title: The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis.
abstract: Cancer is a leading cause of thrombosis. We identify a new procoagulant mechanism that contributes to thromboembolism in prostate cancer and allows for safe anticoagulation therapy development. Prostate cancer-mediated procoagulant activity was reduced in plasma in the absence of factor XII or its substrate of the intrinsic coagulation pathway factor XI. Prostate cancer cells and secreted prostasomes expose long chain polyphosphate on their surface that colocalized with active factor XII and initiated coagulation in a factor XII-dependent manner. Polyphosphate content correlated with the procoagulant activity of prostasomes. Inherited deficiency in factor XI or XII or high-molecular-weight kininogen, but not plasma kallikrein, protected mice from prostasome-induced lethal pulmonary embolism. Targeting polyphosphate or factor XII conferred resistance to prostate cancer-driven thrombosis in mice, without increasing bleeding. Inhibition of factor XII with recombinant 3F7 antibody reduced the increased prostasome-mediated procoagulant activity in patient plasma. The data illustrate a critical role for polyphosphate/factor XII-triggered coagulation in prostate cancer-associated thrombosis with implications for anticoagulation without therapy-associated bleeding in malignancies.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Nickel
authors.affiliation: Clinical Chemistry, Department of Medical Sciences, Clinical Chemistry, University Hospital of Uppsala, Uppsala, Sweden;
authors.forename: Göran
authors.initials: G
authors.lastname: Ronquist
authors.affiliation: Clinical Department of Hematology and Oncology, Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Langer
authors.affiliation: Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Linda
authors.initials: L
authors.lastname: Labberton
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.affiliation: Clinical Department of Hematology and Oncology, Center for Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Institute for Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC;
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: Divisions of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH; and Department of Medicine, Louis Stokes Veterans Administration Hospital, Cleveland, OH.
authors.forename: Evi X
authors.initials: EX
authors.lastname: Stavrou
authors.affiliation: Clinical Chemistry, Department of Medical Sciences, Clinical Chemistry, University Hospital of Uppsala, Uppsala, Sweden;
authors.forename: Gunnar
authors.initials: G
authors.lastname: Ronquist
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Center of Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D045744:Cell Line, Tumor; D005174:Factor XII / Q000378:metabolism*; D015956:Factor XIIa / Q000037:antagonists & inhibitors; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D011122:Polyphosphates / Q000097:blood*; D011471:Prostatic Neoplasms / Q000097:blood* / Q000150:complications*; D011655:Pulmonary Embolism / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D022142:Secretory Vesicles / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood* / Q000209:etiology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011122:Polyphosphates; D005174:Factor XII; D005337:Fibrin; D015956:Factor XIIa; D013917:Thrombin