Impact of turbulence on blood in mechanical circulatory support

机械循环支持中湍流对血液的影响

• 批准号: 10634686
• 负责人: David Bark
• 金额: $ 42.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634686
• 关键词: ADAMTS; Acquired von Willebrand disease; Affect; Anticoagulants; Anticoagulation; Automobile Driving; Binding; Biological Assay; Biomedical Engineering; Blood; Blood Coagulation Disorders; Blood Platelets; Blood coagulation; Cell Death; Cells; Collagen; Complex; Complication; Cytoplasmic Granules; Environment; Equilibrium; Event; Exhibits; Exposure to; Extracorporeal Circulation; Functional disorder; Goals; Growth; Heart failure; Hematologist; Hemorrhage; Hemostatic Agents; Hemostatic function; Heparin; Impairment; Knowledge; Lead; Literature; Mechanics; Medical Device; Membrane; Metalloproteases; Molecular Weight; Pathologic; Pathway interactions; Patients; Persons; Pharmacologic Substance; Phosphatidylserines; Plasma Proteins; Platelet Activation; Platelet Count measurement; Platelet Glycoproteins; Platelet aggregation; Play; Positioning Attribute; Process; Proteins; Publications; Pump; Research; Risk; Risk Reduction; Role; Signal Pathway; Signal Transduction; Surface; System; Therapeutic; Thrombin; Thrombocytopenia; Thrombosis; Thrombus; Viscosity; Whole Blood; Work; cleavage factor; design; experience; functional loss; hemodynamics; improved; inhibitor; lung failure; mechanical circulatory support; microvesicles; new therapeutic target; pediatric patients; prevent; receptor; response; shear stress; thrombotic; tool; ventricular assist device; von Willebrand Factor

PROJECT SUMMARY/ABSTRACT Mechanical circulatory support (MCS) is a critical tool to treat heart or lung failure, in the form of extracorporeal circulation through membrane oxygenation or through a ventricular assist device. Thrombosis and bleeding remain major complications with MCS. As a result, patients receive systemic anticoagulation to prevent thrombosis. However, this can increase the risk for bleeding, which is the most common complication in MCS. To counter this issue, there has been a large effort to eliminate or minimize the need for anticoagulation. Surprisingly, even if anticoagulation is eliminated, studies demonstrate that bleeding remains highly prevalent, while thrombosis remains relatively unaffected. Therefore, there is a need to focus on alternative pathways to bleeding. Almost all patients on MCS experience the bleeding disorder acquired von Willebrand syndrome. Furthermore, patients, especially pediatric patients, experience platelet dysfunction and can exhibit low platelet counts. We attribute these events to the flow environment in MCS. While many groups have focused on the effect of shear stress on blood, our group discovered an unprecedented role for turbulence in driving loss of high and even intermediate molecular weight von Willebrand factor (VWF) multimers, reducing the ability for VWF to bind to platelets and to collagen. Furthermore, there is strong evidence that flow in MCS is causing signals for platelet activation, but also clearance and cell death, with an unknown effect of turbulence. The combination of signals in response to flow can lead to both thrombosis and hemorrhage, depending on the balance of events. Our goal is identify what specific conditions lead to VWF or platelet functional loss in response to flow by pursuing three aims. 1) We will quantify changes in thrombus growth in response to turbulence relative to laminar shear conditions for various anticoagulants. 2) We will quantify the increased cleavage occurring in turbulence relative to laminar flow for similar shear stress conditions and how VWF function varies after flow exposure with and without flow-induced extension. 3) We will assess platelet state after exposure to different flow regimes and how this changes with the presence of VWF or with potential new therapeutic targets. Altogether, this work will distinguish the impact of turbulence relative to shear stress on blood, which could lead to improved design criteria for blood-contacting medical devices and potential therapeutics if we identify specific pathways leading to dysfunctional hemostasis.

项目概要/摘要 机械循环支持 (MCS) 是治疗心肺衰竭的重要工具，其形式为 通过膜氧合或通过心室辅助装置进行体外循环。 血栓和出血仍然是 MCS 的主要并发症。结果，患者接受了系统治疗 抗凝，防止血栓形成。然而，这会增加出血的风险，这是 MCS 最常见的并发症。为了解决这个问题，人们付出了巨大的努力来消除或 最大限度地减少抗凝的需要。令人惊讶的是，即使取消抗凝治疗，研究 表明出血仍然非常普遍，而血栓形成相对不受影响。 因此，需要关注出血的替代途径。几乎所有接受 MCS 的患者 体验获得性血管性血友病综合征的出血性疾病。此外，患者，特别是 儿童患者会出现血小板功能障碍，并可能表现出血小板计数低。我们归因 这些事件到 MCS 中的流环境。虽然许多团体都关注剪切力的影响 由于血液压力，我们的小组发现湍流在导致高和低血压损失方面发挥着前所未有的作用。 甚至中等分子量的冯维勒布兰德因子 (VWF) 多聚体，降低了 VWF 与血小板和胶原蛋白结合。此外，有强有力的证据表明 MCS 中的血流 引起血小板激活信号，但也引起清除和细胞死亡，其影响未知 湍流。响应血流的信号组合可能导致血栓形成和出血， 取决于事件的平衡。我们的目标是确定哪些具体情况会导致 VWF 或血小板 通过追求三个目标来响应流动的功能丧失。 1）我们将量化血栓的变化 各种抗凝剂响应相对于层流剪切条件的湍流的生长。 2）我们 将量化在类似剪切力下相对于层流在湍流中发生的增加的劈裂 应激条件以及 VWF 功能在流暴露后（有或没有流诱导）如何变化 扩大。 3) 我们将评估暴露于不同流态后的血小板状态及其变化 存在 VWF 或潜在的新治疗靶点。总而言之，这项工作将区分 相对于剪切应力的湍流对血液的影响，这可能会导致设计标准的改进 如果我们确定了导致血液接触的医疗设备和潜在疗法的具体途径 止血功能障碍。