Introduction

Vascular devices such as stents, hemodialyzers, and membrane oxygenators can activate blood coagulation and often require the use of systemic anticoagulants to selectively prevent intravascular thrombotic/embolic events or extracorporeal device failure. Coagulation factor (F)XII of the contact activation system has been shown to play an important role in initiating vascular device surface-initiated thrombus formation. As FXII is dispensable for hemostasis, targeting the contact activation system holds promise as a significantly safer strategy than traditional antithrombotics for preventing vascular device-associated thrombosis.

Objective

Generate and characterize anti-FXII monoclonal antibodies that inhibit FXII activation or activity.

Methods

Monoclonal antibodies against FXII were generated in FXII-deficient mice and evaluated for their binding and anticoagulant properties in purified and plasma systems, in whole blood flow-based assays, and in an in vivo non-human primate model of vascular device-initiated thrombus formation.

Results

A FXII antibody screen identified over 400 candidates, which were evaluated in binding studies and clotting assays. One non-inhibitor and six inhibitor antibodies were selected for characterization in functional assays. The most potent inhibitory antibody, 1B2, was found to prolong clotting times, inhibit fibrin generation on collagen under shear, and inhibit platelet deposition and fibrin formation in an extracorporeal membrane oxygenator deployed in a non-human primate.

Conclusion

Selective contact activation inhibitors hold potential as useful tools for research applications as well as safe and effective inhibitors of vascular device-related thrombosis.

中文翻译：

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用于抑制血管装置相关血栓形成的凝血因子 XII 抗体的开发

介绍

支架、血液透析器和膜氧合器等血管装置可以激活血液凝固，并且通常需要使用全身性抗凝剂来选择性地预防血管内血栓/栓塞事件或体外装置故障。接触激活系统的凝血因子 (F)XII 已被证明在启动血管装置表面引发的血栓形成中起重要作用。由于 FXII 对止血来说是可有可无的，因此靶向接触激活系统有望成为比传统抗血栓药物更安全的预防血管装置相关血栓形成的策略。

客观的

生成和表征抑制 FXII 激活或活性的抗 FXII 单克隆抗体。

方法

在 FXII 缺陷小鼠中产生了针对 FXII 的单克隆抗体，并在纯化和血浆系统、基于全血流的测定以及血管装置引发的血栓形成的体内非人灵长类动物模型中评估了它们的结合和抗凝特性.

结果

FXII 抗体筛选确定了 400 多个候选者，这些候选者在结合研究和凝血测定中进行了评估。选择一种非抑制剂和六种抑制剂抗体用于功能测定中的表征。发现最有效的抑制性抗体 1B2 可延长凝血时间，抑制剪切作用下胶原蛋白上的纤维蛋白生成，并抑制部署在非人类灵长类动物体内的体外膜氧合器中的血小板沉积和纤维蛋白形成。

结论

选择性接触激活抑制剂具有作为研究应用的有用工具以及血管装置相关血栓形成的安全有效抑制剂的潜力。