| First Author | Labberton L | Year | 2016 |
| Journal | Nat Commun | Volume | 7 |
| Pages | 12616 | PubMed ID | 27596064 |
| Mgi Jnum | J:242104 | Mgi Id | MGI:5904417 |
| Doi | 10.1038/ncomms12616 | Citation | Labberton L, et al. (2016) Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 7:12616 |
| abstractText | 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_Delta12) binds to the polymer without degrading it. Both PPX and PPX_Delta12 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_Delta12 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. |
