Localization of Short-Chain Polyphosphate Enhances its Ability to Clot Flowing Blood Plasma

Creators: Yeon, Ju Hun; Mazinani, Nima; Schlappi, Travis S.; Chan, Karen Y. T.; Baylis, James R.; Smith, Stephanie A.; Donovan, Alexander J.; Kudela, Damien; Stucky, Galen D.; Liu, Ying; Morrissey, James H.; Kastrup, Christian J.

Abstract

Short-chain polyphosphate (polyP) is released from platelets upon platelet activation, but it is not clear if it contributes to thrombosis. PolyP has increased propensity to clot blood with increased polymer length and when localized onto particles, but it is unknown whether spatial localization of short-chain polyP can accelerate clotting of flowing blood. Here, numerical simulations predicted the effect of localization of polyP on clotting under flow, and this was tested in vitro using microfluidics. Synthetic polyP was more effective at triggering clotting of flowing blood plasma when localized on a surface than when solubilized in solution or when localized as nanoparticles, accelerating clotting at 10–200 fold lower concentrations, particularly at low to sub-physiological shear rates typical of where thrombosis occurs in large veins or valves. Thus, sub-micromolar concentrations of short-chain polyP can accelerate clotting of flowing blood plasma under flow at low to sub-physiological shear rates. However, a physiological mechanism for the localization of polyP to platelet or vascular surfaces remains unknown.

Additional Information

© The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ Received: 10 October 2016. Accepted: 04 January 2017. Published online: 10 February 2017. This work was supported by Award WQ81XWH-11-2-0021 from the U.S. Army Medical Research and Material Command. The U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office. The contents of this article do not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred. Aspects of the work were also funded by the by Natural Sciences and Engineering Research Council of Canada (418652–2012) the Canadian Institutes of Health Research (MOP-119426 and MSH-130166), Canadian Foundation for Innovation (31928) and the British Columbia Knowledge Development Fund. We thank Rustem F. Ismagilov for his helpful suggestions in conceptualizing and planning of experiments. Ju Hun Yeon & Nima Mazinani: These authors contributed equally to this work. Author Contributions: J.H.Y and N.M. contributed equally to this work. J.H.Y., N.M., T.S.S., K.Y.T.C., J.R.B., S.A.S., A.J.D., and D.K., performed experiments and analyzed data; J.H.Y., N.M., T.S.S., C.J.K., J.H.M., Y.L., and G.D.S. conceptualized and planned experiments; J.H.Y., N.M., and C.J.K. wrote the manuscript; and all authors reviewed and edited the manuscript before submission. Competing interests: S.A.S., D.K., G.D.S., and J.H.M. are co-inventors on pending patent applications covering potential medical uses of SNP-polyP. A.J.D. and Y.L. are co-inventors on a pending patent application related to the therapeutic usage and delivery of NP-polyP. D.K., G.D.S., and J.H.M. declare competing financial interests in this work. The remaining authors declare no competing financial interests.

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