ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation.
ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation.
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DOI：
10.1111/jth.15889
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发表时间：
2022-12
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影响因子：
--
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中科院分区：
文献类型：
--
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获得性血管性血友病综合征(AVWS)在使用机械循环支持装置(MCS)的患者中很常见。在这些患者中，装置中的高剪切应力导致ADAMTS13(带有凝血酶反应蛋白1型重复序列的去整合素和金属蛋白酶，编号13)对von Willebrand因子(VWF)的剪切诱导蛋白分解增加。结果，高分子量(HMW)VWF多聚体丢失，导致VWF功能下降和止血功能受损，这可能是这些患者常见的出血并发症的原因。为了对抗ADAMTS13对VWF的这种异常降解，我们开发了一种新的靶向治疗，使用抗ADAMTS13的单抗(MAb)来抑制ADAMTS13对VWF的剪切诱导的蛋白降解。用抑制性抗ADAMTS13mAb3H9或17C7(20μg/mL)或对照抗ADAMTS13mAb5C11或PBS体外循环人或牛血。在不同时间点测定VWF多聚体和功能(胶原结合活性)。接下来，将Impella®泵植入小牛体内，给小牛注射PBS，然后用mAb17C7进行治疗。测定VWF、ADAMTS13和血液参数。我们证明了在体外MCS装置系统中，阻断ADAMTS13可以防止HMW VWF多聚体的丢失。重要的是，我们的抗体可以逆转临床前Impella®诱导的aVWS小牛模型中的aVWS。因此，抑制ADAMTS13可能成为一种治疗MCS患者aVWS的新策略。
Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired haemostasis which could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13. Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/mL) or control anti-ADAMTS13 mAb 5C11 or PBS. VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella® pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13 and blood parameters were determined. We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella®-induced aVWS calf model. Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.
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影响因子：
1.1
作者：
FAVALORO, EJ;GRISPO, L;KOUTTS, J
通讯作者：
KOUTTS, J
影响因子：
--
作者：
Guha, Ashrith;Eshelbrenner, Carrie L;Monsour, Howard P Jr
通讯作者：
Monsour, Howard P Jr
影响因子：
4.4
作者：
Kalbhenn, Johannes;Schmidt, Rene;Zieger, Barbara
通讯作者：
Zieger, Barbara
DOI：
10.1161/atvbaha.108.168369
发表时间：
2008-09-01
影响因子：
8.7
作者：
De Meyer, Simon F.;Vandeputte, Nele;Vanhoorelbeke, Karen
通讯作者：
Vanhoorelbeke, Karen
影响因子：
7.5
作者：
Jilma-Stohlawetz, Petra;Quehenberger, Peter;Jilma, Bernd
通讯作者：
Jilma, Bernd