Multiscale Model of Thrombosis in Artificial Circulation

毫不夸张地说，所有的血液润湿设备都容易发生意外的血栓形成和 流血--后果非常严重。尽管有几十年的临床经验，基础研究， 和计算流体力学建模，仍然几乎不可能避免有害的 血液学效应，无实验试错。事实上，近几年来， 脑室辅助装置(VADs)的血栓栓塞性和出血性不良事件 增加了，而不是减少了。不幸的后果是衰弱程度令人无法接受。 不良事件，如中风和出血。这促使私家侦探和同事们 在过去的二十年里，我们开发了一种精确的计算模型来模拟 人工表面上的血栓沉积。计算机模拟的独特之处在于它能够 解释多尺度上的物理和生物现象，包括贩运 小空间的红细胞和血小板，化学激动剂的合成和运输，以及 血小板与人工表面黏附的正反馈和负反馈的几种途径。 目前的模型已经显示出与实验观测的良好一致性 微流体通道和HeartMate-2血泵。 这一竞争性更新的目标是继续改进这款 模型，并演示其转化为全尺寸的血液润湿设备。这两个具体的 本研究的目的是：SA1，通过添加重要的元素来提高模型的逼真度 血小板解聚、溶栓和von Willebrand介导的血小板机制 粘附性；以及SA2，用于演示和进一步验证模型的性能 当代临床使用的血泵和氧合器。 这些目标的成功实现将产生一个全面的计算模型 血液湿润设备中的血栓形成，我们相信这将有助于不可避免的范例 开发这些设备的转变：用指令性的量化取代反复试验 方法：研究方法。结合计算机优化，该模型的使用将大大加快 开发安全有效的新设备，并将减少不良反应的发生 并发症。我们还设想，这些模型也将被用于法医分析 血栓相关的不良事件，并有助于指导抗凝治疗的管理。

ALL blood-wetted devices, without exaggeration, are susceptible to unintended thrombosis and bleeding – with dire consequences. In spite of decades of clinical experience, basic research, and computational fluid dynamics modeling, it is still virtually impossible to avoid deleterious hematological effects without experimental trail-and-error. In fact, in recent years, the incidence of thromboembolic and hemorrhagic adverse events in ventricular assist devices (VADs) has increased, not decreased. The unfortunate consequence is an unacceptable rate of debilitating adverse events such as stroke and hemorrhage. This has motivated the PI and colleagues over the past two decades to develop an accurate, computational model to simulate the process of thrombus deposition on artificial surfaces. The computer simulation is unique in its ability to account for physical and biological phenomena on multiple-scales, including the trafficking of red blood cells and platelets in small spaces, synthesis and transport of chemical agonists, and several pathways for positive- and negative feedback of platelet adhesion to artificial surfaces. The current model has demonstrated excellent agreement with experimental observations in microfluidic channels and the HeartMate-2 blood pump. The objective of this competitive renewal is to continue improvement of the versatility of this model, and to demonstrate its translation to full-scale blood-wetted devices. The two Specific Aims of this study are: SA1, to improve the fidelity of the model by adding important mechanisms of platelet disaggregation, thrombolysis, and von Willebrand mediated platelet adhesion; and SA2, to demonstrate and further validate the performance of the model with contemporary blood pumps and oxygenators in clinical use. Successful completion of these aims will yield a comprehensive computational model for thrombosis in blood-wetted devices, which we believe will contribute to the inevitable paradigm shift in developing these devices: replacing trial-and-error with prescriptive quantitative methods. Combined with computer optimization, the use of this model will greatly accelerate development of safe and effective new devices, and will reduce the occurrence of adverse complications. We also envision that the models will also be used forensically to analyze thrombosis-related adverse events, and help guide management of anticoagulation therapy.