Recombinant full-length tissue factor pathway inhibitor fails to bind to the cell surface: implications for catabolism in vitro and in vivo

Tissue factor pathway inhibitor (TFPI) plays a key role in the regulation o f tissue factor-initiated blood coagulation secondary to loss of the integr ity of the blood vessel wall. TFPI is a naturally occurring Kunitz-type pro tease inhibitor that inhibits coagulation factor Xa and, in a factor Xa-dep endent manner, mediates feedback inhibition of the factor VIIa/tissuefactor catalytic complex. In vivo full-length TFPI is thought to be primarily bou nd to the vascular endothelium and the high affinity binding requires an in tact carboxy terminus. Here we describe a full-length TFPI molecule, expres sed in mouse C127 cells (TFPIC127), which exhibits virtually no cellular bi nding yet contains the intact carboxy terminus. This TFPI (TFPIC127) is nei ther internalized nor degraded via the TFPI endocytic receptor, LDL-recepto r-related protein. Pharmacokinetic studies of TFPIC127 in vivo demonstrate a 10-fold prolongation in the plasma half-life, compared with that of bacte rial recombinant TFPI. (C) 2000 by The American Society of Hematology.