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首页> 外文期刊>Mathematical medicine and Biology: a journal of the IMA >Multiscale simulation of thrombus growth and vessel occlusion triggered by collagen/tissue factor using a data-driven model of combinatorial platelet signalling
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Multiscale simulation of thrombus growth and vessel occlusion triggered by collagen/tissue factor using a data-driven model of combinatorial platelet signalling

机译：使用组合血小板信号的数据驱动模型，胶凝血糖生长和血管闭塞的多尺度模拟

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摘要

During clotting under flow, platelets bind and activate on collagen and release autocrinic factors such as ADP and thromboxane, while tissue factor (TF) on the damaged wall leads to localized thrombin generation. Towards patient-specific simulation of thrombosis, a multiscale approach was developed to account for: platelet signalling [neural network (NN) trained by pairwise agonist scanning (PAS), PAS-NN], platelet positions (lattice kinetic Monte Carlo, LKMC), wall-generated thrombin and platelet-released ADP/thromboxane convection–diffusion (partial differential equation, PDE) and flow over a growing clot (lattice Boltzmann). LKMC included shear-driven platelet aggregate restructuring. The PDEs for thrombin, ADP and thromboxane were solved by finite element method using cell activation-driven adaptive triangular meshing. At all times, intracellular calcium was known for each platelet by PAS-NN in response to its unique exposure to local collagen, ADP, thromboxane and thrombin. When compared with microfluidic experiments of human blood clotting on collagen/TF driven by constant pressure drop, the model accurately predicted clot morphology and growth with time. In experiments and simulations at TF at 0.1 and 10 molecule-TF/$mu$m$^{2}$ and initial wall shear rate of 200 s$^{-1}$, the occlusive blockade of flow for a 60-$mu$m channel occurred relatively abruptly at 600 and 400 s, respectively (with no occlusion at zero TF). Prior to occlusion, intrathrombus concentrations reached 50 nM thrombin, ~ 1 $mu$M thromboxane and ~ 10 $mu$M ADP, while the wall shear rate on the rough clot peaked at ~ 1000–2000 s$^{-1}$. Additionally, clotting on TF/collagen was accurately simulated for modulators of platelet cyclooxygenase-1, P2Y$_{1}$ and IP-receptor. This multiscale approach facilitates patient-specific simulation of thrombosis under hemodynamic and pharmacological conditions.
机译：在凝血过程中，血小板在胶原蛋白上结合并激活，并释放诸如ADP和血栓素等自认式因子，而受损壁上的组织因子（TF）导致局部凝血酶产生。为了血栓形成的患者特异性模拟，开发了一种多尺度方法来解释：血小板信号[通过成对激动扫描（PAS），PAS-NN]，血小板位置（Lattice Kinetic Monte Carlo，LKMC）培训的血小板信号[神经网络（NN），壁生成的凝血酶和血小板释放的ADP /血晶对流扩散（部分微分方程，PDE）和流过不断增长的凝块（格子Boltzmann）。 LKMC包括剪切驱动的血小板骨料重组。通过使用细胞活化驱动的自适应三角形啮合通过有限元方法解决了凝血酶，ADP和血栓素的PDE。始终，通过PAS-NN已知细胞内钙，响应于其独特暴露于局部胶原蛋白，ADP，血栓乳糖和凝血酶。与恒压驱动驱动的胶原/ TF对人体血液凝血的微流体实验相比，模型准确地预测了凝块形态和随时间的生长。在0.1和10分子-TF / $ mu $ m $ ^ {2} $和初始墙剪率的实验和模拟中，为200s $ ^ { - 1} $的封闭阻滞60 - $ mu $ m通道分别在600和400秒突然发生（零Tf在没有遮挡）。在闭塞之前，肠凝血浓度达到50纳米凝血酶，〜1 $ mu $ m血栓滤蛋和〜10 $ mu $ m adp，而在粗糙的凝块上的墙剪率达到〜1000-2000 $ ^ { - 1 $。此外，对于血小板环氧基酶-1，P2Y $ _ {1} $和IP接收器的调节剂，精确地模拟了TF /胶原蛋白的凝结。这种多尺度方法有助于在血液动力学和药理学条件下促进患者的血栓形成模拟。

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