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NDT Advance Access published online on February 17, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl836
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cyclosporine enhances platelet procoagulant activity

Marian Tomasiak1, Tomasz Rusak1, Marek Gacko2 and Halina Stelmach1

1Department of Physical Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 and 2Department of Vascular Surgery and Transplantology, Medical University of Bialystok, M. Curie-Sklodowskiej 24A, 15-276 Bialystok, Poland

Correspondence and offprint requests to: Dr Marian Tomasiak, Department of Physical Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland. Email: mtomask{at}amb.edu.pl



  Abstract

Background. Clinical use of cyclosporine (CsA) was suggested to be associated with an increased risk of thromboembolic complications. The molecular mechanisms underlying these effects remain unresolved.

Methods. We tested the hypothesis that CsA may produce platelet procoagulant activity due to its interaction with the platelet plasma membrane. To verify this hypothesis the possible relationship between platelet morphology, exposure to platelet phosphatidylserine (PS) and platelet procoagulant activity (measured as phospholipid-dependent thrombin generation) was studied.

Results. It was found that CsA (1–100 µg/ml) potentiates collagen-evoked platelet procoagulant response. Platelets treated in vitro with CsA (20–200 µg/ml 20–60 min) expressed procoagulant activity. The CsA-induced platelet procoagulant response was both dose- and time-related and weaker than that produced by collagen. Flow cytometry studies revealed that CsA treatment results in a left shift (decrease) in the forward and side scatter of the entire platelet population. The shift was unimodal, dose-dependent and less pronounced than that elicited by collagen. Using flow cytometry and fluorescein isothiocyanate-labelled annexin V as a probe for PS, we demonstrated an increased binding of this marker to a CsA-treated platelet population. CsA-evoked PS-expression was dose- and time-dependent and smaller than that produced by collagen. CsA, at concentrations similar to those affecting platelet procoagulant response, released lactate dehydrogenase from platelets.

Conclusions. These observations indicate that the thrombogenic properties of CsA may result from the alteration of lipid organization in platelet plasma membrane, leading to externalization of PS and accelerated thrombin generation.

Keywords: cyclosporine; phosphatidylserine; plasma membrane; platelets procoagulant activity

Received for publication: 7. 7.06
Accepted in revised form: 22.12.06


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