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 没有抗凝的血液学影响，或实验性的反复试验。不幸的人 后果是不可接受的衰弱不良事件的比率，如中风和 大出血。这一长期的挑战在过去的25年里驱使私人投资机构追求 确定性、多尺度、多组分的血栓形成对流-扩散-反应模型 这包含了Virchow三部曲的主要元素：血液的特性，流动的特性， 和表面化学。我们在这个项目的前一阶段取得了重大进展， 现在能够在多个尺度上以惊人的精度预测血小板沉积： 从小缝隙到全尺寸的心脏辅助装置。我们现在希望延长血栓形成 模型包括血栓稳定和重塑。具体目标1将是延长 模型包括纤维蛋白交联化、内皮化和血管疙瘩形成。我们假设 这些改进将增强模型在模拟石油天然气稳定性方面的实用性。 粘连性血栓，因此栓塞的风险，溶栓治疗的效果和发展 新生内膜表面和/或血管疙瘩的生长。具体目标2将是将生物化学 模拟常用抗凝途径，大大改善其临床疗效 翻译。具体目标3将演示增强血栓形成的性能 在一系列临床相关情况下使用宏观设备的模型，包括旋转 带浸血轴承的血泵，导管血泵，机械心脏瓣膜， 还有一个脑室插管。我们将在一系列条件下以参数方式执行模拟 根据血流动力学的不同，在设备内制作“血栓威胁等级”地图 和血液学独立变量：流速、血小板反应性/计数/预激活，以及 抗凝剂。我们还打算将该模型打包成用户友好的、公开可用的 向设计师和从业者推广这一资源的应用程序 改善心血管设备最有害和最持久的并发症之一。

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 anticoagulation, or experimental trail-and-error. The unfortunate consequence is an unacceptable rate of debilitating adverse events such as stroke and hemorrhage. This abiding challenge has driven the PIs over the past 25+ years to pursue a deterministic, multi-scale, multi-constituent, convection-diffusion-reaction model of thrombosis that embraces the principle elements of Virchow’s Triad: properties of blood, character of flow, and surface chemistry. We have made significant progress in the previous phase of this project, and now able to predict platelet deposition with remarkable accuracy at multiple scales: from small crevices to full-sized ventricular assist devices. We now wish to extend the thrombosis model to include thrombus stabilization, and remodeling. Specific Aim 1 will be to extend the model to include fibrin cross-linking, endothelialization and pannus formation. We hypothesize that these improvements will enhance the utility of the model for simulating the stability of adherent thrombus, hence risk of embolization, the effects of thrombolysis and the development of neointimal surface and/or pannus growth. Specific Aim 2 will be to incorporate biochemical pathways to simulate commonly used anticoagulation, and greatly improve its clinical translation. Specific Aim 3 will be to demonstrate the performance of the enhanced thrombosis model with macro-scale devices over a range of clinically relevant conditions, including a rotary blood pump with blood-immersed bearing, a catheter blood pump, a mechanical heart valve, and a ventricular cannula. We will perform simulations parametrically, over a range of conditions to produce a map of “Thrombosis Threat Level” within the device as a function of hemodynamic and hematological independent variables: flow rate, platelet reactivity/count/pre-activation, and anticoagulation. We further intend to package the model in a user-friendly, publicly available application to promote dissemination of this resource for both designers and practitioners to ameliorate one of the most pernicious and abiding complications of cardiovascular devices.