title: Arsenic trioxide induces procoagulant activity through phosphatidylserine exposure and microparticle generation in endothelial cells.
abstract: BACKGROUND
  Coagulopathy is a major cause of early death when arsenic trioxide (As(2)O(3)) therapy fails. In addition to the procoagulant properties of blast cells, the cytotoxic therapy may contribute to the coagulation disorders. The aim of the present study was to evaluate the possible impact of As(2)O(3) on membrane alterations, including phosphatidylserine (PS) exposure and microparticle generation, and the consequent procoagulant properties of endothelial cells.
  
  
  METHODS
  Procoagulant activity (PCA) of human umbilical vein endothelial cells (HUVECs) was assessed by measuring clotting time and through purified coagulation complex assays. PS exposure on HUVEC membrane was observed by confocal microscopy and quantified with flow cytometry. In addition, counts and PCA of endothelial microparticles were determined by flow cytometry and plasma coagulation assay.
  
  
  RESULTS
  As(2)O(3) increased the ability of HUVECs to accelerate coagulation process and promote formation of coagulation complexes. Procoagulant activity corresponded to PS exposed on HUVECs. In coincidence with the PS externalization, As(2)O(3) increased the production of PS-bearing microparticles, which then accelerated fibrin strand formation significantly. By blocking PS, lactadherin was able to inhibit over 90% of the intrinsic tenase/prothrombinase activity of As(2)O(3)-treated HUVECs, and restored coagulation times of As(2)O(3)-treated cells and microparticles to control levels.
  
  
  CONCLUSIONS
  As(2)O(3) increases PCA of HUVECs through PS exposure and PS-bearing microparticle generation, which might cause thrombosis and act as a contributing factor in As(2)O(3) therapy-related coagulopathy.
authors.affiliation: Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin 150001, China. zhoujin1111@126.com
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Huibo
authors.initials: H
authors.lastname: Li
authors.forename: Yueyue
authors.initials: Y
authors.lastname: Fu
authors.forename: Jialan
authors.initials: J
authors.lastname: Shi
authors.forename: Jinxiao
authors.initials: J
authors.lastname: Hou
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Song
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D018613:Microscopy, Confocal; D010087:Oxides / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000494:pharmacology*
chemical_list: D001152:Arsenicals; D010087:Oxides; D010718:Phosphatidylserines; D000077237:Arsenic Trioxide