Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection

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 and Thomas Renné ()
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Linda Labberton: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
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
Antonio Di Gennaro: Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital
Rachel A. Rigg: Clinical Chemistry, L1:00, Karolinska Institutet and University Hospital
James S. Hernandez: Mayo Clinic in Arizona
Lynn Butler: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf
Coen Maas: University Medical Center Utrecht
Evi X. Stavrou: Louis Stokes Veterans Administration Hospital
Thomas Renné: Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12616

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