Physical Determinants of Fibrinolysis in Single Fibrin Fibers
Physical Determinants of Fibrinolysis in Single Fibrin Fibers
复制标题
DOI：
10.1371/journal.pone.0116350
复制
发表时间：
2015-02-25
期刊：
影响因子：
3.7
通讯作者：
Hudson, Nathan E.
中科院分区：
文献类型：
--
作者：
Bucay, Igal;O'Brien, E. Tim, III;Hudson, Nathan E.
纤维蛋白纤维形成血凝块的结构骨架;纤维蛋白溶解是纤溶酶使纤维蛋白纤维溶解的过程，有效地调节凝块的大小和持续时间。为了理解血凝块溶解，必须将凝块结构和纤维性质的影响与酶动力学和灌注速率的影响分开。使用倒置的光学显微镜和荧光标记的纤维悬浮在微图案的脊之间，我们直接测量了单个纤维蛋白纤维的溶解。我们发现，在溶解过程中，64 +/- 6%的纤维在一个点被横切，但29 +/- 3%的纤维长度增加，而不是溶解或被横切。凝血酶和纤溶酶的剂量反应实验表明，伸长行为是独立的纤溶酶浓度，而是依赖于纤维聚合过程中使用的凝血酶的浓度，这与纤维直径成反比。较细的纤维更可能溶解，而直径大于200 +/-30 nm的纤维更可能伸长。由于裂解率大大降低，在细长的纤维，我们假设纤溶酶活性取决于纤维应变。使用聚合物物理和连续介质力学为基础的数学模型，我们表明，纤维在应变状态下，较厚的纤维失去其预应变更迅速地比较薄的纤维在裂解过程中，这可以解释为什么厚纤维伸长和薄纤维裂解。这些结果突出了纤维直径和预应变的细微差异如何导致显著不同的溶解亲合力。
Fibrin fibers form the structural backbone of blood clots; fibrinolysis is the process in which plasmin digests fibrin fibers, effectively regulating the size and duration of a clot. To understand blood clot dissolution, the influence of clot structure and fiber properties must be separated from the effects of enzyme kinetics and perfusion rates into clots. Using an inverted optical microscope and fluorescently-labeled fibers suspended between micropatterned ridges, we have directly measured the lysis of individual fibrin fibers. We found that during lysis 64 +/- 6% of fibers were transected at one point, but 29 +/- 3% of fibers increase in length rather than dissolving or being transected. Thrombin and plasmin dose-response experiments showed that the elongation behavior was independent of plasmin concentration, but was instead dependent on the concentration of thrombin used during fiber polymerization, which correlated inversely with fiber diameter. Thinner fibers were more likely to lyse, while fibers greater than 200 +/- 30 nm in diameter were more likely to elongate. Because lysis rates were greatly reduced in elongated fibers, we hypothesize that plasmin activity depends on fiber strain. Using polymer physics-and continuum mechanics-based mathematical models, we show that fibers polymerize in a strained state and that thicker fibers lose their prestrain more rapidly than thinner fibers during lysis, which may explain why thick fibers elongate and thin fibers lyse. These results highlight how subtle differences in the diameter and prestrain of fibers could lead to dramatically different lytic susceptibilities.