TISSUE FACTOR PATHWAY INHIBITOR AND VON-WILLEBRAND-FACTOR ANTIGEN LEVELS IN ADULT-RESPIRATORY-DISTRESS-SYNDROME AND IN A PRIMATE MODEL OF SEPSIS

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein pri marily synthesized by the endothelium. A major fraction (similar to 85 %) of TFPI remains associated with the endothelium, whereas a small fr action (similar to 15%) is secreted into the blood. In our attempts to search for a marker(s) of endothelial injury in the setting of adult respiratory distress syndrome (ARDS), we retrospectively measured plas ma TFPI levels in patients at risk for and with ARDS caused by several etiologic factors. Plasma von Willebrand factor antigen (VWF-Ag), ano ther endothelial-specific protein, was also measured in these patients . The mean plasma TFPI levels were slightly elevated (similar to 1.3-f old), whereas vWF-Ag levels were significantly elevated (similar to 3- fold) in the at-risk group as compared with those in the normal subjec ts. Both the TFPI (similar to 1.8-fold) and the vWF-Ag (similar to 4-f old) levels were further elevated in the ARDS group. Moreover, the seq uential plasma samples from patients with ARDS had progressively incre ased levels of vWF-AS and TFPI up to Days 4 and 8, respectively. Neith er plasma vWF-Ag nor TFPI levels correlated with mortality in the at-r isk group or the ARDS group. TFPI levels were also measured in broncho alveolar ravage fluids (BALF). The levels (ng/ml) were: normal subject s, 0.05 +/- 0.02 SE; at-risk group, 0.35 +/- 0.16 SE; ARDS group, 0.99 +/- 0.28 SE. Thus, the BALF TFPI levels were increased similar to 7-f old in the at-risk group and similar to 20-fold in the ARDS group rela tive to the value in the normal subjects. These findings indicate incr eased local synthesis of TFPI in the alveolar space both in the at-ris k patients and in those with ARDS. In additional studies in a primate model of sepsis, lethal doses (LD(100)) of E. coli administered to bab oons resulted in a progressive increase in TFPI levels (similar to 2-f old at 6 h), whereas sublethal doses caused only minimal increase (hi similar to 1.2-fold). The vWF-Ag levels were elevated similar to 5-fol d after infusion of LD(100) concentrations of E. coli at 6 h and Lt-fo ld after infusion of sublethal concentrations of E. coli at 24 h. Auto psies on animals in the LD(100) group revealed pulmonary congestion, l eukocyte infiltration, edema, and hemorrhage, all suggestive of acute lung injury. Thus, in the setting of acute lung injury plasma vWF-Ag a ppears to be considerably increased prior to significant damage to the endothelium, whereas increased plasma TFPI occurs only after severe i njury. Increased levels of TFPI in BALF of at-risk patients and of tho se with ARDS appear to represent increased synthesis in the alveolar s pace rather than exudation of plasma TFPI.