EFFECT OF PORCINE ENDOTHELIAL TISSUE FACTOR PATHWAY INHIBITOR ON HUMAN COAGULATION-FACTORS

Background. Delayed xenograft rejection (DXR) is characterized by infl ammation and vascular thrombosis, Activation of coagulation may occur as a result of tissue factor (TF) expression on both activated donor e ndothelial cells (EC) and recipient infiltrating monocytes (Mo), In ad dition, natural anticoagulants associated with porcine endothelial cel ls may not function adequately across species. Methods. In the present study, we examined the interaction of the TF pathway of coagulation w ith the natural anticoagulant TF pathway inhibitor, in xenogeneic leuk ocyte-EC cultures in vitro, and during rejection of discordant xenogra fts in vivo. Results. Coculture of human Mo with pig aortic EC (PAEC) resulted in 1.7-fold and 2-fold higher induction of Mo TF and Mo inter cellular adhesion molecule-1, respectively, when compared with cocultu re with human aortic endothelial cells (HAEC), In addition, TF-depende nt and -independent activation of coagulation factor X was higher on P AEC than on HAEC, Low levels of mRNA for tissue factor pathway inhibit or (TFPI) and its variant, TFPI-2, in resting PAEC were up-regulated b y stimulation with tumor necrosis factor alpha. Procoagulant activity of recombinant human TF complexed to activated factor VII was inhibite d by PAEC and HAEC-associated TFPI by 22% and 56%, respectively, In co ntrast, human activated factor X (factor Xa) activity was inhibited by human, but not porcine, EC-associated TFPI, suggesting functional inc ompatibility of PAEC for human factor Xa, Endothelial TFPI was detecte d in pig control organs and after hyperacute rejection, but was lost f rom the vasculature during DXR. Conclusions. Lack of appropriate human factor Xa inhibition by porcine EC during hyperacute rejection and lo ss of porcine EC TFPI during DXR could promote the development of a pr ocoagulant environment leading to xenograft rejection.