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Neutralizing blood-...
Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
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- Labberton, L (författare)
- Karolinska Institutet
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- Kenne, E (författare)
- Karolinska Institutet
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Long, AT (författare)
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Nickel, KF (författare)
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Di Gennaro, A (författare)
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Rigg, RA (författare)
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Hernandez, JS (författare)
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- Butler, L (författare)
- Karolinska Institutet
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Maas, C (författare)
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Stavrou, EX (författare)
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- Renne, T (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2016-09-06
- 2016
- Engelska.
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12616-
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https://www.nature.c...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
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- art (ämneskategori)
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Labberton, L
-
Kenne, E
-
Long, AT
-
Nickel, KF
-
Di Gennaro, A
-
Rigg, RA
-
visa fler...
-
Hernandez, JS
-
Butler, L
-
Maas, C
-
Stavrou, EX
-
Renne, T
-
visa färre...
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Nature communica ...
- Av lärosätet
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Karolinska Institutet