Multimeric Structural Degradation of vWF in Turbulent Flows

vWF 在湍流中的多聚体结构降解

• 批准号: 10563289
• 负责人: Choon-Sik Jhun
• 金额: $ 66.5万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-05 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563289
• 关键词: ADAMTS; Acquired von Willebrand disease; Address; Adsorption; Alpha Granule; American Heart Association; Aortic Valve Stenosis; Automobile Driving; Award; Binding; Biology; Blood; Blood Coagulation Disorders; Blood Platelets; Blood flow; Budgets; Clinic; Clinical; Complication; Custom; Data; Device Designs; Device Removal; Devices; Doctor of Medicine; Doctor of Philosophy; Enzymes; Event; Excision; Funding; Goals; Hemorrhage; Hemostatic Agents; Human Resources; Implant; In Vitro; Institutional Review Boards; Kinetics; Liquid substance; Literature; Mechanics; Mediating; Medical center; Metabolism; Metalloproteases; Methodology; Modeling; Molecular Weight; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Physicians; Proteins; Publications; Reaction Time; Role; Scientist; Site; Source; Structure; Surface; Syndrome; Testing; Time; Work; blood pump; clinical decision support; clinical effect; clinically relevant; clinically significant; cohort; density; design; experimental study; in silico; in vitro testing; in vivo; innovation; left ventricular assist device; next generation; prospective; shear stress; support tools; tool; von Willebrand Factor

ABSTRACT Acquired von Willebrand Syndrome (AvWS) characterized by the loss of high molecular weight multimers (HMWMs) of von Willebrand factor (vWF) is often associated with nonphysiologic blood flows. AvWS is found in patients with severe aortic stenosis (AS) or continuous-flow left ventricular assist devices (cf-LVADs). Interestingly, this hemostatic abnormality associated with severe AS is fully corrected on the first day after surgery. For AvWS associated with cf-LVADs, it disappears quickly after removal of the device, strongly suggesting that the device itself is responsible for the syndrome. It is widely believed that the supraphysiologic shear stress and/or long exposure time in severe AS and cf-LVADs are responsible for the loss of HMWM. Although the destruction of HMWM is believed to be a combination of mechanical and enzymatic cleavage, the complete mechanism still remains unclear. Also notable is that AvWS is rarely observed in pulsatile blood flow devices. There is a need to understand the degradation mechanism of vWF and exposure time especially when nonphysiologic blood flows are expected. The objective of this proposal is to characterize the degradation of HMWM under fully controlled laminar through turbulent blood flow conditions in terms of power density (energy dissipation rate per unit mass) and clinically relevant exposure times. The central hypothesis is that the degradation of HMWM of vWF is a time-sensitive mechanoenzymatic event that occurs primarily under turbulent flow conditions by exposing the ADAMTS13 to cleavage sites on vWF. Based on our previous publications as well as evidence in the literature, we believe that the majority of vWF multimer degradation is ADAMTS13 mediated. However, we recognize that there are other potential sinks and sources of vWF including adsorption to the surfaces of a device, binding to platelets, and release of vWF from ⍺-granules of activated platelets. We will test and account for these sinks and sources in these experiments. Successful completion of the proposed study will allow us to i) determine the relationship between nonphysiologic blood flow and exposure time involved in the loss of HMWM in cf-LVADs, ii) evaluate the degradation mechanism of HMWM, and iii) characterize the mechanism in terms of mechanoenzymatic, mechanistic, and enzymatic sensitivity through comprehensive vWF biology. Ultimately, the prospective model is expected to be a tool for device design optimization leading to a next-generation blood pump and better clinical outcomes for patients with AvWS.

抽象的 获得的von Willebrand综合征（AVW），其特征是损失高分子量多二聚体 von Willebrand因子（VWF）的（HMWMS）通常与非生理血流有关。 AVW是 在患有严重主动脉狭窄（AS）或连续流左心室辅助装置（CF-LVADS）的患者中发现。 有趣的是，这种与重度相关的止血绝对是在之后的第一天完全校正的 外科手术。对于与CF-LVAD相关的AVW，它在拆除设备后很快消失 表明该设备本身负责综合征。人们普遍认为Supraplysiologic 严重AS和CF-LVADS中的剪切应力和/或长时间暴露时间负责HMWM的损失。 尽管HMWM的破坏被认为是机械和酶促裂解的组合，但 完整的机制仍然不清楚。同样值得注意的是，在脉冲血流中很少观察到AVW 设备。有必要了解VWF和曝光时间的降解机制，尤其是在 预计非生理血流。该提议的目的是表征 HMWM通过湍流条件在功率密度方面通过湍流条件下 （每单位质量的耗能速率）和临床相关的暴露时间。中心假设是 VWF的HMWM降解是一个时间敏感的机械酶事件，在主要发生下发生 通过将ADAMTS13暴露于VWF上的裂解位点，湍流条件。根据我们以前的 出版物以及文献中的证据，我们认为大多数VWF多聚机退化是 ADAMTS13介导。但是，我们认识到VWF还有其他潜在的水槽和来源 包括在设备表面上增加吸收，与血小板结合，并从⍺颗粒中释放。 活化的血小板。我们将在这些实验中测试和说明这些水槽和来源。成功的 拟议研究的完成将使我们能够确定非生理血液之间的关系 CF-LVAD中HMWM丢失涉及的流量和暴露时间，ii）评估降解机制 HMWM和III）以机械酶，机械和酶促的方式来表征该机制 通过全面的VWF生物学敏感。最终，预期模型将成为 设备设计优化，导致下一代血泵和患者的临床结果更好 与avws。