title: Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro.
abstract: BACKGROUND
  Thalidomide (Thal) treatment of patients with multiple myeloma (MM) is associated with vascular thrombosis, but the underlying mechanism is unknown.
  
  
  OBJECTIVE
  To evaluate the hypothesis that Thal, dexamethasone (Dex) and MM serum perturb the hemostatic balance on human umbilical vein endothelial cells (HUVECs).
  
  
  METHODS
  Drugs with or without the serum of MM patients or healthy controls were incubated with HUVECs. Analyses of phosphatidylserine (PS), tissue factor (TF), endothelial protein C receptor (EPCR) and thrombomodulin (TM) were performed using flow cytometry. The production of thrombin and activated protein C (APC) were measured by chromogenic assay. The roles of IL-6 and TNFα in regulating these indicators were also investigated.
  
  
  RESULTS
  We found that Thal or Dex alone could not increase TF and PS expression in HUVECs. However, when pretreated with MM serum, their expression was significantly increased by either Thal or Dex. Concurrent changes were also detected in thrombin generation. In contrast, Thal and Dex had a direct inhibitory effect on the expression of EPCR and TM, and this inhibitory effect was especially significant when MM serum was added. The generation of APC paralleled the expression of EPCR and TM. All of the above outcomes were reversed to a variable extent by anti-IL-6R and anti-TNFα antibodies.
  
  
  CONCLUSIONS
  These findings suggest Thal may act as a procoagulant by altering the balance between procoagulant and anticoagulant proteins on the surface of HUVECs, thereby contributing to thrombogenesis. MM serum plays a synergistic role in this process.
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Guibo
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Shuchuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Yueqiu
authors.initials: Y
authors.lastname: Teng
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China. Electronic address: suyanhua163@163.com.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Su
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000009:adverse effects; D015703:Antigens, CD / Q000096:biosynthesis; D003029:Coagulants / Q000737:chemistry; D003907:Dexamethasone / Q000009:adverse effects; D042783:Endothelial Cells / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D005260:Female; D006487:Hemostasis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000188:drug therapy*; D010718:Phosphatidylserines / Q000737:chemistry; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D013792:Thalidomide / Q000009:adverse effects*; D018180:Thrombomodulin / Q000096:biosynthesis; D013925:Thromboplastin / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020246:Venous Thrombosis / Q000139:chemically induced
chemical_list: D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D003029:Coagulants; D000074283:Endothelial Protein C Receptor; C508600:IL6 protein, human; D015850:Interleukin-6; C478370:PROCR protein, human; D010718:Phosphatidylserines; D011956:Receptors, Cell Surface; C546931:THBD protein, human; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D003907:Dexamethasone; D013925:Thromboplastin
keywords: Deep vein thrombosis; Endothelium; Multiple myeloma; Serum; Thalidomide