Abstract:
:The use of cyclosporine has been associated with an increased incidence of thrombosis and endothelial cell perturbation. To explore possible mechanisms involved, we examined the effects of CSA on the activation of protein C by thrombomodulin. Cultured bovine aortic endothelial cell monolayers were incubated for 24 hr with a wide range of CSA concentrations. After removal of CSA and incubation with thrombin and purified protein C, thrombomodulin-dependent protein C activation was measured with an S-2238-based kinetic chromogenic assay. As compared to control, a significant fall in thrombomodulin activity occurred after 24-hr incubation with 100 (70.8 +/- 15.8%, P less than 0.05), 1000 (64.9 +/- 16.6%, P less than 0.05), or 10,000 (28.9 +/- 12.3%, P less than 0.05) ng/ml of CSA. A comparable inhibition of thrombomodulin activity was also observed in cultured renal artery endothelial cells (67.5 +/- 12.6%, P less than 0.05), after 24-hr incubation with 5000 ng/ml CSA. In cells incubated with 5000 ng/ml of CSA for 4 hr, thrombomodulin activity fell by almost 15% (85.6 +/- 8.3%, P less than 0.05) and tended to plateau between 7 hr (73.8 +/- 12.7%, P less than 0.05), and 24 hr of incubation (72.7 +/- 8.9%, P less than 0.05). These results indicate that CSA produces a time- and dose-dependent reduction in thrombomodulin activity of cultured endothelial cells, downregulating the protein C anticoagulant pathway, thereby increasing the risk of thrombosis.
journal_name
Transplantationjournal_title
Transplantationauthors
Garcia-Maldonado M,Kaufman CE,Comp PCdoi
10.1097/00007890-199103000-00030subject
Has Abstractpub_date
1991-03-01 00:00:00pages
701-5issue
3eissn
0041-1337issn
1534-6080journal_volume
51pub_type
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