Wallisch Michael, Lorentz Christina U, Lakshmanan Hari H S, Johnson Jennifer, Carris Marschelle R, Puy Cristina, Gailani David, Hinds Monica T, McCarty Owen J T, Gruber András, Tucker Erik I
Department of Biomedical Engineering Oregon Health & Science University Portland OR USA.
Aronora, Inc. Portland OR USA.
Res Pract Thromb Haemost. 2020 Feb 11;4(2):205-216. doi: 10.1002/rth2.12309. eCollection 2020 Feb.
The contact factor XII (FXII) activates upon contact with a variety of charged surfaces. Activated FXII (FXIIa) activates factor XI, which activates factor IX, resulting in thrombin generation, platelet activation, and fibrin formation. In both in vitro and in vivo rabbit models, components of medical devices, including extracorporeal oxygenators, are known to incite fibrin formation in a FXII-dependent manner. Since FXII has no known role in hemostasis and its inhibition is therefore likely a safe antithrombotic approach, we investigated whether FXII inhibition also reduces accumulation of platelets in extracorporeal oxygenators.
We aimed to determine the effect of FXII inhibition on platelet deposition in perfused extracorporeal membrane oxygenators in nonhuman primates.
A potent FXII neutralizing monoclonal antibody, 5C12, was administered intravenously to block contact activation in baboons. Extracorporeal membrane oxygenators were temporarily deployed into chronic arteriovenous access shunts. Radiolabeled platelet deposition in oxygenators was quantified in real time using gamma camera imaging. Biochemical assays were performed to characterize the method of action of 5C12.
The anti-FXII monoclonal antibody 5C12 recognized both the alpha and beta forms of human and baboon FXII by binding to the protease-containing domain, and inhibited FXIIa activity. Administration of 5C12 to baboons reduced platelet deposition and fibrin formation in the extracorporeal membrane oxygenators, in both the presence and absence of systemic low-dose unfractionated heparin. The antiplatelet dose of 5C12 did not cause measurable increases in template bleeding times in baboons.
FXII represents a possible therapeutic and safe target for reducing platelet deposition and fibrin formation during medical interventions including extracorporeal membrane oxygenation.
接触因子 XII（FXII）在与多种带电表面接触时被激活。活化的 FXII（FXIIa）激活因子 XI，进而激活因子 IX，导致凝血酶生成、血小板活化和纤维蛋白形成。在体外和体内兔模型中，已知包括体外氧合器在内的医疗器械组件会以 FXII 依赖的方式引发纤维蛋白形成。由于 FXII 在止血过程中没有已知作用，因此抑制它可能是一种安全的抗血栓形成方法，我们研究了抑制 FXII 是否也能减少血小板在体外氧合器中的积聚。
我们旨在确定抑制 FXII 对非人类灵长类动物灌注体外膜肺氧合器中血小板沉积的影响。
静脉注射一种有效的 FXII 中和单克隆抗体 5C12，以阻断狒狒体内的接触激活。将体外膜肺氧合器临时置入慢性动静脉分流通道。使用γ相机成像实时定量氧合器中放射性标记的血小板沉积。进行生化分析以表征 5C12 的作用方式。
抗 FXII 单克隆抗体 5C12 通过结合含蛋白酶结构域识别了人和狒狒 FXII 的α和β形式，并抑制了 FXIIa 的活性。给狒狒注射 5C12 可减少体外膜肺氧合器中血小板沉积和纤维蛋白形成，无论是否存在全身性低剂量普通肝素。5C12 的抗血小板剂量未导致狒狒的模板出血时间出现可测量的增加。
FXII 是在包括体外膜肺氧合在内的医学干预过程中减少血小板沉积和纤维蛋白形成的一个可能的治疗性安全靶点。
