Pathologic Shear and Elongation Rates Do Not Cause Cleavage of Von Willebrand Factor by ADAMTS13 in a Purified System
Pathologic Shear and Elongation Rates Do Not Cause Cleavage of Von Willebrand Factor by ADAMTS13 in a Purified System
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DOI：
10.1007/s12195-020-00631-2
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发表时间：
2020-06-25
影响因子：
2.8
通讯作者：
Di Paola, Jorge
中科院分区：
文献类型：
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作者：
Bortot, Maria;Sharifi, Alireza;Di Paola, Jorge
严重主动脉瓣狭窄患者的病理性血流与获得性血管性血友病综合征相关。该综合征的特征在于血管性血友病因子被其主要蛋白酶，具有血小板反应蛋白1型基序的解聚素和金属蛋白酶，成员13（ADAMTS 13）过度切割，导致VWF功能降低和粘膜皮肤出血。主动脉瓣置换术和血流行为纠正到生理水平逆转了综合征，支持病理性血流和获得性血管性血友病综合征之间的相关性。我们研究了剪切和拉伸速率对血管性血友病因子切割的ADAMTS 13的存在下的影响。方法我们在5例严重主动脉瓣狭窄患者中发现了获得性von Willebrand综合征。这些患者的多普勒超声心动图值用于开发三种计算流体动力学（CFD）主动脉瓣模型（正常、轻度和重度狭窄）。在CFD模拟中确定的剪切，拉伸速率和暴露时间被用作微流体装置的设计参数，以测试病理剪切和拉伸速率对von Willebrand因子的结构和功能的影响。结果在我们的微流体设计中测试的剪切速率（0-10，000 s（-1））、拉伸速率（0-1000 s（-1））和暴露时间（1-180 ms）模拟了在主动脉瓣狭窄患者中鉴定的流动特征。在体外测试的剪切和拉伸速率没有导致过度切割或vonWillebrand因子的功能在蛋白酶的存在下降低。结论ADAMTS 13存在下的高剪切和拉伸速率不足以使血管性血友病因子过度裂解。
Introduction Pathological flows in patients with severe aortic stenosis are associated with acquired von Willebrand syndrome. This syndrome is characterized by excessive cleavage of von Willebrand factor by its main protease, A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13) leading to decreased VWF function and mucocutaneous bleeding. Aortic valve replacement and correction of the flow behavior to physiological levels reverses the syndrome, supporting the association between pathological flow and acquired von Willebrand syndrome. We investigated the effects of shear and elongational rates on von Willebrand factor cleavage in the presence of ADAMTS13. Methods We identified acquired von Willebrand syndrome in five patients with severe aortic stenosis. Doppler echography values from these patients were used to develop three computational fluid dynamic (CFD) aortic valve models (normal, mild and severe stenosis). Shear, elongational rates and exposure times identified in the CFD simulations were used as parameters for the design of microfluidic devices to test the effects of pathologic shear and elongational rates on the structure and function of von Willebrand factor. Results The shear rates (0-10,000s(-1)), elongational rates (0-1000 s(-1)) and exposure times (1-180 ms) tested in our microfluidic designs mimicked the flow features identified in patients with aortic stenosis. The shear and elongational rates testedin vitrodid not lead to excessive cleavage or decreased function of von Willebrand factor in the presence of the protease. Conclusions High shear and elongational rates in the presence of ADAMTS13 are not sufficient for excessive cleavage of von Willebrand Factor.