Coagulation factor Xa is a plasma serine protease that catalyzes prothrombin 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 for the uptake and degradation of factor Xa. I-Factor Xa was degraded by hepatoma cells and embryonic fibroblasts via a process which required cell surface-bound tissue factor pathway inhibitor (TFPI), a potent inhibitor of factor Xa. Uptake and degradation of cell surface-bound I-TFPI was also markedly stimulated in response to factor Xa binding. The intracellular kinetics of I-factor Xa and cell surface-bound I-TFPI display a strikingly similar pattern, suggesting that factor Xa and cell surface-bound TFPI are taken up as a bimolecular complex. Using cell lines either deficient in low density lipoprotein receptor-related protein, an endocytic receptor that mediates the degradation of uncomplexed TFPI (Warshawsky, I., Broze, G. J., Jr., and Schwartz, 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 degradation of factor Xa-TFPI complex was neither low density lipoprotein receptor-related protein nor TF. As the vascular endothelial cell surface retains a substantial pool of TFPI (Sandset, P. M., Alildgaard, U., and Larsen, M. L.(1988) Thromb. Res. 50, 803-813; Novotny, W. F., Brown, 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 TFPI may be actively involved in the clearance of factor Xa from the circulation via mediated uptake and degradation.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				E. N. Harris, J. A. Weigel, and P. H. Weigel The Human Hyaluronan Receptor for Endocytosis (HARE/Stabilin-2) Is a Systemic Clearance Receptor for Heparin J. Biol. Chem., June 20, 2008; 283(25): 17341 - 17350. [Abstract] [Full Text] [PDF]

				J. T.B. Crawley and D. A. Lane The Haemostatic Role of Tissue Factor Pathway Inhibitor Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 233 - 242. [Abstract] [Full Text] [PDF]

				S. Butenas, T. Orfeo, M. T. Gissel, K. E. Brummel, and K. G. Mann The Significance of Circulating Factor IXa in Blood J. Biol. Chem., May 28, 2004; 279(22): 22875 - 22882. [Abstract] [Full Text] [PDF]

				G. Ho, M. Narita, G. J. Broze Jr, and A. L. Schwartz Recombinant full-length tissue factor pathway inhibitor fails to bind to the cell surface: implications for catabolism in vitro and in vivo Blood, March 15, 2000; 95(6): 1973 - 1978. [Abstract] [Full Text] [PDF]

				I. Ott, Y. Miyagi, K. Miyazaki, M. J. Heeb, B. M. Mueller, L. V. M. Rao, and W. Ruf Reversible Regulation of Tissue Factor-Induced Coagulation by Glycosyl Phosphatidylinositol-Anchored Tissue Factor Pathway Inhibitor Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 874 - 882. [Abstract] [Full Text] [PDF]

				E. L. Saenko, A. V. Yakhyaev, I. Mikhailenko, D. K. Strickland, and A. G. Sarafanov Role of the Low Density Lipoprotein-related Protein Receptor in Mediation of Factor VIII Catabolism J. Biol. Chem., December 31, 1999; 274(53): 37685 - 37692. [Abstract] [Full Text] [PDF]

				X. Han, T. J. Girard, P. Baum, D. R. Abendschein, and G. J. Broze Jr Structural Requirements for TFPI-Mediated Inhibition of Neointimal Thickening After Balloon Injury in the Rat Arterioscler. Thromb. Vasc. Biol., October 1, 1999; 19(10): 2563 - 2567. [Abstract] [Full Text] [PDF]

				A. Hamik, H. Setiadi, G. Bu, R. P. McEver, and J. H. Morrissey Down-regulation of Monocyte Tissue Factor Mediated by Tissue Factor Pathway Inhibitor and the Low Density Lipoprotein Receptor-related Protein J. Biol. Chem., February 19, 1999; 274(8): 4962 - 4969. [Abstract] [Full Text] [PDF]

				M. Narita, A. E. Rudolph, J. P. Miletich, and A. L. Schwartz The Low-Density Lipoprotein Receptor-Related Protein (LRP) Mediates Clearance of Coagulation Factor Xa In Vivo Blood, January 15, 1998; 91(2): 555 - 560. [Abstract] [Full Text] [PDF]

				J.-B. Hansen, R. Olsen, and P. Webster Association of Tissue Factor Pathway Inhibitor With Human Umbilical Vein Endothelial Cells Blood, November 1, 1997; 90(9): 3568 - 3578. [Abstract] [Full Text] [PDF]

				Z.-F. Huang, D. Higuchi, N. Lasky, and G. J. Broze Jr Tissue Factor Pathway Inhibitor Gene Disruption Produces Intrauterine Lethality in Mice Blood, August 1, 1997; 90(3): 944 - 951. [Abstract] [Full Text] [PDF]

				G. Ho, G. J. Broze Jr., and A. L. Schwartz Role of Heparan Sulfate Proteoglycans in the Uptake and Degradation of Tissue Factor Pathway Inhibitor-Coagulation Factor Xa Complexes J. Biol. Chem., July 4, 1997; 272(27): 16838 - 16844. [Abstract] [Full Text] [PDF]