell lines evaluated, bend endothelial cells demonstrated the greatest fXa stimulation of I-125-TFPI uptake and degradation, Cross-linking/immunoprecipitation analyses on bend cells also revealed that HSPGs were specifically associated with TFPI and fXa. These data suggest that HSPGs may directly act as the uptake and degradation receptor for TFPI.fXa complexes.