Modelling fibrinolysis: a 3D stochastic multiscale model
Modelling fibrinolysis: a 3D stochastic multiscale model
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DOI：
10.1093/imammb/dqs029
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发表时间：
2014-03-01
影响因子：
1.1
通讯作者：
Fogelson, Aaron L.
中科院分区：
文献类型：
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作者：
Bannish, Brittany E.;Keener, James P.;Fogelson, Aaron L.
纤溶作用是指当组织型纤溶酶原激活剂(TPA)将纤溶酶原激活为纤溶酶(主要的纤溶酶)时，纤维蛋白纤维对稳定血栓的蛋白质的降解。许多实验表明，由粗纤维组成的粗凝块比由细纤维组成的细凝块分解得更快，尽管单个粗纤维比单个细纤维分解得更慢。对此普遍接受的解释是，纤维较少的粗凝块比纤维密度较高的细凝块降解得更快。其他实验则显示了相反的结果。研究纤溶的标准数学工具是确定性的反应-扩散模型，但由于tPA浓度较低，随机模型可能更合适。我们建立了一个三维随机多尺度纤溶模型。一个代表纤维横截面并包含详细生化反应的微型模型提供了关于单个纤维裂解时间、单个tPA分子可以激活的纤溶酶分子的数量以及tPA与给定纤维横截面结合的时间长度的信息。来自微观模型的数据被用于完全纤维蛋白凝块的宏观模型，从中我们获得了溶解前沿速度和tPA分布。我们发现纤维数量影响溶解速度，但tPA分子的数量与暴露于这些分子的血栓表面积相比也是如此。根据这两个量(tPA数和表面积)的值，对于给定的动力学参数，该模型预测粗凝块比细凝块分解得更快或更慢，从而为不同的实验观察提供了可能的解释。
Fibrinolysis, the proteolytic degradation of the fibrin fibres that stabilize blood clots, is initiated when tissue-type plasminogen activator (tPA) activates plasminogen to plasmin, the main fibrinolytic enzyme. Many experiments have shown that coarse clots made of thick fibres lyse more quickly than fine clots made of thin fibres, despite the fact that individual thick fibres lyse more slowly than individual thin fibres. The generally accepted explanation for this is that a coarse clot with fewer fibres to transect will be degraded faster than a fine clot with a higher fibre density. Other experiments show the opposite result. The standard mathematical tool for investigating fibrinolysis has been deterministic reaction-diffusion models, but due to low tPA concentrations, stochastic models may be more appropriate. We develop a 3D stochastic multiscale model of fibrinolysis. A microscale model representing a fibre cross section and containing detailed biochemical reactions provides information about single fibre lysis times, the number of plasmin molecules that can be activated by a single tPA molecule and the length of time tPA stays bound to a given fibre cross section. Data from the microscale model are used in a macroscale model of the full fibrin clot, from which we obtain lysis front velocities and tPA distributions. We find that the fibre number impacts lysis speed, but so does the number of tPA molecules relative to the surface area of the clot exposed to those molecules. Depending on the values of these two quantities (tPA number and surface area), for given kinetic parameters, the model predicts coarse clots lyse faster or slower than fine clots, thus providing a possible explanation for the divergent experimental observations.