title: Immunomodulatory drugs increase endothelial tissue factor expression in vitro.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Division of Hematology, University Hospital of Zurich, CH 8091 Zurich, Switzerland.
authors.forename: Serena
authors.initials: S
authors.lastname: Valsami
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.forename: Maria-Sybille
authors.initials: MS
authors.lastname: Leikauf
authors.forename: Jerzy
authors.initials: J
authors.lastname: Madon
authors.forename: Andres
authors.initials: A
authors.lastname: Kaech
authors.forename: Lars M
authors.initials: LM
authors.lastname: Asmis
mesh_terms: D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D000077269:Lenalidomide; D012333:RNA, Messenger / Q000235:genetics; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D007155:Immunologic Factors; D012333:RNA, Messenger; D013792:Thalidomide; D013925:Thromboplastin; D000077269:Lenalidomide