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Immunomodulatory drugs increase endothelial tissue factor expression in vitro


Valsami, S; Ruf, W; Leikauf, M S; Madon, J; Kaech, A; Asmis, L M (2011). Immunomodulatory drugs increase endothelial tissue factor expression in vitro. Thrombosis Research, 127(3):264-271.

Abstract

INTRODUCTION: Immunomodulatory compounds such as thalidomide (THL) and lenalidomide (LEN) represent treatment options for multiple myeloma. Venous thromboembolism is a potential complication of immunomodulatory treatment in myeloma patients. The optimal thromboprophylactic strategy to prevent this drug-induced hypercoagulable state is debated. It is the aim of this study to investigate i) the effect of immunomodulatory treatment on endothelial cell tissue factor (TF) expression and function, ii) the regulation of the observed TF activity, and iii) the modulating effect of low molecular weight heparin and aspirin on TF activity in vitro. MATERIALS AND METHODS: These aims were addressed in an in vitro culture model, human umbilical vein endothelial cells, using TF activity and antigen assays as well flow cytometry, real time PCR and electron microscopy. RESULTS: At THL and LEN concentrations resembling those observed in myeloma patients in vivo and in the presence of tumor necrosis factor-α (TNFα) we observed significantly increased TF activity in human umbilical vein endothelial cells in vitro. Concordant changes were detected for tissue factor mRNA and TF whole cell antigen. Dalteparin and a mixture of monoclonal anti-TF antibodies inhibited TF activity by 100% and more than 80% respectively, while aspirin's inhibitory effect was only approximately 30%. In the presence of TNFα we detected the generation of endothelial cell-derived microparticles which expressed TF activity. CONCLUSIONS: Our in vitro data support the hypothesis that THL and LEN induce a hypercoagulable state through increased endothelial TF expression.

Abstract

INTRODUCTION: Immunomodulatory compounds such as thalidomide (THL) and lenalidomide (LEN) represent treatment options for multiple myeloma. Venous thromboembolism is a potential complication of immunomodulatory treatment in myeloma patients. The optimal thromboprophylactic strategy to prevent this drug-induced hypercoagulable state is debated. It is the aim of this study to investigate i) the effect of immunomodulatory treatment on endothelial cell tissue factor (TF) expression and function, ii) the regulation of the observed TF activity, and iii) the modulating effect of low molecular weight heparin and aspirin on TF activity in vitro. MATERIALS AND METHODS: These aims were addressed in an in vitro culture model, human umbilical vein endothelial cells, using TF activity and antigen assays as well flow cytometry, real time PCR and electron microscopy. RESULTS: At THL and LEN concentrations resembling those observed in myeloma patients in vivo and in the presence of tumor necrosis factor-α (TNFα) we observed significantly increased TF activity in human umbilical vein endothelial cells in vitro. Concordant changes were detected for tissue factor mRNA and TF whole cell antigen. Dalteparin and a mixture of monoclonal anti-TF antibodies inhibited TF activity by 100% and more than 80% respectively, while aspirin's inhibitory effect was only approximately 30%. In the presence of TNFα we detected the generation of endothelial cell-derived microparticles which expressed TF activity. CONCLUSIONS: Our in vitro data support the hypothesis that THL and LEN induce a hypercoagulable state through increased endothelial TF expression.

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11 citations in Web of Science®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Microscopy and Image Analysis
04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:18 Feb 2011 15:20
Last Modified:05 Apr 2016 14:48
Publisher:Elsevier
ISSN:0049-3848
Publisher DOI:https://doi.org/10.1016/j.thromres.2010.11.018
PubMed ID:21159364

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