The fibrin clot is gelatinous matter formed upon injury to stop blood loss and is later destroyed by fibrinolysis, an enzymatic cascade with feedback. Pharmacological fibrinolysis stimulation is also used to destroy pathological, life-threatening clots and thrombi (thrombolysis). The regulation of the nonlinear spatially nonuniform fibrinolytic process in thrombolysis is not currently well understood. We developed a reaction-diffusion-advection model of thrombolysis by tissue plasminogen activator (TPA) in an occluded vessel with a pressure gradient. Sensitivity-analysis-based model reduction was used to reveal the critical processes controlling different steps of thrombolysis. The propagation of thrombolysis in the system without flow was predominantly controlled by TPA diffusion, whereas transport of other active components was rendered nonessential either by their high fibrin-binding parameters and short lifetimes or their initial uniform distribution. The concentration of the main TPA inhibitor plasminogen activator inhibitor 1 (PAI-1) controlled both the extent of lysis propagation and the shape of fibrin spatial distribution during lysis. Interestingly, PAI-1 remained important even when its concentration was an order of magnitude below that of TPA because of its role at the edge of the diffusing TPA front. The system was robust to reaction rate constant perturbations. Using these data, a reduced model of thrombolysis was proposed. In the presence of flow, convection of TPA was the critical controlling process; although the role of PAI-1 concentration was much less in the presence of flow, its influence became greater in the presence of collateral bypassing vessels, which sufficiently reduced TPA flux through the thrombus. Flow bypass through the collateral vessel caused a decrease in TPA flux in the clotted vessel, which increased the PAI-1/TPA ratio, thus making PAI-1-induced inhibition relevant for the regulation of spatial lysis up to its arrest.

中文翻译：

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在 PAI-1 存在下 TPA 通量的重新分布调节空间溶栓

纤维蛋白凝块是在受伤时形成的凝胶状物质，用于阻止失血，后来被纤维蛋白溶解破坏，纤维蛋白溶解是一种具有反馈的酶促级联反应。药理学纤维蛋白溶解刺激也用于破坏病理性的、危及生命的凝块和血栓（血栓溶解）。溶栓中非线性空间非均匀纤溶过程的调节目前尚不清楚。我们在具有压力梯度的闭塞血管中开发了组织纤溶酶原激活剂 (TPA) 溶栓的反应-扩散-平流模型。使用基于敏感性分析的模型简化来揭示控制溶栓不同步骤的关键过程。在没有流动的系统中溶栓的传播主要由 TPA 扩散控制，而其他活性成分的运输由于其高纤维蛋白结合参数和短寿命或其初始均匀分布而变得无关紧要。主要 TPA 抑制剂纤溶酶原激活剂抑制剂 1 (PAI-1) 的浓度控制了溶解传播的程度和溶解过程中纤维蛋白空间分布的形状。有趣的是，即使 PAI-1 的浓度比 TPA 低一个数量级，PAI-1 仍然很重要，因为它在扩散的 TPA 前沿边缘发挥作用。该系统对反应速率常数扰动是稳健的。使用这些数据，提出了一种简化的溶栓模型。在流动的情况下，TPA的对流是关键的控制过程；虽然在流动的情况下 PAI-1 浓度的作用要小得多，在存在侧支旁路血管的情况下，它的影响变得更大，这充分降低了通过血栓的 TPA 流量。通过侧支血管的血流旁路导致凝血血管中 TPA 通量的减少，这增加了 PAI-1/TPA 的比率，从而使 PAI-1 诱导的抑制与空间裂解的调节相关，直至其停滞。