RECEPTOR-MEDIATED ENDOCYTOSIS OF COAGULATION-FACTOR XA REQUIRES CELL SURFACE-BOUND TISSUE FACTOR PATHWAY INHIBITOR

Coagulation factor Xa is a plasma serine protease that catalyzes proth rombin to thrombin conversion, which, in turn, leads to the generation of the fibrin clot. Of the several parameters that govern the plasma level of factor Xa, control of its catabolism is of crucial importance . However, little is known regarding the mechanisms by which factor Xa is catabolized. In the present study we examine the cellular basis fo r the uptake and degradation of factor Xa. I-125-Factor Xa was degrade d by hepatoma cells and embryonic fibroblasts via a process which requ ired cell surface-bound tissue factor pathway inhibitor (TFPI), a pote nt inhibitor of factor Xa. Uptake and degradation of cell surface-boun d I-125-TFPI was also markedly stimulated in response to factor Xa bin ding. The intracellular kinetics of I-125-factor Xa and cell surface-b ound I-125-TFPI display a strikingly similar pattern, suggesting that factor Xa and cell surface-bound TFPI are taken up as a bimolecular co mplex. Using cell lines either deficient in low density lipoprotein re ceptor-related protein, an endocytic receptor that mediates the degrad ation of uncomplexed TFPI (Warshawsky, I., Broze, G. J., Jr., and Schw artz, A. L. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 6664-6668), or deficient in tissue factor (TF), an integral membrane protein capable of forming quarternary complexes with factor Xa, TFPI, and factor VIIa , we demonstrated that the receptor that mediates the uptake and degra dation of factor Xa-TFPI complex was neither low density lipoprotein r eceptor-related protein nor TF. As the vascular endothelial cell surfa ce retains a substantial pool of TFPI (Sandset, P. M., Alildgaard, U., and Larsen, M. L. (1988) Thromb. Res. 50, 803-813; Novotny, W. F., Br own, S. G., Miletich, J. P., Rader, D. J., and Broze, G. J., Jr. (1991 ) Blood 78, 387-393), our data suggest that endothelial cell surface T FPI may be actively involved in the clearance of factor Xa from the ci rculation via mediated uptake and degradation.