Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
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DOI：
10.1038/ncomms12616
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发表时间：
2016-09-01
影响因子：
16.6
通讯作者：
Renne, Thomas
中科院分区：
文献类型：
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作者：
Labberton, Linda;Kenne, Ellinor;Renne, Thomas
聚磷酸盐是一种无机促凝血聚合物。在这里，我们开发了聚磷酸盐的特异性抑制剂，并表明该策略以 XII 因子依赖性方式提供血栓保护。重组大肠杆菌外多磷酸酶 (PPX) 特异性降解多磷酸盐，而缺乏结构域 1 和 2 的 PPX 变体 (PPX_Delta 12) 与聚合物结合而不降解它。 PPX 和 PPX_Delta 12 都会干扰多磷酸盐，但不会干扰组织因子或核酸驱动的凝血酶形成。靶向聚磷酸盐以 XII 因子依赖性方式消除促凝血血小板活性，减少纤维蛋白积聚并阻止血液中血栓形成。在野生型小鼠中输注 PPX 和 PPX_Delta 12 会干扰动脉血栓形成，并保护动物免受活化血小板诱导的静脉血栓栓塞，且不会增加损伤部位的出血。相比之下，针对缺乏 XII 因子的动物，靶向多磷酸盐并不能提供额外的预防血栓形成的保护作用。我们的数据提供了一种在不增加出血风险的情况下对抗血栓性疾病的概念验证方法，表明多磷酸盐通过因子 XII 驱动血栓形成。
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_Delta 12) binds to the polymer without degrading it. Both PPX and PPX_Delta 12 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_Delta 12 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.