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 of tissue factor pathway inhibitor and von Willebrand factor antigen in plasma of heart transplant outpatients. Tissue factor pathway inhibitor was quantified in plasma of blood donors (n = 50) and heart transplant outpatients (n = 50) by a chromogenic substrate assay with a mean of 32.4 micrograms/l and 98.2 micrograms/l, respectively. Von Willebrand factor antigen was determined with an enzyme-linked immunoassay with a mean of 90.9% for blood donors and 184.5% in plasma of heart transplant recipients. In addition, we investigated the effect of cyclosporine A on endothelial cell cultures over an incubation period of four days. A dose-dependent effect of cyclosporine A on the release of endothelial tissue factor pathway inhibitor and von Willebrand factor antigen was determined in a concentration range from 100 to 200 micrograms/l cyclosporine A. The tissue factor pathway inhibitor and von Willebrand factor antigen concentrations in the cell culture supernatant increased during the incubation time according to the cyclosporine A concentration 2-3 fold and 2 fold, respectively. For a further elucidation of the cyclosporine A effect we investigated the influence of cremophor EL, the vehicle of cyclosporine A. Cremophor EL alone did not increase the tissue factor pathway inhibitor release. However, the release was enhanced 2-4 fold after co-stimulation with the calcium ionophore A 23187 (10(-4) mol/l) in a concentration-dependent mode. We conclude that a generalized endothelial damage or activation is most probably caused by cyclosporine A and its vehicle cremophor EL. This process probably depends upon the increase of cytosolic free calcium, as described for the liberation of von Willebrand factor by endothelial cells.
Tiemann
C
C
Institut für Laboratoriums- und Transfusionsmedizin, Ruhr-Universität Bochum, Bad Oeynhausen, Germany.
Prohaska
W
W
Körfer
R
R
Körner
M
M
Brinkmann
T
T
Kleesiek
K
K
D000293:Adolescent; D000328:Adult; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000494:pharmacology; D016027:Heart Transplantation; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D008074:Lipoproteins / Q000097:blood* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D014677:Pharmaceutical Vehicles / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism
D007476:Ionophores; D008074:Lipoproteins; D014677:Pharmaceutical Vehicles; C051928:lipoprotein-associated coagulation inhibitor; D014841:von Willebrand Factor; D000001:Calcimycin; C000515:cremophor EL; D016572:Cyclosporine; D005990:Glycerol; D002118:Calcium