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Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection

Author

Listed:
  • Linda Labberton

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital)

  • Ellinor Kenne

    (Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital)

  • Andy T. Long

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf)

  • Katrin F. Nickel

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital)

  • Antonio Di Gennaro

    (Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital)

  • Rachel A. Rigg

    (Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital
    School of Medicine, Oregon Health & Science University)

  • James S. Hernandez

    (Mayo Clinic in Arizona)

  • Lynn Butler

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital)

  • Coen Maas

    (University Medical Center Utrecht)

  • Evi X. Stavrou

    (Louis Stokes Veterans Administration Hospital
    Case Western Reserve University)

  • Thomas Renné

    (Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
    Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital)

Abstract

Polyphosphate is an inorganic procoagulant polymer. Here we develop specific inhibitors of polyphosphate and show that this strategy confers thromboprotection in a factor XII-dependent manner. Recombinant Escherichia coli exopolyphosphatase (PPX) specifically degrades polyphosphate, while a PPX variant lacking domains 1 and 2 (PPX_Δ12) binds to the polymer without degrading it. Both PPX and PPX_Δ12 interfere with polyphosphate- but not tissue factor- or nucleic acid-driven thrombin formation. Targeting polyphosphate abolishes procoagulant platelet activity in a factor XII-dependent manner, reduces fibrin accumulation and impedes thrombus formation in blood under flow. PPX and PPX_Δ12 infusions in wild-type mice interfere with arterial thrombosis and protect animals from activated platelet-induced venous thromboembolism without increasing bleeding from injury sites. In contrast, targeting polyphosphate does not provide additional protection from thrombosis in factor XII-deficient animals. Our data provide a proof-of-concept approach for combating thrombotic diseases without increased bleeding risk, indicating that polyphosphate drives thrombosis via factor XII.

Suggested Citation

  • Linda Labberton & Ellinor Kenne & Andy T. Long & Katrin F. Nickel & Antonio Di Gennaro & Rachel A. Rigg & James S. Hernandez & Lynn Butler & Coen Maas & Evi X. Stavrou & Thomas Renné, 2016. "Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12616
    DOI: 10.1038/ncomms12616
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    Cited by:

    1. Chanel C. La & Stephanie A. Smith & Sreeparna Vappala & Reheman Adili & Catherine E. Luke & Srinivas Abbina & Haiming D. Luo & Irina Chafeeva & Matthew Drayton & Louise A. Creagh & Maria Guadalupe Jar, 2023. "Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Jing Wang & Xinyang Zhao & Yucheng Tao & Xiuxiu Wang & Li Yan & Kuang Yu & Yi Hsu & Yuncong Chen & Jing Zhao & Yong Huang & Wei Wei, 2024. "Biocompatible aggregation-induced emission active polyphosphate-manganese nanosheets with glutamine synthetase-like activity in excitotoxic nerve cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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