Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection.
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.
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Linda
L
Labberton
Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Ellinor
E
Kenne
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Andy T
AT
Long
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Katrin F
KF
Nickel
Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Antonio
0000-0002-7946-8348
A
Di Gennaro
Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.|Department of Biomedical Engineering, School of Medicine, Oregon Health &Science University, 3303 SW Bond Avenue, Portland, Oregon 97239, USA.
Rachel A
RA
Rigg
Division of Laboratory Medicine, Mayo Clinic in Arizona, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA.
James S
JS
Hernandez
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Lynn
L
Butler
Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
Coen
0000-0003-4593-0976
C
Maas
Department of Medicine, Louis Stokes Veterans Administration Hospital, 10701 East Boulevard, Cleveland, Ohio 44106, USA.|Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Evi X
EX
Stavrou
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.|Clinical Chemistry, Department of Molecular Medicine and Surgery, L1:00, Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Thomas
T
Renné
D017766:Acid Anhydride Hydrolases / Q000378:metabolism; D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005174:Factor XII / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D009154:Mutation; D010974:Platelet Aggregation / Q000187:drug effects*; D011122:Polyphosphates / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000517:prevention & control*
D001779:Blood Coagulation Factors; D011122:Polyphosphates; D005174:Factor XII; D013917:Thrombin; D017766:Acid Anhydride Hydrolases; C020137:exopolyphosphatase