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.

项目摘要/摘要 机械循环支持（MCS）是治疗心脏或肺部衰竭的关键工具，形式 通过膜氧合或通过心室辅助装置的体外循环。 血栓形成和出血仍然与MCS的主要并发症。结果，患者接受了全身性 抗凝可预防血栓形成。但是，这可能会增加出血的风险，这是 MC中最常见的并发症。为了解决这个问题，已经付出了巨大的努力来消除或 最小化抗凝需求。令人惊讶的是，即使消除了抗凝治疗， 证明出血仍然很普遍，而血栓形成仍然相对不受影响。 因此，有必要专注于出血的替代途径。 MCS上的几乎所有患者 体验出血障碍获得的冯·威勒布兰综合症。此外，尤其是患者 小儿患者，患有血小板功能障碍，可表现出低血小板计数。我们属于 这些事件是MC中的流动环境。尽管许多小组都专注于剪切的影响 对血液的压力，我们的小组发现湍流在驱动高高和高中丧失方面的作用 甚至中间分子量von willebrand因子（VWF）多聚体，也降低了 VWF与血小板结合并与胶原蛋白结合。此外，有强有力的证据表明MC的流量是 引起血小板激活的信号，但也引起清除和细胞死亡，其影响未知 湍流。响应流动信号的组合可以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特定条件导致VWF或血小板 通过追求三个目标来响应流动的功能损失。 1）我们将量化血栓的变化 响应于湍流的各种抗凝剂的层状剪切条件的生长。 2）我们 将量化相对于层流的湍流中发生的裂解增加 压力条件以及VWF功能在流动暴露后如何变化，并没有流动诱导 扩大。 3）我们将在暴露于不同流动方案后评估血小板状态以及如何改变 有VWF或潜在的新治疗靶标。总之，这项工作将区分 湍流相对于剪切应力对血液的影响，这可能会导致设计标准的提高 如果我们确定领先的特定途径，用于血液接触的医疗设备和潜在的治疗剂 到功能失调的止血。