Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Thromb Haemost. 2013 Jun;11 Suppl 1(0 1):224-32. doi: 10.1111/jth.12220.
Accurate computer simulation of blood function can inform drug target selection, patient-specific dosing, clinical trial design, biomedical device design, as well as the scoring of patient-specific disease risk and severity. These large-scale simulations rely on hundreds of independently measured physical parameters and kinetic rate constants. However, the models can be validated against large-scale, patient-specific laboratory measurements. By validation with high-dimensional data, modeling becomes a powerful tool to predict clinically complex scenarios. Currently, it is possible to accurately predict the clotting rate of plasma or blood in a tube as it is activated with a dose of tissue factor, even as numerous coagulation factors are altered by exogenous attenuation or potentiation. Similarly, the dynamics of platelet activation, as indicated by calcium mobilization or inside-out signaling, can now be numerically simulated with accuracy in cases where platelets are exposed to combinations of agonists. Multiscale models have emerged to combine platelet function and coagulation kinetics into complete physics-based descriptions of thrombosis under flow. Blood flow controls platelet fluxes, delivery and removal of coagulation factors, adhesive bonding, and von Willebrand factor conformation. The field of blood systems biology has now reached a stage that anticipates the inclusion of contact, complement, and fibrinolytic pathways along with models of neutrophil and endothelial activation. Along with '-omics' data sets, such advanced models seek to predict the multifactorial range of healthy responses and diverse bleeding and clotting scenarios, ultimately to understand and improve patient outcomes.
准确的血液功能计算机模拟可以为药物靶点选择、患者特异性剂量、临床试验设计、生物医学设备设计以及患者特异性疾病风险和严重程度评分提供信息。这些大规模模拟依赖于数百个独立测量的物理参数和动力学速率常数。然而，这些模型可以通过与大规模、患者特异性的实验室测量进行验证。通过高维数据验证，建模成为预测临床复杂情况的有力工具。目前，即使在许多凝血因子被外源衰减或增强改变的情况下，也可以准确预测血浆或血液在试管中被组织因子激活时的凝血速率。同样，血小板在暴露于激动剂组合时的钙动员或内翻信号等动力学现在可以通过数值模拟以高精度进行模拟。多尺度模型已经出现，将血小板功能和凝血动力学结合起来，形成了在流动条件下血栓形成的完整物理描述。血流控制血小板通量、凝血因子的输送和清除、黏附结合和血管性血友病因子构象。血液系统生物学领域现在已经达到了一个阶段，预计将包括接触、补体和纤维蛋白溶解途径以及中性粒细胞和内皮细胞激活模型。随着“组学”数据集的出现，这种先进的模型旨在预测健康反应的多因素范围和各种出血和凝血情况，最终是为了了解和改善患者的预后。
