EFFECT OF CYCLOSPORINE-A ON THE RELEASE OF TISSUE FACTOR PATHWAY INHIBITOR FROM ENDOTHELIAL-CELLS IN HEART-TRANSPLANT PATIENTS AND CELL-CULTURE

We investigated the influence of cyclosporine A on the concentration o f tissue factor pathway inhibitor and von Willebrand factor antigen in plasma of heart transplant outpatients. Tissue factor pathway inhibit or was quantified in plasma of blood donors (n = 50) and heart transpl ant outpatients (n = 50) by a chromogenic substrate assay with a mean of 32.4 mu g/l and 98.2 mu g/l, respectively. Von Willebrand factor an tigen was determined with an enzyme-linked immunoassay with a mean of 90.9% for blood donors and 184.5% in plasma of heart transplant recipi ents. In addition, we investigated the effect of cyclosporine A on end othelial cell cultures over an incubation period of four days. A dose- dependent effect of cyclosporine A on the release of endothelial tissu e factor pathway inhibitor and von Willebrand factor antigen was deter mined in a concentration range from 100 to 200 mu g/l cyclosporine A. The tissue factor pathway inhibitor and von Willebrand factor antigen concentrations in the cell culture supernatant increased during the in cubation time according to the cyclosporine A concentration 2-3 fold a nd 2 fold, respectively. For a further elucidation of the cyclosporine A effect we investigated the influence of cremophor EL, the vehicle o f cyclosporine A. Cremophor Fl, alone did not increase the tissue fact or pathway inhibitor release. However, the release was enhanced 2-4 fo ld after co-stimulation with the calcium ionophore A 23187 (10(-4)mol/ l) In a concentration-dependent mode. We conclude that a generalized e ndothelial damage or activation is most probably caused by cyclosporin e A and its vehicle cremophor EL. This process probably depends upon t he increase of cytosolic free calcium, as described for the liberation of von Willebrand factor by endothelial cells.