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.
Highlights
IntroductionRecombinant Escherichia coli exopolyphosphatase (PPX) degrades polyphosphate, while a PPX_D12-treated mice (PPX) variant lacking domains 1 and 2 (PPX_D12) binds to the polymer without degrading it
Fibrin formation constitutes a homeostatic mechanism to prevent excess bleeding; fibrin production contributes to thrombosis[27]
In contrast to all other factors of the coagulation cascade, factor XII (FXII) contributes to thrombosis but appears to be dispensable in haemostasis[28]
Summary
Recombinant Escherichia coli exopolyphosphatase (PPX) degrades polyphosphate, while a PPX variant lacking domains 1 and 2 (PPX_D12) binds to the polymer without degrading it Both PPX and PPX_D12 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. Anticoagulant therapy interferes with the formation of clots within the vasculature and is the mainstay of treatment for the prevention and management of thromboembolic events Available anticoagulants such as heparin derivatives, vitamin K antagonists (for example, warfarin) and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation[2]. Targeting polyP with PPX variants reduces fibrin formation in the plasma, blunts procoagulant activity of activated platelets and interferes with thrombus formation in blood. The data show that polyP operates via FXII in vivo, and identify a new strategy for treating thrombosis that involves inhibition of polyP and does not affect haemostasis
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