Towards understanding the effect of fibrinogen interactions on fibrin gel structure
Towards understanding the effect of fibrinogen interactions on fibrin gel structure
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DOI：
10.1103/physreve.107.024413
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发表时间：
2023-02-01
影响因子：
2.4
通讯作者：
Fogelson, Aaron L.
中科院分区：
文献类型：
--
作者：
Nelson, Anna C.;Fogelson, Aaron L.
纤维蛋白凝胶化涉及血浆蛋白纤维蛋白原酶促转化为纤维蛋白单体，然后聚合形成凝胶，该凝胶是血凝块的主要结构成分。由于纤维蛋白原提供了制造纤维蛋白的材料，因此通常认为它可以促进凝胶化过程。然而，纤维蛋白原可以结合到纤维蛋白低聚物上的某个位点，阻止另一种纤维蛋白低聚物结合在那里，从而减慢聚合过程。 “可溶性纤维蛋白低聚物”是纤维蛋白和纤维蛋白原的混合物，存在于血浆中，可作为各种凝血障碍的生物标志物，因此了解纤维蛋白聚合过程中纤维蛋白和纤维蛋白原之间的相互作用可能具有医学重要性。我们提出了纤维蛋白聚合的动力学凝胶模型，该模型解释了纤维蛋白原的双重作用和拮抗作用。它建立在我们早期的纤维蛋白聚合模型的基础上，提出了一种新的分支形成机制，这是凝胶化的必要组成部分。先前的模型捕获了有关凝胶结构决定因素的显着实验观察结果，但不包括纤维蛋白原结合。在这里，我们添加了纤维蛋白原和纤维蛋白之间的模型反应，因此低聚物现在是纤维蛋白和纤维蛋白原的混合物，并且表征它们的动力学导致方程比以前更加复杂。使用矩生成函数方法，我们推导了一个封闭的矩方程组，并跟踪它们的动力学，直到特定二阶矩的有限时间爆炸表明凝胶已经形成。在以纤维蛋白和纤维蛋白原单体的初始混合物开始的模拟中，纤维蛋白原的相对浓度足够高，可以防止凝胶化；临界浓度随着支链形成速率的增加而增加。在仅以特定速率转化为纤维蛋白的纤维蛋白原单体开始的模拟中，转化速率、纤维蛋白原与寡聚物的结合以及分支形成共同决定了凝胶是否形成、形成需要多长时间以及所产生的凝胶的结构特性。
Fibrin gelation involves the enzymatic conversion of the plasma protein fibrinogen to fibrin monomers which then polymerize to form the gel that is a major structural component of a blood clot. Because fibrinogen provides the material from which fibrin is made, it is generally regarded as promoting the gelation process. However, fibrinogen can bind to a site on a fibrin oligomer, preventing another fibrin oligomer from binding there, thus slowing the polymerization process. "Soluble fibrin oligomers," which are mixtures of fibrin and fibrinogen, are found in the blood plasma and serve as biomarkers for various clotting disorders, so understanding the interplay between fibrin and fibrinogen during fibrin polymerization may have medical importance. We present a kinetic gelation model of fibrin polymerization which accounts for the dual and antagonistic roles of fibrinogen. It builds on our earlier model of fibrin polymerization that proposed a novel mechanism for branch formation, which is a necessary component of gelation. This previous model captured salient experimental observations regarding the determinants of the structure of the gel, but did not include fibrinogen binding. Here, we add to that model reactions between fibrinogen and fibrin, so oligomers are now mixtures of fibrin and fibrinogen, and characterizing their dynamics leads to equations of substantially greater complexity than previously. Using a moment generating function approach, we derive a closed system of moment equations and we track their dynamics until the finite time blow-up of specific second moments indicates that a gel has formed. In simulations begun with an initial mixture of fibrin and fibrinogen monomers, a sufficiently high relative concentration of fibrinogen prevents gelation; the critical concentration increases with the branch formation rate. In simulations begun with only fibrinogen monomers that are converted to fibrin at a specified rate, the rates of conversion, fibrinogen binding to oligomers, and branch formation together determine whether a gel forms, how long it takes to form, and the structural properties of the gel that results.