Clot Permeability, Agonist Transport, and Platelet Binding Kinetics in Arterial Thrombosis
Clot Permeability, Agonist Transport, and Platelet Binding Kinetics in Arterial Thrombosis
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DOI：
10.1016/j.bpj.2020.08.041
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发表时间：
2020-11-17
影响因子：
3.4
通讯作者：
Fogelson, Aaron L.
中科院分区：
文献类型：
--
作者：
Du, Jian;Kim, Dongjune;Fogelson, Aaron L.
贴壁血小板聚集体的形成是动脉血栓形成的关键过程。增长的聚集体经历由在聚集体上或通过聚集体移动的流体施加在其上的摩擦阻力。这些力的大小强烈地受到发展中的骨料的渗透性的影响;渗透性取决于骨料的孔隙度。聚集是通过形成分子键的集合体介导的;每个键都涉及一种血浆蛋白，该蛋白桥接两种不同血小板表面上特异性受体之间的差距。在任何时候存在的键在聚集体上维持拖曳力的能力决定了它是否保持完整或脱落单个血小板或更大的碎片（栓子）。我们研究血小板聚集在冠状动脉大小的动脉使用计算模拟和体外实验。计算模型跟踪血小板之间键的形成和断裂，并将血栓视为一种不断发展的多孔粘弹性材料，其移动方式与背景流体不同。这种相对运动产生流体和血栓彼此施加的拖曳力。这些力是从实验测量参数化的渗透率-孔隙度关系计算的。基于在我们的流动室实验中形成的闭塞性血栓的测量值的这种关系，沿着其他生理参数值，该模型在与实验相似的时间尺度上产生稳定的致密血栓。当我们使用其他人报道的较低渗透率参数化渗透率-孔隙率关系时，键形成不足以平衡早期血栓上的阻力并保持其完整。在高剪切流下，血小板释放的可溶性激动剂仅限于血栓和下游边界层，从而限制血栓生长到血管腔内。通过血管性血友病因子介导的过程，将未活化血小板的结合和活化添加到模型中，允许更大的生长，并使激动剂诱导的活化更有效。
The formation of wall-adherent platelet aggregates is a critical process in arterial thrombosis. A growing aggregate experiences frictional drag forces exerted on it by fluid moving over or through the aggregate. The magnitude of these forces is strongly influenced by the permeability of the developing aggregate; the permeability depends on the aggregate's porosity. Aggregation is mediated by formation of ensembles of molecular bonds; each bond involves a plasma protein bridging the gap between specific receptors on the surfaces of two different platelets. The ability of the bonds existing at any time to sustain the drag forces on the aggregate determines whether it remains intact or sheds individual platelets or larger fragments (emboli). We investigate platelet aggregation in coronary-sized arteries using both computational simulations and in vitro experiments. The computational model tracks the formation and breaking of bonds between platelets and treats the thrombus as an evolving porous, viscoelastic material, which moves differently from the background fluid. This relative motion generates drag forces which the fluid and thrombus exert on one another. These forces are computed from a permeability-porosity relation parameterized from experimental measurements. Basing this relation on measurements from occlusive thrombi formed in our flow chamber experiments, along with other physiological parameter values, the model produced stable dense thrombi on a similar timescale to the experiments. When we parameterized the permeability-porosity relation using lower permeabilities reported by others, bond formation was insufficient to balance drag forces on an early thrombus and keep it intact. Under high shear flow, soluble agonist released by platelets was limited to the thrombus and a boundary layer downstream, thus restricting thrombus growth into the vessel lumen. Adding to the model binding and activation of unactivated platelets through von Wille-brand-factor-mediated processes allowed greater growth and made agonist-induced activation more effective.