Tissue Factor Pathway Inhibitor

Tissue factor pathway inhibitor (TFPI) is a factor Xa-dependent inhibitor of the factor VIIa/tissue factor (TF) catalytic complex that initiates blood coagulation. TFPI is expressed by, and found on the surface of, endothelial cells (ECs), where it inhibits intravascular TF activity and thereby helps to prevent the development of intravascular thrombosis (1). The identification, cloning, and characterization of TFPI in the mid-1980s represented the culmination of many studies performed in the earlyandmid-1900s (2). These early studies demonstrated that serum contains a calcium-dependent factor that inhibits the procoagulant activity of tissue extracts and whose preincubation with serum prevents the toxicity of TF infused into mice (3). Studies by P. F. Hjort in the 1950s demonstrated that the serum factor inhibited the TF/factor VIIa/calcium complex, but not TF or factor VIIa individually, indicating that factor VIIa and TF function as a catalytic complex. In 1985, Sanders and coworkers described a factor Xa-dependent inhibitor of the factor VIIa/TF catalytic complex present in the lipoprotein fraction of plasma (4). This finding led to the purification and identification of TFPI from conditioned medium of HepG2 cells by Broze and coworkers in 1987 (5). Subsequent cloning and cDNA sequence analysis revealed TFPI to be a trivalent Kunitz-type serine protease inhibitor that inhibits factor Xa via the second Kunitz domain and factor VIIa/TF via the first Kunitz domain (6,7). Initially, TFPI was referred to as either lipoprotein-associated coagulation inhibitor (LACI) or extrinsic pathway inhibitor (EPI). For purposes of standardization, a group of interested investigators at the International Society for Thrombosis and Haemostasis, meeting in 1991, recommended the name TF pathway inhibitor .