Polyphosphate nanoparticles on the platelet surface trigger contact system activation

Johan J. F. Verhoef, Arjan D. Barendrecht, Katrin F. Nickel, Kim Dijkxhoorn, Ellinor Kenne, Linda Labberton, Owen J. T. McCarty, Raymond Schiffelers, Harry F. Heijnen, Antoni P. Hendrickx, Huub Schellekens, Marcel H. Fens, Steven de Maat, Thomas Renné and Coen Maas

Key Points

  • Activated platelets expose insoluble membrane-associated polyphosphate nanoparticles that are complexed with divalent metal ions.

  • Platelet polyphosphate nanoparticles, but not soluble polyphosphate polymers, activate the contact system.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.


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.

  • Submitted August 19, 2016.
  • Accepted December 23, 2016.
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