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 获得性血管性血友病综合征 (AvWS)，其特征是高分子量多聚体缺失 血管性血友病因子 (vWF) (HMWM) 通常与非生理性血流相关。 见于严重主动脉瓣狭窄 (AS) 或连续流左心室辅助装置 (cf-LVAD) 的患者。 ，这种与严重 AS 相关的止血异常在术后第一天就得到完全纠正 对于与 cf-LVAD 相关的 AvWS，在移除装置后，它会迅速消失，强烈。 人们普遍认为，该装置本身是导致该综合征的原因。 严重 AS 和 cf-LVAD 中的剪切应力和/或长时间暴露是造成 HMWM 损失的原因。 尽管 HMWM 的破坏被认为是机械和酶裂解的结合，但 完整的机制仍不清楚。还值得注意的是，在脉动血流中很少观察到 AvWS。 需要了解 vWF 的降解机制和暴露时间，尤其是在使用时。 该提案的目的是描述非生理性血流的退化特征。 在功率密度方面，HMWM 在完全受控层流和湍流血流条件下 （每单位质量的能量耗散率）和临床相关的暴露时间。 vWF 的 HMWM 降解是一种时间敏感的机械酶促事件，主要发生在 通过将 ADAMTS13 暴露于 vWF 上的裂解位点来模拟湍流条件。 出版物以及文献中的证据，我们认为大多数 vWF 多聚体降解是 然而，我们认识到 vWF 还有其他潜在的汇和来源。 包括吸附到装置表面、与血小板结合以及从 ⍺ 颗粒中释放 vWF 我们将在这些成功的实验中测试并解释这些汇和源。 完成拟议的研究将使我们能够 i) 确定非生理性血液之间的关系 cf-LVAD 中 HMWM 损失涉及的流量和暴露时间，ii) 评估降解机制 HMWM，以及 iii) 从机械酶学、机械学和酶学方面描述机制 最终，该前瞻性模型有望成为一种工具。 设备设计优化带来下一代血泵并为患者带来更好的临床结果 与 AvWS。