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Nat Commun. 2016 Sep 6;7:12616. doi: 10.1038/ncomms12616.

Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection.

Author information

1
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
2
Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
3
Department of Biomedical Engineering, School of Medicine, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.
4
Division of Laboratory Medicine, Mayo Clinic in Arizona, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA.
5
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
6
Department of Medicine, Louis Stokes Veterans Administration Hospital, 10701 East Boulevard, Cleveland, Ohio 44106, USA.
7
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

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.

PMID:
27596064
PMCID:
PMC5025862
DOI:
10.1038/ncomms12616
[Indexed for MEDLINE]
Free PMC Article

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