on March 8, 2007
Published online before print March 8, 2007, doi: 10.1161/ATVBAHA.107.141580
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Submitted on December 21, 2006
Accepted on February 22, 2007
Darbepoetin-Alpha Does Not Promote Microvascular Thrombus Formation in Mice. Role of eNOS-Dependent Protection Through Platelet and Endothelial Cell Deactivation
Nicole Lindenblatt ;
From the Institute for Experimental Surgery (N.L., B.V.) and the Department of General Surgery (N.L., E.K.), University of Rostock, and the Institute for Clinical & Experimental Surgery (M.D.M.), University of Saarland, Germany.
* To whom correspondence should be addressed. E-mail: brigitte.vollmar{at}med.uni-rostock.de.
Objective--Erythropoietin (EPO) treatment has become the standard treatment of renal anemia. Though a link between hematopoiesis-stimulating drugs and thrombosis has not been proven, it is generally assumed that systemic application of EPO and its analogues increases the risk for thrombotic events.
Methods and Results--Here we show in C57BL/6J mice that 4-week treatment with the long-lasting EPO analogue darbepoetin-alpha (DPO) at a dose of 10 µg/kg/week induces a reduction of platelet reactivity using flow cytometry and Western blot analysis of tyrosine-specific platelet phosphorylation. Additionally, immunohistochemistry of endothelial adhesion molecule expression and ELISA of circulating endothelial activation markers demonstrated a reduced endothelial activation. Immunohistochemistry and RT-PCR analysis revealed a significant (P<0.05) increase of eNOS expression. Further, DPO did not exert prothrombogenic effects in a murine intravital microscopic thrombosis model of the cremaster muscle. The role of eNOS in prevention of DPO-mediated microvascular thrombosis is further underlined by a significantly accelerated thrombus formation on DPO treatment in eNOS (-/-) mice.
Conclusion--Thus, DPO-related erythropoiesis with a raised hematocrit is not associated with an increased risk for thrombosis as long as endothelial NO production serves as compensatory mechanism.
Key words: endothelium • intravital microscopy • nitric oxide • platelets • thrombosis
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