Fibrinogen and Fibrin in Hemostasis and Thrombosis.
Fibrinogen and Fibrin in Hemostasis and Thrombosis.
复制标题
DOI：
10.1161/atvbaha.117.308564
复制
发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Wolberg AS
中科院分区：
文献类型：
--
作者：
Kattula S;Byrnes JR;Wolberg AS
多种机制介导凝血酶的产生，因此凝血酶浓度存在于纤维蛋白形成过程中。首先，凝血过程中存在的促凝剂和抗凝剂水平强烈影响促凝剂活性。例如，凝血酶原水平升高与凝血酶生成增加35,42紧密纤维蛋白网络的形成，35和小鼠静脉血栓重量增加有关。这些研究旨在模拟与循环凝血酶原水平升高相关的G20210A凝血酶原突变人类的临床情况，44表明凝血酶生成增加部分通过促进异常纤维蛋白沉积和结构来增加静脉血栓形成的风险。其次，凝血酶生成的位置影响纤维蛋白网络的形成。凝血酶原复合物（Xa、Va和凝血酶原）的有效组装和活性需要脂质表面。凝血酶原在细胞表面的定位建立了凝血酶浓度梯度，影响纤维蛋白的形成和网络结构。在成纤维细胞和内皮细胞上原位凝血酶生成的体外实验显示，细胞表面近端比远端纤维网络密度大得多。29这些结构上的差异导致血栓不同区域的纤溶敏感性有本质上的差异；位于细胞表面附近的纤维蛋白明显比位于细胞表面远端的纤维蛋白更耐裂解。第三，纤维蛋白形成过程中的血流（剪切）通过（重新）供应促凝蛋白和去除活性酶影响局部凝血酶浓度。46流动也使纤维蛋白纤维排列，31,32，这可能对纤维蛋白形成和机械和纤维蛋白溶解稳定性有深远的影响。此外，剪切速率影响在组织因子+胶原包被板上触发的凝块形成，导致血栓不同区域的纤维蛋白沉积不同。48通过纳米压痕分析来评估血块的生物物理特性，结果表明这种纤维蛋白分布模式决定了血块的微弹性，这可能会影响血栓的稳定性和栓塞的风险。第四，凝血酶通过血栓的运动在很大程度上受到由细胞堆积密度介导的溶质运输机制的影响；这也可能影响凝块不同区域的纤维蛋白沉积量。49
Multiple mechanisms mediate thrombin generation and consequently the thrombin concentration present during fibrin formation. First, the levels of pro-and anticoagulants present during coagulation strongly influence procoagulant activity. For example, elevated levels of prothrombin are associated with increased thrombin generation, 35, 42 formation of dense fibrin networks, 35 and increased venous thrombus weight in mice. 43 These studies, designed to model the clinical situation in humans with the G20210A prothrombin mutation associated with increased circulating prothrombin levels, 44 suggest that increased thrombin generation enhances venous thrombosis risk in part by promoting abnormal fibrin deposition and structure. Second, the location of thrombin generation impacts fibrin network formation. Effective assembly and activity of the prothrombinase complex (factors Xa, Va, and prothrombin) requires a lipid surface. 45 Localization of prothrombinase on a cell surface establishes a thrombin concentration gradient that influences both fibrin formation and network structure. In vitro experiments using in situ thrombin generation on fibroblasts and endothelial cells reveal a significantly denser fiber network proximal versus distal to the cell surface. 29 These structural differences give rise to substantially different fibrinolytic susceptibilities in different regions of the clot; fibrin located near the cell surface is significantly more resistant to lysis than fibrin located distal to the cell surface. 29 Third, blood flow (shear) present during fibrin formation influences local thrombin concentrations by (re) supplying procoagulant proteins and removing activated enzymes. 46 Flow also aligns fibrin fibers, 31, 32 which may have profound effects on fibrin formation and mechanical and fibrinolytic stability. 47 Furthermore, the shear rate affects clot formation triggered on tissue factor-plus collagen-coated plates, resulting in different fibrin deposition in different regions of a thrombus. 48 Nanoindentation analysis to evaluate clot biophysical properties shows that this fibrin distribution pattern determines clot microelasticity, which may impact thrombus stability and risk of embolization. 48 Fourth, thrombin movement through the thrombus is substantially influenced by solute transport mechanisms mediated by cell packing density; this may also influence the amount of fibrin deposition in different regions of the clot. 49