Impact of turbulence on blood in mechanical circulatory support

项目摘要/摘要 机械循环支持(MCS)是治疗心肺衰竭的关键工具，其形式为 通过膜氧合或通过心脏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。结果，患者接受了全身性 抗凝以防止血栓形成。然而，这会增加出血的风险，这是 MCS最常见的并发症。为了应对这个问题，已经做出了很大的努力来消除或 将抗凝需求降至最低。令人惊讶的是，即使抗凝被消除，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，有必要把重点放在出血的替代途径上。几乎所有服用MCS的患者 体验获得性血管性血友病综合征的出血障碍。此外，患者，特别是 儿童患者，出现血小板功能障碍，并可表现出低血小板计数。我们的属性 这些事件发生在MCS中的流动环境中。虽然许多研究小组关注的是剪切的影响 在血液压力方面，我们的团队发现了湍流在推动高血压和高血压的损失中所发挥的前所未有的作用。 即使是中等分子量的von Willebrand因子(VWF)多聚体，也会降低 VWF与血小板和胶原蛋白结合。此外，有强有力的证据表明，MCS中的流量 导致血小板激活的信号，但也清除和细胞死亡，与未知的影响 颠簸。对血流作出反应的信号组合可能导致血栓形成和出血， 这取决于事件的平衡。我们的目标是确定哪些特定条件会导致VWF或血小板 通过追求三个目标来应对流动造成的功能损失。1)我们将量化血栓的变化 各种抗凝剂在层流剪切条件下对湍流的响应生长。2)我们 对于类似的剪切，将量化湍流中相对于层流发生的解理增加 流暴露后的应力状态和VWF函数的变化 分机。3)我们将评估暴露在不同流动模式下的血小板状态以及这种状态是如何变化的 VWF的存在或潜在的新治疗靶点。总而言之，这项工作将区分 相对于切应力的湍流对血液的影响，这可能导致改进设计标准 对于接触血液的医疗设备和潜在的治疗方法，如果我们确定特定的路径 到功能失调的止血。

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.