Du Jian, Kim Dongjune, Alhawael Ghadah, Ku David N, Fogelson Aaron L
Department of Mathematics, Florida Institute of Technology, Melbourne, Florida.
Department of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia.
Biophys J. 2020 Nov 17;119(10):2102-2115. doi: 10.1016/j.bpj.2020.08.041. Epub 2020 Oct 14.
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 Willebrand-factor-mediated processes allowed greater growth and made agonist-induced activation more effective.
壁黏附性血小板聚集体的形成是动脉血栓形成中的一个关键过程。不断增大的聚集体会受到在其上方或穿过其流动的流体施加的摩擦阻力。这些力的大小受到正在形成的聚集体渗透性的强烈影响；渗透性取决于聚集体的孔隙率。聚集是由分子键集合的形成介导的；每个键都涉及一种血浆蛋白，该蛋白在两个不同血小板表面的特定受体之间架起桥梁。在任何时刻存在的键维持聚集体上阻力的能力决定了它是保持完整还是脱落单个血小板或更大的碎片（栓子）。我们使用计算模拟和体外实验来研究冠状动脉大小动脉中的血小板聚集。计算模型追踪血小板之间键的形成和断裂，并将血栓视为一种不断演变的多孔、粘弹性材料，其移动方式与背景流体不同。这种相对运动会产生流体和血栓相互施加的阻力。这些力是根据从实验测量参数化的渗透率 - 孔隙率关系计算得出的。基于我们流动腔实验中形成的闭塞性血栓的测量结果以及其他生理参数值建立这种关系，该模型在与实验相似的时间尺度上产生了稳定的致密血栓。当我们使用其他人报告的较低渗透率对渗透率 - 孔隙率关系进行参数化时，键的形成不足以平衡早期血栓上的阻力并使其保持完整。在高剪切流下，血小板释放的可溶性激动剂局限于血栓和下游的边界层，从而限制了血栓向血管腔生长。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激活添加到模型中，可使血栓生长更大，并使激动剂诱导的激活更有效。
