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.

摘要