New Potential Therapeutic Modalities: Tissue Factor Pathway Inhibitor

Abstract

Tissue Factor Pathway Inhibitor (TFPI) is an endogenous inhibitor of the extrinsic pathway of coagulation. TFPI is a serine protease inhibitor that inhibits factor Xa directly and the factor VIIa/tissue factor catalytic complex in a Xa dependent fashion. TFPI is a multivalent inhibitor with three tandemly arranged Kunitz-type protease inhibitor domains, that appears to provide the protein with distinct functional properties, which make the inhibitor well suited for a regulatory role. TFPI is synthesized and secreted by endothelial cells. Circulating TFPI is lipoprotein associated. Control of thrombus formation in the microvasculature is likely to lead to the development of therapeutic modalities for the treatment of severe sepsis, especially when the thrombotic process is known to be a stimulus for multiple organ failure. A large pool of endogenous TFPI is found bound to the endothelium, while a small pool is stored in platelets. The concept of utilizing TFPI to protect the integrity of microvasculature, inhibit the initiation and propagation of multiple organ failure through the reduction of microthrombi formation, was examined in several models of sepsis, with and without severe DIC. There was significant survival benefit by the administration of recombinant TFPI to septic animals, in bacteremia and peritonitis models, several hours after the onset of symptoms. TFPI was found to exhibit anti-inflammatory activities as demonstrated by the decrease of IL-6 and IL-8 levels in the treated animals. TFPI was reported to bind endotoxin in vitro and reduce Fas levels in vivo suggesting the attenuation of apoptosis, in the target microvascular endothelial cells. TFPI was tested for safety and tolerability in normal human volunteers and more recently in patients with severe sepsis. The human clinical data suggest that TFPI is safe and well tolerated. TFPI is currently in phase II studies in severe sepsis patients.