Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 1973-1978
Recombinant full-length tissue factor pathway inhibitor fails to
bind to the cell surface: implications for catabolism in vitro and in
vivo
Guyu Ho,
Masaaki Narita,
George J. Broze Jr, and
Alan L. Schwartz
From the Departments of Pediatrics, Molecular Biology and
Pharmacology, Medicine, and Cell Biology and Physiology, Washington
University School of Medicine and St. Louis Children's Hospital, St
Louis, MO
Tissue factor pathway inhibitor (TFPI) plays a key role in the
regulation of tissue factor-initiated blood coagulation secondary to
loss of the integrity of the blood vessel wall. TFPI is a naturally occurring Kunitz-type protease inhibitor that inhibits coagulation factor Xa and, in a factor Xa-dependent manner, mediates
feedback inhibition of the factor VIIa/tissuefactor catalytic
complex. In vivo full-length TFPI is thought to be primarily bound to
the vascular endothelium and the high affinity binding requires an intact carboxy terminus. Here we describe a full-length TFPI molecule, expressed in mouse C127 cells (TFPIC127), which exhibits
virtually no cellular binding yet contains the intact carboxy terminus.
This TFPI (TFPIC127) is neither internalized nor degraded
via the TFPI endocytic receptor, LDL-receptor-related protein.
Pharmacokinetic studies of TFPIC127 in vivo demonstrate a
10-fold prolongation in the plasma half-life, compared with that of
bacterial recombinant TFPI.
