title: Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice.
abstract: ESSENTIALS: Cancer patients have a high rate of venous thrombosis (VT) but the underlying mechanisms are unknown. Tumor-derived, tissue factor-positive microvesicles in platelet activation in vitro and in vivo were studied. Tumor-derived, tissue factor-positive microvesicles enhanced VT in mice. Platelets may contribute to VT in some cancer patients, and this could be prevented with antiplatelet drugs.
  
  
  BACKGROUND
  Cancer patients have an approximately 4-fold increased risk of venous thromboembolism (VTE) compared with the general population, and cancer patients with VTE have reduced survival. Tumor cells constitutively release small membrane vesicles called microvesicles (MVs) that may contribute to thrombosis in cancer patients. Clinical studies have shown that levels of circulating tumor-derived, tissue factor-positive (TF(+) ) MVs in pancreatic cancer patients are associated with VTE. Objectives We tested the hypothesis that TF(+) tumor-derived MVs (TMVs) activate platelets in vitro and in mice.
  
  
  METHODS
  We selected two human pancreatic adenocarcinoma cell lines expressing high (BxPc-3) and low (L3.6pl) levels of TF as models to study the effect of TF(+) TMVs on platelets and thrombosis.
  
  
  CONCLUSIONS
  We found that both types of TF(+) TMVs activated human platelets and induced aggregation in vitro in a TF and thrombin-dependent manner. Further, injection of BxPc-3 TF(+) TMVs triggered platelet activation in vivo and enhanced thrombosis in two mouse models of venous thrombosis in a TF-dependent manner. Importantly, BxPc-3 TF(+) TMV-enhanced thrombosis was reduced in Par4-deficient mice and in wild-type mice treated with clopidogrel, suggesting that platelet activation was required for enhanced thrombosis. These studies suggest that TF(+) TMV-induced platelet activation contributes to thrombosis in cancer patients.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Geddings
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hisada
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Boulaftali
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Getz
authors.affiliation: Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.|Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Whelihan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fuentes
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Cooley
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.|Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.|Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Key
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: A S
authors.identifier: http://orcid.org/0000-0002-2845-2303
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Bergmeier
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.|Division of Hematology/Oncology, Thrombosis and Hemostasis Program, UNC McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.|Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology; D000818:Animals; D001792:Blood Platelets / Q000166:cytology; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles; D000077144:Clopidogrel; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000503:physiopathology; D010190:Pancreatic Neoplasms / Q000503:physiopathology; D015539:Platelet Activation; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000188:drug therapy; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000502:physiology*; D013927:Thrombosis / Q000188:drug therapy*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D010975:Platelet Aggregation Inhibitors; D013925:Thromboplastin; D000077144:Clopidogrel; D013917:Thrombin; D013988:Ticlopidine
keywords: blood platelets; cancer; cell-derived microparticles; thromboplastin; thrombosis; venous thrombosis