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.
Nat Commun. 2016 Sep 6;7:12616. doi: 10.1038/ncomms12616.
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.
多聚磷酸盐是一种无机促凝血聚合物。在这里，我们开发了多聚磷酸盐的特异性抑制剂，并表明这种策略以因子 XII 依赖的方式提供抗血栓形成保护。重组大肠埃希菌外切多聚磷酸酶 (PPX) 特异性降解多聚磷酸盐，而缺乏结构域 1 和 2 的 PPX 变体 (PPX_Δ12) 与聚合物结合但不降解它。PPX 和 PPX_Δ12 均干扰多聚磷酸盐而非组织因子或核酸驱动的凝血酶形成。靶向多聚磷酸盐以因子 XII 依赖的方式消除促凝血血小板活性，减少纤维蛋白积聚并阻碍血流下的血栓形成。PPX 和 PPX_Δ12 在野生型小鼠中的输注干扰动脉血栓形成，并保护动物免受激活血小板诱导的静脉血栓栓塞，而不会增加损伤部位的出血。相比之下，靶向多聚磷酸盐不能为因子 XII 缺乏的动物提供额外的抗血栓形成保护。我们的数据提供了一种对抗血栓性疾病的概念验证方法，而不会增加出血风险，表明多聚磷酸盐通过因子 XII 驱动血栓形成。
