A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk
A Factor XIIa Inhibitory Antibody Provides Thromboprotection in Extracorporeal Circulation Without Increasing Bleeding Risk
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DOI：
10.1126/scitranslmed.3006804
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发表时间：
2014-02-05
影响因子：
17.1
通讯作者：
Renne, Thomas
中科院分区：
文献类型：
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作者：
Larsson, Magnus;Rayzman, Veronika;Renne, Thomas
目前使用的抗凝剂可预防血栓形成，但会增加出血。我们展示了一种基于血浆蛋白酶因子XII功能中和抗体的无出血风险的抗凝治疗。我们使用噬菌体展示筛选针对活化因子XII（FXIIa）的抗体，并证明重组全人抗体3F7结合到FXIIa酶口袋中。3F7干扰FXIIa介导的凝血，消除流动下的血栓形成，并阻断小鼠和兔的实验性血栓形成。我们采用了用于婴儿治疗的体外膜肺氧合（ECMO）心肺转流系统，以分析3F7在家兔中的临床适用性。3F7与肝素一样有效地提供血栓保护，并且两种药物都防止了体外回路内的纤维蛋白沉积和血栓形成。与肝素不同，3F7治疗不会损害止血能力，也不会增加伤口出血。这些数据表明，靶向FXIIa是旁路系统中血栓保护的一种安全模式，并提供了一种临床相关的抗凝策略，不会因过度出血而复杂化。
Currently used anticoagulants prevent thrombosis but increase bleeding. We show an anticoagulation therapy without bleeding risk based on a plasma protease factor XII function-neutralizing antibody. We screened for antibodies against activated factor XII (FXIIa) using phage display and demonstrated that recombinant fully human antibody 3F7 binds into the FXIIa enzymatic pocket. 3F7 interfered with FXIIa-mediated coagulation, abolished thrombus formation under flow, and blocked experimental thrombosis in mice and rabbits. We adapted an extracorporeal membrane oxygenation (ECMO) cardiopulmonary bypass system used for infant therapy to analyze clinical applicability of 3F7 in rabbits. 3F7 provided thromboprotection as efficiently as heparin, and both drugs prevented fibrin deposition and thrombosis within the extracorporeal circuit. Unlike heparin, 3F7 treatment did not impair the hemostatic capacity and did not increase bleeding from wounds. These data establish that targeting of FXIIa is a safe mode of thromboprotection in bypass systems, and provide a clinically relevant anticoagulation strategy that is not complicated by excess bleeding.