Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection

• Published in: Nature communications 2016-09, Vol.7 (1), p.12616-12616, Article 12616
• Main Authors: Labberton, Linda, Kenne, Ellinor, Long, Andy T., Nickel, Katrin F., Di Gennaro, Antonio, Rigg, Rachel A., Hernandez, James S., Butler, Lynn, Maas, Coen, Stavrou, Evi X., Renné, Thomas
• Format: Article
• Language: English
• Subjects: 631/154/51/2314; 631/45/49; 64/60; 692/4017; 692/4019/592/1339; 82/80; Acid Anhydride Hydrolases - metabolism; Animals; Anticoagulants; Blood clots; Blood Coagulation Factors - genetics; Blood Coagulation Factors - metabolism; E coli; Escherichia coli - metabolism; Factor XII - genetics; Factor XII - metabolism; Female; Gene Deletion; Humanities and Social Sciences; Humans; Medicin och hälsovetenskap; Medicine; Mice; Molecular weight; multidisciplinary; Mutation; Platelet Aggregation - drug effects; Polymers; Polyphosphates - antagonists & inhibitors; Polyphosphates - metabolism; Protein Binding; Protein Domains; Proteins; Science; Thrombin - metabolism; Thromboembolism; Thrombosis; Thrombosis - prevention & control
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12616

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. The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.