Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
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Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. / 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.
in: NAT COMMUN, Jahrgang 7, 06.09.2016, S. 12616.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
AU - Labberton, Linda
AU - Kenne, Ellinor
AU - Long, Andy T
AU - Nickel, Katrin F
AU - Di Gennaro, Antonio
AU - Rigg, Rachel A
AU - Hernandez, James S
AU - Butler, Lynn
AU - Maas, Coen
AU - Stavrou, Evi X
AU - Renné, Thomas
N1 - Paper of the Month September, bitte die Erstautorin (Doktorandin), Frau Labberton dem Institut zuschreiben. Danke sehr!
PY - 2016/9/6
Y1 - 2016/9/6
N2 - 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.
AB - 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.
KW - Journal Article
KW - POM-Newsletter
U2 - 10.1038/ncomms12616
DO - 10.1038/ncomms12616
M3 - SCORING: Journal article
C2 - 27596064
VL - 7
SP - 12616
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -