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）是治疗心力衰竭或肺衰竭的关键工具，其形式为 通过膜氧合或通过心室辅助装置进行体外循环。 血栓形成和出血仍然是MCS的主要并发症。因此，患者接受全身性 抗凝，以防止血栓形成。然而，这可能会增加出血的风险，这是 MCS中最常见的并发症。为了解决这个问题，已经做出了很大的努力来消除或 最大限度地减少抗凝治疗的需要。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MCS患者 患有出血性疾病获得性血管性血友病综合征此外，患者尤其 儿科患者经历血小板功能障碍，并可表现出低血小板计数。我们的属性 将这些事件添加到MCS中的流环境中。虽然许多研究小组关注的是剪切力的影响， 强调血液，我们的小组发现了一个前所未有的作用，动荡的驱动损失高， 即使是中等分子量的血管性血友病因子（VWF）多聚体，也降低了血管性血友病因子（VWF）的表达能力。 VWF与血小板和胶原蛋白结合。此外，有强有力的证据表明，MCS中的流动是 引起血小板活化的信号，但也清除和细胞死亡，具有未知的影响， 急流.响应于流动的信号的组合可导致血栓形成和出血， 取决于事态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应对流动的功能丧失。1)我们将量化血栓的变化 对于各种抗凝剂，相对于层流剪切条件，响应于湍流的生长。2)我们 将量化在湍流中发生的相对于层流的增加的解理，对于类似的剪切 应力条件和VWF功能如何在有和没有流动诱导的流动暴露后变化 扩展名. 3)我们将评估暴露于不同流动状态后的血小板状态及其变化 与VWF的存在或与潜在的新的治疗靶点。总之，这项工作将区分 湍流相对于剪切应力对血液的影响，这可能导致改进设计标准 对于血液接触医疗器械和潜在的治疗，如果我们确定特定的途径， 到功能性止血