Von Willebrand Factor Hyperactivity, Angiogenesis and LVAD-Induced Bleeding

血管性血友病因子过度活跃、血管生成和 LVAD 诱发的出血

• 批准号: 10587655
• 负责人: Angelo Nascimbene
• 金额: $ 62.23万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587655
• 关键词: ADAMTS; Acquired von Willebrand disease; Adhesiveness; Adhesives; Angiodysplasia; Arteriovenous malformation; Artificial Intelligence; Binding; Biological Assay; Biophysics; Blood; Blood Platelets; Blood Vessels; Blood flow; Blood specimen; Cardiac; Clinical; Clinical Management; Clinical Research; Complication; Data; Devices; Endothelial Cells; Ensure; Equilibrium; Exposure to; Extracorporeal Membrane Oxygenation; Flow Cytometry; Functional disorder; Generations; Heart; Heart Diseases; Hemorrhage; Hemostatic Agents; Hemostatic function; Homeostasis; Hyperactivity; Impairment; Implant; In Vitro; Institution; Laboratories; Ligands; Link; Machine Learning; Mass Spectrum Analysis; Mediating; Metalloproteases; Methods; Microfluidics; Modeling; Morbidity - disease rate; Mucous Membrane; Multivariate Analysis; Mus; Operative Surgical Procedures; Outcome; Pathology; Patients; Pattern; Peptides; Plasma; Process; Pump; Reporting; Research; Risk; Role; Sampling; Source; System; Techniques; Technology; Testing; Therapeutic Agents; Thrombosis; Vascular Endothelial Growth Factors; angiogenesis; biophysical analysis; biophysical techniques; cleavage factor; design; experience; experimental study; extracellular vesicles; gain of function; implantable device; implantation; improved; in vivo; innovation; insight; left ventricular assist device; longitudinal analysis; loss of function; mouse model; predictive marker; prevent; shear stress; synergism; therapeutic target; von Willebrand Factor; von Willebrand factor receptor

Project Summary Left ventricular assist device (LVAD) provides cardiac support for patients with end stage heart disease and has significantly improved the survival of these patients, but device-related bleeding remains common and are associated with poor clinical outcomes. Even latest (3rd) generation devices have been able to significant impact device thrombosis (e.g.MOMENTUM3 trial), however with some surprise they have not been able to resolve LVAD related bleeding which remains a significant source of morbidity and complicates clinical management, ultimately leading to poor clinical outcomes. The LVAD-associated bleeding is often called acquired von Willebrand syndrome (aVWS) that is believed to be caused by excessive cleavage of VWF multimers by ADAMTS-13. However, this tentative mechanism has not been experimentally validated and significant gaps remain. The loss of large VWF multimers is observed in nearly all patients, but only a fraction of patients experience significant bleeding. High shear stress is known to promote VWF cleavage and activation to bind platelets, but this shear-induced VWF activation has not been studied in patients on LVAD. We hypothesize that: 1) Plasma VWF multimers in LVAD patients are subjected to higher rates of cleavage and activation than healthy subjects and patients with end stage heart disease prior to LVAD implant 2) LVAD- induced high shear stress results in VWF dysfunctions responsible for impaired hemostasis and triggers downstream VWF mediated angiogenesis 3) These shear-induced structural changes of VWF can be detected in patients on LVAD and can predict bleeding propensity developed after LVAD implantation. We propose to test these hypotheses with three specific aims. First, develop predictive markers for LVAD-induced hemostatic complications by comprehensively analyzing the imbalance between VWF activity and cleavage in longitudinal plasma samples from 240 patients collected before and after LVAD implantation using flow cytometry, mass spectrometry, microfluidic chamber systems, and conventional VWF functional tests. Second, study shear- induced structural changes of the VWF A1 and A2 domains and their roles in regulating rates of VWF cleavage and activation using in vitro techniques and mouse models. Third study how VWF synergizes with extracellular vesicles to promote immature angiogenesis, which leads to bleeding-prone arteriovenous malformation. The objectives of this mechanistic study are to: 1) define shear-induced structural changes of VWF using state-of- art biophysical techniques and study how these changes influence VWF cleavage and activity, 2) study how high shear stress disrupts the inhibitory interaction between the A1 and A2 domains to alter the A1 interface with the platelet VWF receptor GP Ib and to unfold A2 for cleavage, and 3) investigate the role of VWF in angiogenesis. We have assembled a team of experts in related clinical and research fields from 3 institutions to conduct this innovative research focused on improving LVAD outcomes and provide insight on how aVWS may play a role in surgical and percutaneous continuous flow devices.

项目摘要 左心室辅助装置（LVAD）为患有终心阶段心脏病和的患者提供心脏支持 这些患者的存活率显着提高，但与设备相关的出血仍然很普遍，并且是 与临床结果不佳有关。即使是最新（第三代）的设备也能够发挥重要意义 撞击装置的血栓形成（例如Momentum3试验），但是有些惊讶，他们无法 解决LVAD相关的出血，这仍然是发病率的重要来源，并使临床复杂化 管理，最终导致临床结果不佳。 LVAD相关的出血通常称为 获得的von Willebrand综合征（AVW）被认为是由VWF过多的裂解引起的 ADAMTS-13的多聚体。但是，这种暂定机制尚未经过实验验证，并且 仍然存在明显的差距。几乎所有患者都观察到大型VWF多聚体的损失，但只有一小部分 患者的出血大量出血。已知高剪切应力会促进VWF裂解和 与血小板结合的激活，但是这种剪切诱导的VWF激活尚未在LVAD患者中研究。 我们假设：1）LVAD患者的等离子体VWF多聚体受到更高的裂解率 与健康受试者和LVAD植入之前的终心心脏病患者相比，激活和激活2）LVAD- 诱导的高剪切应力导致VWF功能障碍，导致止血和触发受损 下游VWF介导的血管生成3）可以检测到这些剪切诱导的VWF的结构变化 在LVAD的患者中，可以预测LVAD植入后出现的出血倾向。我们建议 用三个特定目标测试这些假设。首先，开发LVAD诱导止血的预测标记 通过全面分析VWF活动与纵向裂解之间的不平衡来并发症 LVAD植入前后收集的240名患者的血浆样品使用流式细胞仪，质量 光谱，微流体室系统和常规的VWF功能测试。第二，研究剪切 - VWF A1和A2域的诱导结构变化及其在调节VWF裂解速率中的作用 并使用体外技术和小鼠模型激活。第三研究VWF如何与细胞外合成 促进未成熟血管生成的囊泡，导致容易出血的动静脉畸形。这 这项机械研究的目标是：1）使用最新 - 艺术生物物理技术并研究这些变化如何影响VWF的裂解和活动，2）研究如何 高剪切应力破坏了A1和A2域之间的抑制作用以改变A1界面 使用血小板VWF受体GPib并展开A2进行裂解，3）研究VWF在 血管生成。我们已经组建了来自3个机构的相关临床和研究领域专家团队 进行这项创新研究的重点是改善LVAD的结果，并提供有关如何AVWS的见解 可能在手术和经皮连续流动装置中发挥作用。