COMPUTER MODELING OF FIBRIN POLYMERIZATION KINETICS CORRELATED WITH ELECTRON-MICROSCOPE AND TURBIDITY OBSERVATIONS - CLOT STRUCTURE AND ASSEMBLY ARE KINETICALLY CONTROLLED
COMPUTER MODELING OF FIBRIN POLYMERIZATION KINETICS CORRELATED WITH ELECTRON-MICROSCOPE AND TURBIDITY OBSERVATIONS - CLOT STRUCTURE AND ASSEMBLY ARE KINETICALLY CONTROLLED
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DOI：
10.1016/s0006-3495(92)81594-1
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发表时间：
1992-07-01
影响因子：
3.4
通讯作者：
NAGASWAMI, C
中科院分区：
文献类型：
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作者：
WEISEL, JW;NAGASWAMI, C
尽管人们对纤维蛋白聚合了解很多，但由于它很复杂，各种修饰的效果并不直观明显，并且许多实验观察结果仍然无法解释。这里提出的动力学模型基于有关组装机制的信息，解释了大多数实验观察结果，并允许测试有关各种因素影响的假设。写出描述聚合动力学的微分方程，然后进行数值求解。结果与浊度曲线和电子显微镜观察相关。纤维蛋白聚合中中间体的浓度以及纤维直径、纤维和原纤维长度均由这些模型计算得出。最简单的模型包括三个步骤：纤维蛋白肽 A 裂解、原纤维形成以及原纤维横向聚集形成纤维。每根纤维的平均原纤维数与浊度直接相关，可以计算并绘制为时间的函数。在浊度曲线中观察到的滞后期无法通过这样的模型精确模拟，但可以通过修改模型来模拟，使得低聚物在聚集之前必须达到最小长度。这里和其他地方报道的许多观察结果都可以用这个模型来解释；可以修改基本模型以考虑其他实验观察结果。模型预测了纤维蛋白肽裂解速率变化的影响，与电子显微镜和浊度观察结果一致。仅纤维生长起始或向纤维添加原纤维的速率常数的变化就足以解释各种其他观察结果，例如离子强度或纤维蛋白肽 B 去除或血小板反应蛋白的影响。纤维横向聚集的影响也已被建模：在存在血小板因子 4 的情况下形成的凝块的浊度曲线和电子显微照片中观察到了这种行为。因此，凝块结构和影响结构的因素的许多方面与这些聚合步骤的速率直接相关，尽管这些影响通常并不明显。因此，在很大程度上，血块结构是由动力学决定的。
Although much is known about fibrin polymerization, because it is complex, the effects of various modifications are not intuitively obvious and many experimental observations remain unexplained. A kinetic model presented here that is based on information about mechanisms of assembly accounts for most experimental observations and allows hypotheses about the effects of various factors to be tested. Differential equations describing the kinetics of polymerization were written and then solved numerically. The results have been related to turbidity profiles and electron microscope observations. The concentrations of intermediates in fibrin polymerization, and fiber diameters, fiber and protofibril lengths have been calculated from these models. The simplest model considered has three steps: fibrinopeptide A cleavage, protofibril formation, and lateral aggregation of protofibrils to form fibers. The average number of protofibrils per fiber, which is directly related to turbidity, can be calculated and plotted as a function of time. The lag period observed in turbidity profiles cannot be accurately simulated by such a model, but can be simulated by modifying the model such that oligomers must reach a minimum length before they aggregate. Many observations, reported here and elsewhere, can be accounted for by this model; the basic model may be modified to account for other experimental observations. Modeling predicts effects of changes in the rate of fibrinopeptide cleavage consistent with electron microscope and turbidity observations. Changes only in the rate constants for initiation of fiber growth or for addition of protofibrils to fibers are sufficient to account for a wide variety of other observations, e.g., the effects of ionic strength or fibrinopeptide B removal or thrombospondin. The effects of lateral aggregation of fibers has also been modeled: such behavior has been observed in turbidity curves and electron micrographs of clots formed in the presence of platelet factor 4. Thus, many aspects of clot structure and factors that influence structure are directly related to the rates of these steps of polymerization, even though these effects are often not obvious. Thus, to a large extent, clot structure is kinetically determined.