title: OC-04 - Tissue factor positive microvesicles activate platelets in vitro and in vivo and enhance thrombosis in mice.
abstract: BACKGROUND
  Cancer patients have a 4- to 7- fold increased risk of venous thromboembolism (VTE) compared with general population. Most tumor cells express tissue factor (TF) and constitutively release small membrane microvesicles called tumor microvesicles (TMVs). Clinical studies have shown that circulating MP-TF activity is associated with VTE in pancreatic cancer but not in other types of cancer. Thrombin is a potent platelet agonist and activates platelets via protease activated receptors (PARs).
  
  
  OBJECTIVE
  To determine the contribution of the TF+ TMV-thrombin-platelet pathway to cancer-associated thrombosis.
  
  
  METHODS
  A human pancreatic adenocarcinoma cell line expressing high levels of TF (BxPc-3) was selected to study the effect of TF+ TMVs on platelet activation and thrombosis.
  
  
  RESULTS
  TF+ TMVs induced platelet activation in vitro in a thrombin-dependent manner. The presence of orthotopically grown BxPc-3 tumors in mice was associated with increased levels of thrombin-antithrombin III complexes (TATc) and larger thrombi in an inferior vena cava stenosis model compared with control mice. Furthermore, injection of BxPc-3 TF+ TMVs into mice triggered platelet activation and enhanced venous thrombosis in a TF-dependent manner. Importantly, BxPc-3 TF+ TMV-enhanced thrombosis was reduced in Par4-deficient mice and wild-type mice treated with the platelet inhibitor clopidogrel, suggesting that platelet activation was required for the enhanced thrombosis.
  
  
  CONCLUSIONS
  These studies suggest that platelet inhibitors may reduce thrombosis in cancer patients with elevated levels of TF+ TMVs.
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute.
authors.forename: Y
authors.initials: Y
authors.lastname: Hisada
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: J E
authors.initials: JE
authors.lastname: Geddings
authors.affiliation: Department of Biochemistry and Biophysics.
authors.forename: Y
authors.initials: Y
authors.lastname: Boulaftali
authors.affiliation: Department of Biochemistry and Biophysics.
authors.forename: T M
authors.initials: TM
authors.lastname: Getz
authors.affiliation: Department of Medicine, University of North Carolina; Chapel Hill, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Whelihan
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: R
authors.initials: R
authors.lastname: Fuentes
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: R
authors.initials: R
authors.lastname: Dee
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: B C
authors.initials: BC
authors.lastname: Cooley
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute; Department of Pathology and Laboratory Medicine; Department of Medicine, University of North Carolina; Chapel Hill, North Carolina, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Key
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: A S
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: Department of Biochemistry and Biophysics.
authors.forename: W
authors.initials: W
authors.lastname: Bergmeier
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute; Department of Pathology and Laboratory Medicine; Department of Biochemistry and Biophysics; Department of Medicine, University of North Carolina; Chapel Hill, North Carolina, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mackman