title: Mechanistic insight into the procoagulant activity of tumor-derived apoptotic vesicles.
abstract: Chemotherapy induces the release of apoptotic vesicles (ApoV) from the tumor plasma membrane. Tumor ApoV may enhance the risk of thrombotic events in cancer patients undergoing chemotherapy. However, the relative contribution of ApoV to coagulation and the pathways involved remain poorly characterized. In addition, this study sets out to compare the procoagulant activity of chemotherapy-induced ApoV with their cell of origin and to determine the mechanisms of ApoV-induced coagulation.
  
  
  
  We utilized human and murine cancer cell lines and chemotherapeutic agents to determine the requirement for the coagulation factors (tissue factor; TF, FII, FV, FVII, FVIII, FIX and phosphatidylserine) in the procoagulant activity of ApoV. The role of previously identified ApoV-associated FV was determined in a FV functional assay.
  
  
  
  ApoV were significantly more procoagulant per microgram of protein compared to parental living or dying tumor cells. In the phase to peak fibrin generation, procoagulant activity was dependent on phosphatidylserine, TF expression, FVII and the prothrombinase complex. However, the intrinsic coagulation factors FIX and FVIII were dispensable. ApoV-associated FV could not support coagulation in the absence of supplied, exogenous FV.
  
  
  
  ApoV are significantly more procoagulant than their parental tumor cells. ApoV require the extrinsic tenase and prothrombinase complex to activate the early phase of coagulation. Endogenous FV identified on tumor ApoV is serum-derived and functional, but is non-essential for ApoV-mediated fibrin generation.
  
  
  
  This study clarifies the mechanisms of procoagulant activity of vesicles released from dying tumor cells.
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand.
authors.forename: Morad-Rémy
authors.initials: MR
authors.lastname: Muhsin-Sharafaldine
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand.
authors.forename: Bailey R
authors.initials: BR
authors.lastname: Kennedy
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Saunderson
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand.
authors.forename: Catrin R
authors.initials: CR
authors.lastname: Buchanan
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Dunn
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand.
authors.forename: James M
authors.initials: JM
authors.lastname: Faed
authors.affiliation: Department of Microbiology & Immunology, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin, Otago, New Zealand. Electronic address: alex.mclellan@otago.ac.nz.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: McLellan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005165:Factor V / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001779:Blood Coagulation Factors; D009363:Neoplasm Proteins; D010718:Phosphatidylserines; C022475:prothrombinase complex; D005165:Factor V; D013925:Thromboplastin; D013917:Thrombin; D015951:Factor Xa; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant
keywords: Apoptosis; Blood coagulation; Cell-derived microparticles; Factor V; Tissue factor