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(Circulation. 1997;96:4232-4238.)
© 1997 American Heart Association, Inc.

Articles

Cyclosporin A Inhibits Monocyte Tissue Factor Activation in Cardiac Transplant Recipients

Hans Hölschermann, MD; Oliver Kohl, MD; Ulrich Maus, PhD; Frank Dürfeld, MD; Angelika Bierhaus, PhD; Peter P. Nawroth, MD; Jürgen Lohmeyer, MD; Harald Tillmanns, MD; ; Werner Haberbosch, MD

From the Department of Internal Medicine, Division of Cardiology (H.H., O.K., F.D., H.T., W.H.), and the Department of Internal Medicine, Division of Pneumology (U.M., J.L.), Justus-Liebig-University, Giessen, and the Department of Internal Medicine, Ruprecht-Karls-University Heidelberg (A.B., P.P.N), Germany.

Correspondence to Dr Hans Hölschermann, Department of Internal Medicine, Division of Cardiology, University of Giessen, Klinikstr 36, D-35392 Giessen, Germany. E-mail hans.f.hoelschermann{at}innere.med.uni-giessen.de

Background Fibrin deposition and thrombosis have been implicated in both allograft rejection and vasculopathy after cardiac transplantation. Because monocytes play a pivotal role in the pathophysiology of intravascular coagulation activation through their ability to synthesize tissue factor (TF), we asked (1) whether monocyte TF activation occurs in cardiac transplant recipients and (2) whether monocyte TF expression is affected by treatment with cyclosporin A (CsA).

Methods and Results We measured levels of TF activity in peripheral blood mononuclear cells and highly purified monocytes/macrophages from 10 consecutive cardiac transplant recipients and 10 healthy control subjects. TF activity generated by both unstimulated and endotoxin-stimulated cells was significantly higher in transplant recipients than in control subjects (P<.05). Increased monocyte TF expression in transplant recipients was shown to be adversely affected by treatment with CsA: TF induction was markedly reduced by CsA serum concentrations reaching peak CsA drug levels. Inhibition of TF induction in the presence of high CsA blood concentrations was also observed when stimulation of cells was performed with interferon- or interleukin-1ß. As shown by reverse transcription–polymerase chain reaction and electrophoretic mobility shift assay, respectively, treatment with CsA leads to decreased TF mRNA expression and reduced activation of the NF-B transcription factor, which is known to contribute to the induction of the TF promotor in human monocytes.

Conclusions This study demonstrates that TF activation, occurring in mononuclear cells of cardiac transplant recipients, is inhibited by treatment with CsA. Inhibition of monocyte TF induction by CsA may contribute to its successful use in cardiac transplant medicine and might be useful in managing further settings of vascular pathology also known to involve TF expression and NF-B activation.

Key Words: vasculature • transplantation • blood cells • coagulation

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