Cyclosporine enhances platelet procoagulant activity.
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 microg/ml) potentiates collagen-evoked platelet procoagulant response. Platelets treated in vitro with CsA (20-200 microg/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.
Tomasiak
Marian
M
Department of Physical Chemistry, Medical University of Bialystok, Kilinskiego 1, 15-089 Bialystok, Poland. mtomask@amb.edu.pl
Rusak
Tomasz
T
Gacko
Marek
M
Stelmach
Halina
H
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003094:Collagen / Q000502:physiology; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D006736:Horses; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D008027:Light; D051379:Mice; D010718:Phosphatidylserines / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology*; D012542:Scattering, Radiation; D013917:Thrombin / Q000096:biosynthesis
D007166:Immunosuppressive Agents; D010718:Phosphatidylserines; D016572:Cyclosporine; D003094:Collagen; D013917:Thrombin