Efficacy and Safety of Tifacogin (Recombinant Tissue Factor Pathway Inhibitor) in Severe Sepsis

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Abstract
Systemic activation of coagulation and thrombus formation in the microvasculature accompanies organ dysfunction and excess mortality in severe sepsis.1 Tissue factor (thromboplastin) is a major initiator of the blood coagulation process.2 Tissue factor is a transmembrane cell surface receptor for plasma clotting factor VII and exhibits homology with the cytokine-receptor family.3 Tissue factor pathway inhibitor (TFPI) is an endogenous serine protease inhibitor, synthesized and secreted by endothelial cells, which inhibits factor Xa directly and the factor VIIa/tissue factor catalytic complex in a Xa dependent fashion.4,5 A significant portion of endogenous TFPI is bound to the microvasculature through low-affinity binding to glycosaminoglycans. This pool of TFPI is releasable into the circulation by exposure to heparin. A small pool of TFPI is stored in platelets and secreted on activation and degranulation. The majority of circulating TFPI is bound to lipoproteins.5 The circulating concentrations of TFPI vary widely in healthy volunteers and in patients with sepsis.6 A study by Shimura et al7 suggested that full-length TFPI was consumed in predisseminated intravascular coagulation conditions and that the truncated form of TFPI-antigen increased in patients with disseminated intravascular coagulation. The functional properties of circulating TFPI are not well delineated.