title: Polyphosphate nanoparticles on the platelet surface trigger contact system activation.
abstract: Polyphosphate is an inorganic polymer that can potentiate several interactions in the blood coagulation system. Blood platelets contain polyphosphate, and the secretion of platelet-derived polyphosphate has been associated with increased thrombus formation and activation of coagulation factor XII. However, the small polymer size of secreted platelet polyphosphate limits its capacity to activate factor XII in vitro. Thus, the mechanism by which platelet polyphosphate contributes to thrombus formation remains unclear. Using live-cell imaging, confocal and electron microscopy, we show that activated platelets retain polyphosphate on their cell surface. The apparent polymer size of membrane-associated polyphosphate largely exceeds that of secreted polyphosphate. Ultracentrifugation fractionation experiments revealed that membrane-associated platelet polyphosphate is condensed into insoluble spherical nanoparticles with divalent metal ions. In contrast to soluble polyphosphate, membrane-associated polyphosphate nanoparticles potently activate factor XII. Our findings identify membrane-associated polyphosphate in a nanoparticle state on the surface of activated platelets. We propose that these polyphosphate nanoparticles mechanistically link the procoagulant activity of platelets with the activation of coagulation factor XII.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Johan J F
authors.identifier: 0000-0003-2483-597X
authors.initials: JJ
authors.lastname: Verhoef
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Arjan D
authors.identifier: 0000-0002-0653-5538
authors.initials: AD
authors.lastname: Barendrecht
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.|Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katrin F
authors.identifier: 0000-0003-1287-6766
authors.initials: KF
authors.lastname: Nickel
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Dijkxhoorn
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Ellinor
authors.identifier: 0000-0002-2784-5244
authors.initials: E
authors.lastname: Kenne
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Linda
authors.identifier: 0000-0002-1858-867X
authors.initials: L
authors.lastname: Labberton
authors.affiliation: Department of Biomedical Engineering, Department of Cell & Developmental Biology, Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR; and.
authors.forename: Owen J T
authors.identifier: 0000-0001-9481-0124
authors.initials: OJ
authors.lastname: McCarty
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Raymond
authors.identifier: 0000-0002-1012-9815
authors.initials: R
authors.lastname: Schiffelers
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Harry F
authors.identifier: 0000-0002-8819-9231
authors.initials: HF
authors.lastname: Heijnen
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Antoni P
authors.initials: AP
authors.lastname: Hendrickx
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Huub
authors.initials: H
authors.lastname: Schellekens
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marcel H
authors.identifier: 0000-0002-0515-8806
authors.initials: MH
authors.lastname: Fens
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Steven
authors.identifier: 0000-0003-1179-374X
authors.initials: S
authors.lastname: de Maat
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.|Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.identifier: 0000-0003-4594-5975
authors.initials: T
authors.lastname: Renné
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Coen
authors.identifier: 0000-0003-4593-0976
authors.initials: C
authors.lastname: Maas
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D005174:Factor XII / Q000378:metabolism; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry; D011122:Polyphosphates / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D011122:Polyphosphates; D005174:Factor XII