Multiscale Model of Thrombosis in Artificial Circulation

毫不夸张地说，所有血液润湿器械都容易发生意外血栓形成， 流血-带来可怕的后果。尽管有几十年的临床经验，基础研究， 和计算流体动力学建模，实际上仍然不可能避免有害的 血液学效应而无需实验性试错。事实上，近年来， 心室辅助装置（VAD）的血栓栓塞和出血不良事件 增加，而不是减少。不幸的结果是， 不良事件，如中风和出血。这促使PI和同事们 在过去的二十年里，开发了一个精确的计算模型来模拟 人工表面血栓沉积。计算机模拟的独特之处在于， 在多个尺度上解释物理和生物现象，包括 小空间中的红细胞和血小板，化学激动剂的合成和运输，以及 血小板粘附到人造表面的正反馈和负反馈的几种途径。 目前的模型已被证明与实验观察结果非常一致， 微流体通道和HeartMate-2血泵。 这次竞争性更新的目的是继续改善这种多功能性， 模型，并证明其转化为全尺寸的血液润湿装置。的两个具体 本研究的目的是：SA 1，通过添加重要的 血小板解聚、血栓溶解和血管性血友病介导的血小板机制 粘附力;和SA 2，以证明并进一步验证模型的性能， 现代血液泵和氧合器在临床上的应用。 成功完成这些目标将产生一个全面的计算模型， 我们相信，这将有助于不可避免的范式， 开发这些设备的转变：用规定的定量方法取代试错法 方法.结合计算机优化，这一模式的使用将大大加快 开发安全有效的新器械，并将减少不良事件的发生 并发症我们还设想，这些模型也将用于法医分析， 血栓形成相关的不良事件，并帮助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.