Department of Chemical and Biomolecular Engineering, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, United States of America.
PLoS One. 2021 Nov 23;16(11):e0260366. doi: 10.1371/journal.pone.0260366. eCollection 2021.
A highly reduced extrinsic pathway coagulation model (8 ODEs) under flow considered a thin 15-micron platelet layer where transport limitations were largely negligible (except for fibrinogen) and where cofactors (FVIIa, FV, FVIII) were not rate-limiting. By including thrombin feedback activation of FXI and the antithrombin-I activities of fibrin, the model accurately simulated measured fibrin formation and thrombin fluxes. Using this reduced model, we conducted 10,000 Monte Carlo (MC) simulations for ±50% variation of 5 plasma zymogens and 2 fibrin binding sites for thrombin. A sensitivity analysis of zymogen concentrations indicated that FIX activity most influenced thrombin generation, a result expected from hemophilia A and B. Averaging all MC simulations confirmed both the mean and standard deviation of measured fibrin generation on 1 tissue factor (TF) molecule per μm2. Across all simulations, free thrombin in the layer ranged from 20 to 300 nM (mean: 50 nM). The top 2% of simulations that produced maximal fibrin were dominated by conditions with low antithrombin-I activity (decreased weak and strong sites) and high FIX concentration. In contrast, the bottom 2% of simulations that produced minimal fibrin were dominated by low FIX and FX. The percent reduction of fibrin by an ideal FXIa inhibitor (FXI = 0) ranged from 71% fibrin reduction in the top 2% of MC simulations to only 34% fibrin reduction in the bottom 2% of MC simulations. Thus, the antithrombotic potency of FXIa inhibitors may vary depending on normal ranges of zymogen concentrations. This reduced model allowed efficient multivariable sensitivity analysis.
一个高度简化的外在途径凝血模型（8 个 ODE），考虑了一个薄的 15 微米血小板层，其中传输限制在很大程度上可以忽略不计（除了纤维蛋白原），并且辅因子（FVIIa、FV、FVIII）不是限速的。通过包括凝血酶对 FXI 的反馈激活和纤维蛋白对抗凝血酶-I 的活性，该模型准确地模拟了测量的纤维蛋白形成和凝血酶通量。使用这个简化模型，我们对 5 种血浆酶原和 2 种纤维蛋白结合位点的凝血酶进行了 10,000 次蒙特卡罗（MC）模拟，模拟值上下波动 50%。对酶原浓度的敏感性分析表明，FIX 活性对凝血酶生成的影响最大，这是血友病 A 和 B 的预期结果。对所有 MC 模拟的平均值确认了在每 μm2 1 个组织因子（TF）分子上测量的纤维蛋白生成的平均值和标准偏差。在所有模拟中，层中的游离凝血酶范围在 20 到 300 nM（平均值：50 nM）之间。在产生最大纤维蛋白的前 2%的模拟中，占主导地位的是抗凝血酶-I 活性（弱和强位点减少）和 FIX 浓度高的条件。相比之下，产生最小纤维蛋白的后 2%的模拟中，占主导地位的是 FIX 和 FX 浓度低。理想的 FXIa 抑制剂（FXI = 0）的纤维蛋白减少百分比从前 2%的 MC 模拟中的 71%纤维蛋白减少到后 2%的 MC 模拟中的 34%纤维蛋白减少。因此，FXIa 抑制剂的抗血栓形成效力可能取决于酶原浓度的正常范围。这个简化模型允许进行有效的多变量敏感性分析。
